Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][N:4]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH3:5].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[S:20]([CH2:2][CH2:3][N:4]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH3:5])([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(CCO)c1ccc(C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)CCN(C)c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 0.5 mol of 4-[N-2-hydroxyethyl-N-methylamino]benzaldehyde in methylene chloride at 0° C. are added 0.51 mol of p-toluenesulfonyl chloride, 0.51 mol of triethylamine, and 0.005 mol of N,N-dimethylaminopyridine, and the reaction medium is warmed slowly to room temperature. After standing at room temperature for one hour, the reaction product medium is washed with cold 1N HCL, saturated sodium bicarbonate solution, and water. The organic solution is separated and dried over molecular sieves, filtered through cotton, and evaporated to yield the 4-[N-2-tosylethyl-N-methylamino]-benzaldehyde as a crystalline product, which then is recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:35])[CH:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9]/[C:10](=[N:37]\[OH:38])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:35])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CCN(S(N)(=O)=O)CC3)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CCN(S(N)(=O)=O)CC3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-4-(4-(1-(4-chloro-2-methylphenyl)-3-(2-methylpyridin-4-yl)-3-oxopropyl)phenyl)piperidine-1-sulfonamide and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=527.3 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][C:15](=O)[C:14]=3[CH:21]=2)=[CH:6][CH:5]=1.CO.[ClH:26]>C1COCC1.B>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:21]=2)=[CH:6][CH:5]=1.[ClH:26]
Reactant: O=C1NCCOc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: FC(F)(F)Oc1ccc(-c2ccc3c(c2)CNCCO3)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (660 mgs, 2.0 mmol) in THF (6 mL), 1.0M Borane in THF (6.0 mL, 6.0 mmol) was added and the mixture was heated at 70° C. After 16 h, the mixture was cooled to rt and Methanol (22 mL) and 6.0M HCl (22 mL) was added and stirred at rt for 2 h. The reaction mixture was then concentrated and the solids formed were filtered and washed with ether and dried to give 7-(4-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine as HCl salt. The above compound (100 mgs, 0.29 mmol), pyrimidine-2-carboxylic acid (47 mgs, 0.38 mmol), HATU (143 mgs, 0.38 mmol), in DMF (1 mL) was added NMM (0.1 mL, 0.86 mmol) and stirred at 60° C. for 30 min. The reaction mixture was then diluted with EtOAc and washed with NaHCO3, brine and dried (MgS(O)4). The mixture was the filtered, concentrated and chromatographed (SiO2, 50% EtOAc/DCM) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:29].O>C(Cl)Cl>[Br:29][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(CCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(CCNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of {3-[(5-chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phenyl}methanol (0.30 g, 0.78 mmol) in methylene chloride (5.0 mL) was added slowly a solution of boron tribromide in methylene chloride (2.3 mL, 2.3 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when water was added. The mixture was allowed to warm up to rt. Both aqueous layer (no product in it) and organic layer (containing small amounts of product, plus byproducts) were checked and discarded. The remaining solid residue was triturated with cold EtOAc and then filtered. The cake was washed with cold EtOAc and then H2O to give the desired product as a white powder (0.30 g, 89%). LCMS for C19H19BrClN4O (M+H)+: m/z=433.0, 435.0, 437.0. 1H NMR (400 MHz, CD3OD): δ 7.94 (s, 1H), 7.60 (s, 1H), 7.40 (m, 2H), 7.32 (m, 1H), 7.05 (m, 1H), 6.60 (m, 3H), 4.54 (s, 2H), 3.76 (t, J=6.4 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:47](O)(=[O:50])[C:48]#[CH:49].O>C(Cl)(Cl)Cl>[Cl:25][C:24]1[C:23]([O:26][CH3:27])=[CH:22][C:21]([O:28][CH3:29])=[C:20]([Cl:30])[C:19]=1[NH:18][C:16](=[O:17])[N:15]([C:11]1[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:47](=[O:50])[C:48]#[CH:49])[CH:10]=1)[CH3:31]
