Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].S([N:23]=[N+:24]=[N-])(C(F)(F)F)(=O)=O.CO>O.ClCCl.[O-]S([O-])(=O)=O.[Cu+2].C(OCC)(=O)C>[N:2]([CH2:3][CH:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6])=[N+:23]=[N-:24]
Reactant: COC(=O)C(O)CN
Reactant: [N-]=[N+]=NS(=O)(=O)C(F)(F)F
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(O)CN=[N+]=[N-]
Temperature: 0 °C
Yield: 57 %

Procedure:
To an ice-cold mixture of methyl 3-amino-2-hydroxypropionate hydrochloride (19) (27.1 g, 0.17 mol) in water (100 mL) and dichloromethane (100 mL) was added sodium carbonate (19.82 g, 0.187 mol) and CuSO4. 5H2O (0.3 g, 1.2 mmol) with stirring. Triflylazide from experiment 10(B)(i) (crude, 44.6 g, 0.25 mol) was added dropwise keeping the reaction temperature at 0-5° C. Methanol (about 100 mL) was added until the reaction mixture became homogeneous. The reaction mixture was allowed to come to room temperature and then stirred for 20 h. Water (500 mL) was added and the aqueous solution thoroughly extracted with dichloromethane (5×100 mL). The combined organic layers were washed with water (2×200 mL), saturated sodium carbonate (2×200 mL), and then dried (anhydrous sodium sulfate). After removal of the solvent, the residue was chromatographed over silica gel. Elution with 30% ethyl acetate in hexanes furnished the product as a colorless oil (14.0 g; Yield: 57%) Rf 0.57 (30% ethyl acetate in hexanes).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C[S-].[Na+]>CN(C)C=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH3:20])=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: CCCCc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1ccc(C(=O)c2ccc(O)cc2)cc1
Yield: 96.2 %

Procedure:
4-n-Butylphenyl 4-methoxyphenyl ketone (863 mg) obtained in Example 147 was dissolved in N,N-dimethylformamide (50 ml), sodium thiomethoxide (563 mg) was added, and the admixture was refluxed with heat for 7 hours under argon. The reaction mixture was treated in the same manner as described in Example 33 to obtain 787 mg of the title compound (yield: 96%).
Reaction SMILES: C1C(=O)N(OC(CCCCCN[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]2[S:27][CH2:26][C@@H:25]3[NH:28][C:29]([NH:31][C@H:24]23)=[O:30])=[O:18])=O)C(=O)C1.CN(C=[O:36])C>>[OH:36][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:24]2[C@@H:25]([NH:28][C:29]([NH:31]2)=[O:30])[CH2:26][S:27]1)=[O:18]
Reactant: CN(C)C=O
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CCC1=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 3 h

Procedure:
Purified antibodies or their fragments, obtained as described in paragraph A at 1 mg/ml in PBS, were biotinylated for 3 hours at 25° C. (ambient temperature) by adding 37 μl of 10 mg/ml solution of NHS-LC-Biotin, Product #21335; Pierce, Rockford, Ill) in anhydrous DMF. Subsequently, the derivatized antibody was buffer-exchanged on a G25F column into PBS and stored at 0-4° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)[C:8]([OH:10])=O)[CH3:3].C(Cl)(=O)C(Cl)=O.[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1>CN(C=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)[C:8]([NH:34][C:31]1[CH:32]=[CH:33][N:29]([CH3:28])[N:30]=1)=[O:10])[CH3:1]
Reactant: Cn1ccc(N)n1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
DMF (2 drops) was added to a solution of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (40.0 g, 0.14 mol) and oxalyl chloride (14.6 mL, 0.17 mol) in DCM (700 mL) The mixture was stirred at ambient temperature for 4 hours and the DCM and excess oxalyl chloride evaporated in vacuo. The residual acid chloride was dissolved in DCM (300 mL) and added dropwise to 1-methyl-3-aminopyrazole (14.25 g, 0.147 mol) and triethylamine (41 mL, 0.29 mmol) in DCM (300 mL), at 0° C. Stirred at ambient temperature for 24 hours. The DCM was evaporated in vacuo, and the residue partitioned between ethyl acetate (400 mL) and 1N hydrochloric acid (200 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate (200 mL) and brine (100 mL), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 50% ethyl acetate in isohexane, to give the desired compound (51 g). 1H NMR δ (CDCl3): 1.30 (d, 6H), 3.61 (s, 3H), 4.50 (sept, 1H), 5.01 (s, 2H), 6.66 (m, 1H), 6.88 (m, 1H), 7.00 (m, 1H), 7.06 (m, 1H), 7.24 (m, 1H), 7.39 (m, 5H), 9.50 (s, 1H). m/z 366 (M+H)+
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[O:12])[S:8][CH:9]=1)=[N+]=[N-]>CCO.[Pd]>[NH2:1][CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[O:12])[S:8][CH:9]=1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN=[N+]=[N-])cs2)c(C(=O)C2CCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1

