Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:17]=[C:18]([Cl:38])[C:19]([O:22][C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=3)[C:26](O)=[O:27])=[N:20][CH:21]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C:64]1[S:65][CH:66]=[CH:67][N:68]=1>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:17]=[C:18]([Cl:38])[C:19]([O:22][C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=3)[C:26]([NH:63][C:64]3[S:65][CH:66]=[CH:67][N:68]=3)=[O:27])=[N:20][CH:21]=2)=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: Nc1nccs1
Reactant: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
DIPEA (0.129 mL) was added to a suspension of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (168 mg), HATU (190 mg) and 2-aminothiazole (40 mg) in DMF (2 mL) and the mixture stirred at RT for 16 hours. Water (30 mL) was added and the mixture extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 50-100% ethyl acetate in isohexane, to give the desired compound (75 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C[C@H]1CCCN1
Product: C[C@@H]1CCCN1C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-2-methylpyrrolidine (1.2 equiv) to give 171 (14.8 mg, M+1 381.1)
Reaction SMILES: [CH3:1][N:2]([CH3:22])/[CH:3]=[N:4]/[S:5]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:7])=[O:6].[CH2:23](Br)[CH:24]=[CH2:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:25]([O:14][C:13]1[C:8]([S:5](=[O:7])(=[O:6])/[N:4]=[CH:3]/[N:2]([CH3:1])[CH3:22])=[C:9]([NH:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH:10]=[CH:11][CH:12]=1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: CN(C)/C=N/S(=O)(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(NC(=O)C(C)(C)C)c1S(=O)(=O)/N=C/N(C)C

Procedure:
A solution of N-(2-{[1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}-3-hydroxy-phenyl)-2,2-dimethyl-propionamide (600 mg, 1.84 mmol) in DMF (4 ml) is treated at 70° C. with allyl bromide (217 μl, 2.57 mmol) and K2CO3 (380 mg) for 45 min with stirring. After evaporation of the solvent, the residue is partitioned between water and EtOAc. The organic layer is dried (Na2SO4) and evaporated yielding N-(3-allyloxy-2-{[1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}-phenyl)-2,2-dimethyl-propionamide.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].[O:10]1[CH2:33][CH:11]1[CH2:12][O:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[N:17]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:16]([CH3:32])([CH3:31])[CH2:15]1>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:33][CH:11]([OH:10])[CH2:12][O:13][CH:14]2[CH2:15][C:16]([CH3:31])([CH3:32])[N:17]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:18]([CH3:20])([CH3:21])[CH2:19]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CCCCCCCCON1C(C)(C)CC(OCC2CO2)CC1(C)C
Reactant: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OCC(O)COC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)cc1

Procedure:
4-Vinylphenol is reacted with 4-(2,3-epoxypropoxy)-1-octyloxy-2,2,6,6-tetra-methylpiperidine (=epoxide A3) analogously to Example B6) to form the title product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.[Cl:23][C:24]1[C:33]([CH:34]=O)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][O:27][C:26]=2[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl.CO>[ClH:23].[Cl:23][C:24]1[C:33]([CH2:34][NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]3[C:13]4=[C:14]([F:22])[CH:15]=[N:16][C:17]5[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=54)[CH2:10]3)[CH2:4][CH2:3]2)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][O:27][C:26]=2[CH:25]=1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Reactant: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cl
Product: O=C1COc2cc(Cl)c(CNC3CCN(C[C@@H]4Cn5c(=O)ccc6ncc(F)c4c65)CC3)nc2N1
Reaction time: 16 h

Procedure:
A mixture of (4R)-4-[(4-amino-1-piperidinyl)methyl]-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one Enantiomer 1 (50 mg, 016 mmol) and 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003064421, Example 15(c) (33 mg, 0.16 mmol) in anhydrous dichloromethane (1.5 mL) and anhydrous methanol (0.1 mL) was treated with triacetoxyborohydride (105 mg, 0.49 mmol). After 16 hours, an aqueous solution of sodium bicarbonate was added. The free base of the title compound came out of solution and was isolated by filtration, washed with water and dried in vacuo (50 mg, 60%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO[CH:13]=[CH:14][C:15](=[O:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:4]1([C:3]2[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O/N=C(\Cl)c1ccccc1
Reactant: COC=CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1conc1-c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To a mixture of (E)- and/or (Z)-N-hydroxy-benzenecarboximidoyl chloride (7.41 g, 48 mmol) and 4-methoxy-3-buten-2-one (4.77 mL, 48 mmol) in dichloromethane (48 mL) was added triethylamine (6.64 mL, 48 mmol) dropwise under ice-bath cooling keeping the temperature below 5° C. The reaction mixture was then stirred at 5° C. for 15 min, and then the ice-bath was removed and stirring was continued for 30 min (resulting in an increase in temperature to 32° C. Then the mixture was re-cooled under ice-bath cooling for another 30 min and then the ice-bath was removed again and allowed to warm up to room temperature and left overnight. The resulting mixture was then poured into HCl (1 N) and ice-water and then extracted with ethyl acetate. The organic extract was then dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (6.35 g, 71%) which was obtained as a light yellow solid. MS: m/e (EI)=187.1 [M].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:14][NH2:15]>C(Cl)(Cl)Cl>[CH3:14][NH:15][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:13])([F:12])[F:1]
Reactant: CN
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1ccccc1C(F)(F)F

Procedure:
2-(Trifluoromethyl)benzoyl chloride and methylamine (2M, THF solution) were reacted in chloroform at room temperature to obtain N-methyl-2-(trifluoromethyl)benzamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[N:17]1([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O.CCOC(C)=O>[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:31][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)[CH3:30])[N:7]=1)([CH3:15])[CH3:14]
Reactant: CC(N)c1ccc(N2CCCCC2)cc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(N2C(=O)OC[C@@H]2C(C)C)n1)c1ccc(N2CCCCC2)cc1
Yield: 36.6 %