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C#CC(=O)Nc1ccccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
The compound was synthesized following the approach outlined in Procedure 2C (Example 108) modifying step (g) to the following procedure: To a solution of 1-[6-(2-amino-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-urea (50 g, 0.108 mmol) and DCC (46 g, 0.22 mmol) in chloroform (50 mL) was added a solution of propiolic acid (16 mg, 0.22 mmol) in chloroform (50 mL) at 0° C., and the resulting mixture was stirred at room temperature overnight. Water (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by reverse phase column and prep-TLC to obtain the title compound (5 mg, yield: 9.1%). 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 10.36 (s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 7.30-7.25 (m, 2H), 6.96 (s, 1H), 6.50 (s, 1H), 4.42 (s, 1H), 4.00 (s, 6H), 3.35 (s, 3H); MS (ESI): 515 [M+H]+
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.Br[CH:15]([CH3:23])[C:16](=O)[CH2:17][C:18]([O:20][CH3:21])=[O:19]>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:16]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:4][CH:5]=2)[O:8][C:15]=1[CH3:23]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C
Yield: 2.3 %

Procedure:
A mixture of 3.62 g (19.1 mmol) of 4-trifluoromethylbenzamide and 4.0 g (19 mmol) of methyl 4-bromo-3-oxo-pentanoate in 15 mL of toluene and 10 mL of dioxane (with 2 mL of EtOH) was refluxed for 22 h. The solution was concentrated under reduced pressure. The residue was taken into EtOAc and washed with water, brine, and dried over MgSO4. The crude material was purified by silica gel chromatography (10%-40% EtOAc in hexanes) to yield 130 mg of a yellow solid: 1H NMR (CDCl3, 400 MHz) δ8.1 (d, 2H, J=8.3), 7.65 (d, 2H, J=8.4), 3.75 (s, 3H), 3.58 (s, 2H), 2.39 (s, 3H); low resolution MS (ES+) m/e 300.0 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[O:10][C:9]2[C:11]([NH:15][C:16](=[O:30])[CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:20]=3)=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1.[NH3:32]>C(O)C>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]([CH:18]=[CH:17][C:16]([NH:15][C:11]2[C:9]3[O:10][CH:5]([CH2:4][C:3]([NH2:32])=[O:2])[CH2:6][O:7][C:8]=3[CH:14]=[CH:13][CH:12]=2)=[O:30])=[CH:20][CH:21]=1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC(=O)OC)CO3)cc1
Reactant: N
Solvent: CCO
Product: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC(N)=O)CO3)cc1
Reaction time: 72 h

Procedure:
8-(p-pentylcinnamoyl)amino-l,4-benzodioxane-2-acetic acid methyl ester (341 mg; synthesized in reference example 3) was dissolved into ethanol which was saturated with ammonia (20 ml). The solution was allowed to stand for 3 days at 100° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate=2:1) to give the title compound (191 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH3:10])=[O:8].C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.CCOCC>[Br:18][C:5]1[S:1][C:2]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:4]=1
Reactant: COC(=O)Cc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Br)s1
Reaction time: 3 h
Yield: 82.1 %

Procedure:
Referring once again to FIG. 3, a solution of methyl 2-(thiophen-2-yl)acetate (27.44 g, 175.7 mmol) was dissolved in DMF (500 mL) and stirred in the dark as NBS (37.52 g, 210.8 mmol) was added portion wise. The reaction was stirred for three hours at which TLC indicated completion of the reaction. The reaction was diluted with ether and the organic phase was washed with ammonium chloride and water, then dried with magnesium sulfate and concentrated by rotovap. The resulting crude oil was purified by triturating with hexanes, decanting off the organic phase above the oil, then subjecting the oil to chromatography on a gradient plug of silica gel (hexanes to 10% EtOAc in hexanes) to yield the product as a yellow oil (33.90 g, 144.2 mmol, 82%). The product matches literature data. Kranich, R., et al., “Rational Design of Novel, Potent Small Molecule Pan-Selectin Antagonists,”J. Med. Chem. 50:1101-1115 (2007). 1H NMR (CDCl3) δ: 6.89 (d, J=4.0 Hz, 1H), 6.69 (dt, J=4.0 Hz, 1H), 3.76 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:26])[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C1C=CC=CC=1.[BH4-].[Na+]>CO>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:26])=[CH:17][CH:18]=1)=[O:21]
Reactant: COC(=O)c1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 3.43 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 4.5 g of methyl 4-(2-oxopropoxy)benzoate (prepared as described in European Patent Publication No. 6735), 100 ml of benzene, 100 ml of absolute methanol and 2.7 g of sodium borohydride were used, to give the title compound as crystals, melting at 99°-101° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:11]1[CH2:10][CH:9]([NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH2:12]1
Reactant: Cc1ccnc(NC2CN(C(=O)OC(C)(C)C)C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccnc(NC2CNC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-[(4-methyl-2-pyridyl)amino]azetidine-1-carboxylate (120 mg, 0.456 mmol) was dissolved in DCM (10 ml) under nitrogen. Trifluoroacetic acid (0.843 ml, 11.4 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was dissolved in methanol and passed through a SCX column. The product was eluted by 2M ammonia in methanol, the solution was evaporated to dryness and the residue was used directly in the next step. MS (ESI) m/z=164.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:6](I)=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[Cl:15])[N:4]([CH3:16])[N:3]=1.C([Li])CCC.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:6]([CH:25]([C:24]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:23]=2[F:22])[OH:26])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[Cl:15])[N:4]([CH3:16])[N:3]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: Cn1nc(Br)c(I)c1-c1ccc(F)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nc(Br)c(C(O)c2ccc(F)cc2F)c1-c1ccc(F)cc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-bromo-5-(2-chloro-4-fluorophenyl)-4-iodo-1-methyl-1H-pyrazole (i.e. the product of Step D) (250 mg, 0.602 mmol) in tetrahydrofuran (3 mL) at −78° C. was added dropwise n-butyllithium (2.5 M solution in hexanes, 0.36 mL, 0.90 mmol). Stirring was continued for 1 h at −78 to −40° C., and then the reaction mixture was cooled to −78° C. and 2,4-difluorobenzaldehyde (103 mg, 0.72 mmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3 h, and then saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (10 to 50% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as an off-white solid (35 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4](O)[CH2:3]1.[P:9](Cl)([Cl:12])([Cl:11])=[S:10].N1C=CC=CC=1>ClC=C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([P:9]([Cl:12])([Cl:11])=[S:10])[CH2:3]1
Reactant: CC1CCCC(O)C1
Reactant: S=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC=C(Cl)Cl