Procedure:
To a solution of (1-(4-azidomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methylphenyl)-urea) (7.7 g, 20 mmol) in EtOH (100 mL) was added catalytic amount of palladium on charcoal (200 mg) and the reaction mixture was hydrogenated (1 atmos) for 3-4 hours to give 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea. This crude product was then purified by flash column chromatography with DCM:EtOAc (80:20 to 50:50) as eluent to give the desired amine (5.7 g, 80%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([F:44])=[C:39](B(O)O)[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([F:44])=[C:37]([C:7]2[CH:8]=[C:9]3[C@@:20]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[N:15][CH:16]=[C:17]([CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:18]=4)[O:13][C:10]3=[CH:11][CH:12]=2)[CH:36]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1ncc(C3CCOCC3)cc12
Reactant: OB(O)c1cc(Cl)ccc1F
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+]
Product: NC1=N[C@@]2(CO1)c1cc(-c3cc(Cl)ccc3F)ccc1Oc1ncc(C3CCOCC3)cc12
Reaction time: 1.5 h

Procedure:
A vial was charged with (S)-2′-amino-3-(tetrahydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (70.0 mg, 0.144 mmol), 5-chloro-2-fluorophenylboronic acid (75 mg, 0.433 mmol), potassium carbonate (100 mg, 0.721 mmol), and Pd(PPh3)4 (8.33 mg, 7.21 μmol). The vial was flushed with Ar (g), then Dioxane (721 μL) and water (0.3 mL) were added in sequence. The vial was sealed and placed in an 80° C. for 1.5 hours. The mixture was diluted with brine (20 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 24-g Redi-Sep Gold column with 0-60% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-7-(5-chloro-2-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: [CH3:1][N:2]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:3]([CH2:10][S:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4](N(C)OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])O.[Na+]>C(OCC)C.O>[CH3:1][N:2]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:3]([CH:4]=[O:5])[CH2:10][S:11][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CON(C)C(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H](C=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -35 °C
Yield: 59.1 %

Procedure:
4.2 g of N-(-N-methyl-2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)propionyl)-N,O-dimethylhydroxylamine in 15 cm3 of diethyl ether are added, at a temperature in the region of -45° C., to a suspension of 0.386 g of lithium aluminium hydride in 35 cm3 of diethyl ether. The temperature is allowed, with stirring, to rise to approximately 0° C. After cooling to a temperature in the region of -35° C., a solution of 1.77 g of sodium hydrogen carbonate in 6.5 cm3 of water is added. The organic phase is washed 3 times with 10 cm3 of a normal hydrochloric acid solution, then twice with 10 cm3 of a saturated sodium hydrogen carbonate solution and finally with 10 cm3 of a saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. 2.2 g of N-methyl-N-tert-butoxycarbonyl-S-(triphenylmethyl)cysteinal are obtained, which are used in the following stage without other purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>CS(C)=O.C(NCC)C.C(OCC)(=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.[Cu](I)I>[C:21]1([C@@H:19]2[CH2:20][C@H:18]2[C:16]([N:13]2[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:5]3[N:4]=[CH:3][C:2]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:7][N:6]=3)[CH2:11][CH2:12]2)=[O:17])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCC(CNc2ncc(Br)cn2)CC1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cnc(NCC2CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-N-[(1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methyl]pyrimidin-2-amine (EXAMPLE 153) (0.300 g, 0.722 mmol), trimethylsilylacetylene (0.177 g, 1.81 mmol), Pd(PPh3)4 (0.083 g, 0.072 mmol), and copper iodide (0.007 g, 0.036 mmol) in DMSO (1 mL) and diethylamine (1 mL) was heated in a sealed tube at 100° C. for 3 h. The reaction mixture was cooled to RT, diluted with ethyl acetate (50 mL), washed with water (10 mL), and brine (10 mL), then dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (35 g), eluting with 10:1–10:89–80 CH2Cl2:2-propanol:hexane to give the title compound.
Reaction SMILES: Br[CH:2]1[CH:12](Br)[CH2:11][CH:5]2[O:6][C:7]([CH3:10])([CH3:9])[O:8][CH:4]2[CH2:3]1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:9][C:7]1([CH3:10])[O:6][CH:5]2[CH:11]=[CH:12][CH:2]=[CH:3][CH:4]2[O:8]1
Reactant: CC1(C)OC2CC(Br)C(Br)CC2O1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC2C=CC=CC2O1