Product: CC1CCCC(P(=S)(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A mixture of 3-methylcyclohexanol (5.0 g, 43.8 mmol) in trichloroethylene (300 mL) is added dropwise to a 0°-4° C. mixture of thiophosphoryl chloride (11.13 g, 65.7 mmol) and anhydrous pyridine (5.20 g, 65.7 mmol) in trichloroethylene (125 mL) over a 1 hour period under a nitrogen atmosphere. The resultant reaction mixture is stirred at 0°-4° C. for 1 hour and is then warmed to room temperature and stirred at room temperature for 8 hours. A white solid gradually precipitates. The white solid is filtered from the reaction mixture. The resultant reaction mixture is concentrated in vacuo to a residue. Successive aliquots of toluene (100 mL) are added to the residue and then separately are evaporated in vacuo to give 7.57 g (70%) of (3-methylcyclohexyl)-thiophosphoryl dichloride which can be used directly without further purification as the starting material for Example 23.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Br:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.O1CCCC1.O>[NH2:8][C:7]1[C:2]([Br:1])=[N:3][C:4]([CH3:12])=[CH:5][C:6]=1[Br:11]
Reactant: Cc1cc(Br)c([N+](=O)[O-])c(Br)n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(Br)c(N)c(Br)n1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
2,4-Dibromo-6-methyl-3-nitropyridine (1.0 g, 3.38 mmol) was dissolved in a mixture of methanol (4 mL) and tetrahydrofuran (6 mL), and a solution of sodium hydrosulfite (3.0 g, 17.23 mmol) in water (7 mL) was added thereto over 5 minutes with stirring at 65° C. Subsequently, the mixture was stirred for 30 minutes at 65° C. To the mixture, a solution of sodium hydrosulfite (3.0 g, 17.23 mmol) in water (7 mL) was further added over 5 minutes, and the mixture was stirred for 30 minutes at 65° C. The resultant mixture was allowed to cool, diluted with water, and then the mixture was extracted with chloroform. The organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentrating under reduced pressure, to thereby yield 0.89 g of 3-amino-2,4-dibromo-6-methylpyridine as a colorless solid (yield 99%). The product was crystallized from hexane, to thereby obtain colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[CH:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:31]=1.CCN(CC)CC>C(Cl)Cl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]3[S:11][C:12]([C:15](=[O:16])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:23])=[CH:13][N:14]=3)[CH:4]=2)(=[O:34])=[O:33])[CH:31]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: Cc1ccccc1C(=O)c1cnc(Nc2cccc(CN)c2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1cnc(Nc2cccc(CNS(=O)(=O)c3cc(F)ccc3C)c2)s1

Procedure:
A mixture of 35.8 mg (0.1 mmol)[2-(3-aminomethyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone; hydrochloride, 25 mg (0.12 mmol) 5-fluoro-2-methyl-benzenesulfonyl chloride (commercially available) and 69 ul (0.5 mmol) NEt3 in 3 ml DCM was stirred at 60° C. for 16 h. After evaporation of the volatiles the residue was taken up in 1.5 ml MeOH/formic acid 2/1 and subjected to reversed phase HPLC purification eluting with a gradient of acetonitrile/water. After evaporation of the product fractions 31 mg (62%) of the title compound was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14]2[C:13]([NH2:16])=[N:12][NH:11][C:10]=2[C:9]1([CH3:18])[CH3:17])=O)(C)(C)C.[Cl:19][CH:20]([C:24](=O)[CH3:25])[C:21](=O)[CH3:22].Cl>CC(O)=O>[ClH:19].[Cl:19][C:20]1[C:24]([CH3:25])=[N:16][C:13]2[N:12]([N:11]=[C:10]3[C:9]([CH3:17])([CH3:18])[NH:8][CH2:15][C:14]3=2)[C:21]=1[CH3:22]
Reactant: CC(C)(C)OC(=O)N1Cc2c(N)n[nH]c2C1(C)C
Reactant: CC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2c(C)c1Cl)C(C)(C)NC3
Reaction time: 4 h
Yield: 136.5 %

Procedure:
A mixture of 3-amino-6,6-dimethyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (500 mg; 1.98 mmol; 1 eq.) and 3-chloro-pentane-2,4-dione (226 μL; 1.98 mmol; 1.00 eq.) in AcOH (1.5 mL) was stirred at room temperature for 1 hour whereupon 32% aq. HCl (584 μL; 5.94 mmol; 3 eq.) was added. The resulting mixture was stirred for 4 hours then poured onto iPrOH (6 mL). The formed precipitate was filtered off and dried to afford the title compound (388 mg, 68%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.37 (brs, 2H), 4.59 (s, 2H), 2.83 (s, 3H), 2.62 (s, 3H), 1.74 (s, 6H). HPLC (max plot) 98.1%, Rt 1.97 min. UPLC/MS: (MS+) 234.1 ([M+H]+).
Reaction SMILES: C([O:8][C:9]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:10]=1[C:11]([C:13]1[N:17]([O:18][CH2:19][O:20][CH:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH3:22])[C:16]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:15][CH:14]=1)=[O:12])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH2:27]([C:16]1[N:17]([O:18][CH2:19][O:20][CH:21]([Si:23]([CH3:24])([CH3:26])[CH3:25])[CH3:22])[C:13]([C:11](=[O:12])[C:10]2[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:9]=2[OH:8])=[CH:14][N:15]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1ncc(C(=O)c2ccc(OC)cc2OCc2ccccc2)n1OCOC(C)[Si](C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCc1ncc(C(=O)c2ccc(OC)cc2O)n1OCOC(C)[Si](C)(C)C
Yield: 88 %

Procedure:
A solution of 5-(2-Benzyloxy-4-methoxybenzoyl)-2-n-butyl-1-trimethylsilylethyloxymethoxy-1H-imidazole (549 mg, 1.1 mmol) in EtOAc (15 ml) was stirred with 10% Pd/C (87 mg) under H2 (1 atm) for 18 h. Filtration and evaporation afforded the title compound as a yellow oil (407 mg, 91% ).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[CH2:8])(=[O:4])[NH:2][NH2:3].[CH3:9][C:10]1([CH3:26])[CH2:15][CH:14]([NH:16][C:17](=[O:23])[C:18](OCC)=[O:19])[CH2:13][C:12]([CH3:25])([CH3:24])[NH:11]1>CO>[CH3:9][C:10]1([CH3:26])[CH2:15][CH:14]([NH:16][C:17](=[O:23])[C:18]([NH:3][NH:2][C:1]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4])=[O:19])[CH2:13][C:12]([CH3:25])([CH3:24])[NH:11]1
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Reactant: C=CCOC(=O)NN
Solvent: CO
Product: C=CCOC(=O)NNC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Temperature: 50 °C
Reaction time: 1.33 h
Yield: 85.7 %

Procedure:
Into a 250 ml 3-neck flask was added 9.2 grams (0,079 mole) of allyl carbazate from (A), 34.2 grams (0.08 mole) of a 60% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate and 50 ml of methanol. The flask was equipped with a magnetic stirrer, thermometer and a Dean Stark trap with a reflux The reaction was heated in an oil bath and the methanol was distilled off through the Dean Stark trap. After the methanol distillation ceased, a vacuum was applied to the system to remove any residual methanol and the reaction was cooked for 80 minutes at 90° C. The reaction was cooled to 50° C. and 50 ml of methanol was added and the reaction heated back up to reflux to dissolve the residue. The methanol solution was cooled and concentrated to 25 ml. Upon addition of 25 ml of methyl t-butyl ether, a white solid formed. The solid was filtered off and dried in a vacuum oven over night. The dry powder weighed 22.1 grams (85.7% yield) and assayed 100% by liquid chromatography. The infrared scan of the product contained a weak carbonyl at 1750 cm-1 and a strong carbonyl at 1680 cm-1.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.S([O:17][CH2:18][CH2:19][O:20][NH2:21])(O)(=O)=O>>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:21][O:20][CH2:19][CH2:18][OH:17])=[O:11]
Reactant: NOCCOS(=O)(=O)O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Nc1ccccc1C(=O)NOCCO
Yield: 66.6 %

Procedure:
1H-3,1-benzoxazine-2,4-dione (320 mg, 1.96 mmol) and 2-(aminooxy)ethanol hemisulfate (990 mg, 3.92 mmol) were reacting using the procedure of example 15.07, starting material. The crude product was purified by flash chromatography on silica gel eluting with 0 to 80% EtOAc in DCM. The solvent was evaporated to dryness to afford 2-amino-N-(2-hydroxyethoxy)benzamide (256 mg, 66.5%) as a pale yellow oil which solidified on standing. NMR Spectrum: (DMSOd6) 3.57-3.64 (m, 2H), 3.85-3.92 (m, 2H), 4.75 (bs, 1H), 6.27 (bs, 2H), 6.49 (dd, 1H), 6.71 (d, 1H), 7.15 (ddd, 1H), 7.34 (dd, 1H), 11.39 (bs, 1H); Mass spectrum: MH+ 197
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH2:12][C@H:13]1[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:15][C:14]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:26].[K+]>O1CCOCC1>[CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH2:12][C@@H:13]([CH2:17][C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[OH:15])[C:14]([OH:25])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C1O[C@@H](c2ccc(F)cc2)C[C@@H]1CC=CCOCc1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)[C@@H](CC=CCOCc1ccccc1)C[C@@H](O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3S,5R)-3-(4-(benzyloxy)but-2-enyl)-5-(4-fluorophenyl)dihydrofuran-2(3H)-one (643 mg, 1.9 mmol) in 7 mL dioxane was added 7 mL aqueous 5% KOH at 25° C. After being stirred for 30 min at room temperature the reaction was quenched by the addition of 10 mL of 1M aqueous HCl. The mixture was extracted ethyl acetate (2×50 mL) and the combined organic layers were washed with brine (2×30 mL). The solution was dried over Na2SO4 before being concentrated under reduced pressure. The crude product was used directly in the next reaction without further purification.