Procedure:
The compound obtained in Step (11) was placed in a reaction vessel, and air in the vessel was replaced with nitrogen. After that, the compound was dissolved in dehydrated toluene (116 ml). Distilled DBU (6.0 ml, 40.1 mmol) was added to the solution, and the mixture was refluxed for 6 hours. After the reaction product had been filtrated, sodium hydrogen carbonate was added to the filtrate, and the organic layer was dried over magnesium sulfate, whereby 2,2-dimethyl-3a,7a-dihydrobenzo[1.3]dioxol was obtained. The compound was used in the next reaction without being further purified.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].C=O.[C:24](O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH3:24])[CH2:18][CH2:19]2)[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCN(C)CC1
Yield: 86.3 %

Procedure:
2-nitro-4-(1-piperidin-4-ylmethoxy)5-methoxybenzonitrile (771 mg, 2.65 mmol) in CH2Cl2 (8 ml) and MeOH (4 ml) was reacted for 0.5 hour with formaldehyde (13.3 M, 300 μl, 4 mmol), acetic acid (191 mg, 3.18 mmol) and NaBH(OAc)3 (674 mg, 3.18 mmol) slowly added over 15 minutes. The solution was evaporated, the oily residue was taken up in a mixture of Na2CO3 and ethylacetate, extracted with ethylacetate. The organic phase was dried over MgSO4, evaporated to give title compound as a yellow solid (698 mg, 86%).
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][OH:5].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.CCOCC>N1C=CC=CC=1>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC[C@H](C)CCC[C@H](C)CCCC(C)C)cc1
Reaction time: 40 h
Yield: 94.7 %

Procedure:
A solution of 10.44 g (45.8 mmol) of (3R,7R)-3,7,11-trimethyldodecan-1-ol in 150 mL of anhydrous pyridine was stirred in an acetone-ice bath while 17.4 g (91.3 mmol) of p-toluenesulfonyl chloride was added in one portion. The mixture was stirred in the acetone-ice bath for 2 hr then kept at 0° C. for 40 hr before being quenched by the addition of 300 mL of ice-water. The product was isolated by extraction with 3×300 mL of ether. The ether extracts were combined, washed with 400 mL of cold 3N HCl and saturated brine, then dried (MgSO4), filtered and concentrated in vacuo. There was obtained 16.6 g (94.9%) of (3R,7R)-3,7,11-trimethyldodecyl p-toluenesulfonate.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][O:5][CH3:6].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][C@@H:3]([NH:7][C:8]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:17])[CH2:4][O:5][CH3:6])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@@H](CO)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzyl [(2R)-1-hydroxy-3-methoxypropan-2-yl]carbamate (30 g, 0.13 mol) in DCM (300 mL) at 0° C. was added triethylamine (19.0 g, 0.188 mol) and methanesulfonylchloride (21.6 g, 0.188 mol) and then the reaction mixture was allowed to warm to ambient temperature. After 16 hours, the reaction mixture was washed with brine, and the organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (10% ethyl acetate/petroleum ether) to give (2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxypropyl methanesulfonate. MS ESI calc'd. for C13H20NO6S [M+H]+ 318. found 318. 1H NMR (400 MHz, CDCl3) δ 7.36-7.33 (m, 5H), 5.24 (d, J=8.0 Hz, 1H), 5.10 (s, 2H), 4.28 (d, J=5.6 Hz, 2H), 4.12-4.09 (m, 1H), 3.55-3.42 (m, 2H), 3.35 (s, 3H), 2.99 (s, 3H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Br[C:6]1[C:7](=[O:18])[C:8]2[C:13]([C:14](=[O:17])[C:15]=1[Br:16])=[CH:12][CH:11]=[CH:10][CH:9]=2.[NH4+].[Cl-].[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>[Cl-].[Cl-].[Zn+2]>[CH2:23]([C:6]1[C:7](=[O:18])[C:8]2[C:13]([C:14](=[O:17])[C:15]=1[Br:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:22][CH2:21][CH2:25][CH2:8][CH2:7][CH2:6][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: O=C1C(Br)=C(Br)C(=O)c2ccccc21
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCCCCCCCCC1=C(Br)C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 24 %

Procedure:
To 0.155 g (1.16 mmoles) of AlCl3 in 20 mL of THF was added 5.0 g (3.48 mmoles) of dodecyl MgBr (0.697 mmole/g). This mixture was added to 1.00 g (3.17 mmoles) of 2,3-dibromo-1,4-naphthoquinone in 50 mL of THF. A brown solution was obtained. Then, 0.40 g (2.94 mmoles) of ZnCl2 was added and the mixture was stirred overnight. The mixture was poured into 100 mL of NH4Cl solution, extracted with 3×50 mL of ether, dried over MgSO4, filtered, and solvent was removed. The residue was flash-chromatographed (on silica, toluene eluant). Thus, 0.390 g (0.76 mmole, 24%) of 2-n-dodecyl-3-bromo-1,4-naphthoquinone was obtained. mp 98° to 100° C. 1H NMR (δ, CDCl3): 8.11 (m,2H), 7.70 (m,2H), 2.90 (m,2H), 1.33 (br. s,20H), 0.90 (m,3H). IR (cm-1, CHCl3): 1678s, 1599m, 1579w, 1280s.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].F[C:15]1[CH:16]=[C:17]([C:24]2[S:28][C:27]([N:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:30][C@@H:31]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[N:26][N:25]=2)[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22]>O1CCOCC1>[C:46]([O:45][C:44]([NH:43][C@@H:31]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=1)[CH2:30][N:29]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[C:27]1[S:28][C:24]([C:17]2[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:15]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:16]=2)=[N:25][N:26]=1)=[O:50])([CH3:47])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
Diethyl malonate (2.83 mL, 18.7 mmol) in 30 mL of 1,4-dioxane was added to sodium hydride (0.748 g, 60% dispersion in mineral oil, 18.7 mmol) in 10 mL of 1,4-dioxane at room temperature under nitrogen. The mixture became a clear solution within 5 minutes. The mixture was stirred for another 15 minutes followed by addition of the tert-butyl (S)-1-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate as described in Schemes 1a and 1b (3.0 g, 4.7 mmol). After overnight stirring, the solvent was removed. The residue was partitioned between EtOAc and saturated NH4Cl. The combined organic portions were washed with brine and dried over sodium sulfate. The crude product was used in the following reaction without purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=[O:9])[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-:17][Mn](=O)(=O)=O.[K+].[OH-].[K+]>O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:17])=[O:9])[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(C=O)c(=O)n(-c2ccccc2)n1C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Temperature: 75 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a mixture of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde (2 g, 9.25 mmol) in water (100 mL) at 75° C. is added a solution of KMnO4 (1.5 g, 9.49 mmol) in water (200 mL) slowly. After the addition is complete, the reaction mixture is stirred at 75° C. for another 1 hour. Solid KOH is added to make the solution alkaline and the mixture is filtered while it is hot. To the filtrate is added EtOH (10 mL) and EtOAc (50 mL). The organic phase is separated and discarded. The aqueous phase is acidified with concentrated HCl to pH 5 and extracted with EtOAc (60 mL) and DCM (60 mL). The organic phases are combined, dried, and concentrated to give the title product (1.9 g, 88.46%yield). MS (m/z): 233.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]=2[O:26][CH3:27])=[O:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1)(=[O:39])=[O:38].C(N(C(C)C)CC)(C)C>C(O)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]=2[O:26][CH3:27])=[O:9])=[CH:6][N:5]=[C:4]([NH:46][CH:43]2[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(=O)c1cnc(Cl)nc1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Yield: 59.8 %

Procedure:
To a solution of (4-amino-2-chloro-pyrimidin-5-yl)-[3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-methanone (860 mg, 2.0 mmol, Example 269) in ethanol (12 mL) was added 1-methanesulfonyl-piperidin-4-ylamine trifluoroacetate salt (613.8 mg, 2.1 mmol, Example 162) and diisopropylethylamine (1.2 mL, 6.889 mmol). The mixture was heated at reflux for 4 hours and then concentrated to dryness. The residue was dissolved in ethyl acetate (20 mL). The solution was washed with brine (1×10 mL) and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 45-60% ethyl acetate in hexanes) yielded [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-[3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-methanone as white glass (684 mg, 60%). LR-MS (M+) 572.1.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:7]([CH2:15][O:16]C)=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=1[CH3:12].O>C(Cl)Cl>[Cl:5][C:6]1[C:7]([CH2:15][OH:16])=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=1[CH3:12]
Reactant: COCc1nc(SC)nc(C)c1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CSc1nc(C)c(Cl)c(CO)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1M BBr3 in CH2Cl2 (9.5 ml, 9.5 mmol) was added to a solution of the title compound from Step C (0.52 g, 2.78 mmol) in CH2Cl2 (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 h. Water (1 mL) was added. The mixture was extracted with CH2Cl2 (3×10 mL), and dried over Na2SO4. The solvent was removed. The residue was purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexane (3/7) to give the title compound as a colorless gum. 1H NMR (CDCl3, 500 MHz) δ 4.76 (d, J=4.5 Hz, 1H), 3.88 (m, 1H), 2.61 (s, 3H), 2.59 (s, 3H).