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (93 mg, 0.38 mmol) and 1-(4-(piperidin-1-yl)phenyl)ethanamine (410 mg, 2.01 mmol, 5.2 equiv) in DMSO (1 mL) was heated at 110° C. for 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 100%) provided (4S)-4-isopropyl-3-(2-((1-(4-(piperidin-1-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (57 mg) in 36% yield. A mixture of (4S)-4-isopropyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one was resolved on a column (AD-H 4.6×100 mm) using 5 to 55% MeOH with 0.2% Et2NH in CO2 to give (S)-4-isopropyl-3-(2-((R)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-((S)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:13]=[N:14][C:15]3[CH:16]=[C:17]4[CH:24]=[N:23][NH:22][C:18]4=[CH:19][C:20]=3[N:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Br[CH2:26][CH2:27][O:28][C:29](=[O:31])[CH3:30].O>CN(C=O)C>[C:29]([O:28][CH2:27][CH2:26][N:22]1[C:18]2=[CH:19][C:20]3[N:21]=[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([F:3])[CH:5]=4)[CH:13]=[N:14][C:15]=3[CH:16]=[C:17]2[CH:24]=[N:23]1)(=[O:31])[CH3:30].[C:29]([O:28][CH2:27][CH2:26][N:23]1[CH:24]=[C:17]2[C:18]([CH:19]=[C:20]3[C:15](=[CH:16]2)[N:14]=[CH:13][C:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([F:3])[CH:5]=2)=[N:21]3)=[N:22]1)(=[O:31])[CH3:30]
Reactant: COc1ccc(-c2cnc3cc4cn[nH]c4cc3n2)cc1F
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cnc3cc4cn(CCOC(C)=O)nc4cc3n2)cc1F
Product: COc1ccc(-c2cnc3cc4cnn(CCOC(C)=O)c4cc3n2)cc1F
Reaction time: 0.25 h

Procedure:
NaH (60%; 0.35 g) is added into a stirring solution of 2.14 g of 7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline in 30 ml of anhydrous DMF and stirred for 15 minutes, then 1.34 g of 2-bromoethylacetate is added into the mixture slowly. The resulting mixture is stirred at room temperature for 21/2 hours then poured into water and the product is filtered off, washed with water and dried. This is purified by column chromatography using 5% →20% ethylacetate in methylene chloride as eluent to obtain 1-(2-acetoxyethyl)-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (m.p. 164°-166° C.) and 2-(2-acetoxyethyl)-7-(3-fluoro-4-methoxyphenyl)-2H-pyrazolo[3,4-g]quinoxaline (m.p. 175°-178° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18](Cl)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18]([C:35]2[CH:36]=[N:37][CH:38]=[C:33]([S:32][CH3:31])[CH:34]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1cncc(B(O)O)c1
Reactant: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2nc(-c3cncc(SC)c3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 71.6 %

Procedure:
To a teflon-lined septum sealed Schlenk tube, a mixture of Compound 1e (4.0 g; 9.20 mmol), 5-(methylthio)pyridin-3-yl boronic acid (Compound 1f) (2.32 g; 13.7 mmol), K2CO3 (2.50 g; 18.1 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) (0.45 g, 0.55 mmol) in a mixture of ethanol (18 mL) and H2O (4.5 mL) was irradiated in a microwave reactor at 130° C. for 30 min. The resultant mixture was diluted with EtOAc, washed with saturated NH4Cl(aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 1g (3.45 g; 72% yield) as pale-yellow solid. 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 8.40 (d, 1H), 8.21 (s, 1H), 7.99 (br. s, 1H), 7.12-7.18 (m, 2H), 6.93-6.96 (m, 2H), 5.77 (br. s, 0.6H), 4.90 (br. s, 0.4H), 4.22-4.32 (m, 1H), 3.86 (s, 3H), 3.18-3.56 (m, 4H), 2.47 (s, 3H), 1.80-2.15 (m, 4H), 1.46-1.52 (m, 9H); MS: m/z 524.2 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].FC(F)(F)S(O)(=O)=O.[C:13]1([C:19]2[N:20]=[N:21][C:22]3[C:29]4([CH3:32])[CH2:30][CH2:31][CH:26]([C:27]([CH3:34])([CH3:33])[O:28]4)[C:23]=3[N+:24]=2[O-:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH2:2].[N+:1]([C:15]1[CH:14]=[C:13]([C:19]2[N:20]=[N:21][C:22]3[C:29]4([CH3:32])[CH2:30][CH2:31][CH:26]([C:27]([CH3:34])([CH3:33])[O:28]4)[C:23]=3[N+:24]=2[O-:25])[CH:18]=[CH:17][CH:16]=1)([O-:4])=[O:2]
Reactant: CC12CCC(c3c1nnc(-c1ccccc1)[n+]3[O-])C(C)(C)O2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CC12CCC(c3c1nnc(-c1cccc([N+](=O)[O-])c1)[n+]3[O-])C(C)(C)O2
Product: O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 0.2 ml. (0.005 mole) fuming nitric acid and 1.5 g. (0.01 mole) trifluoromethanesulfonic acid in 15 ml. anhydrous methylene chloride maintained at a temperature of -30° C. there is added dropwise a solution of 0.60 g. (0.002 mole) 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide in 15 ml. methylene chloride, maintaining the temperature at -30° C. throughout the addition. The resulting mixture is allowed to stir at ambient temperature for 72 hours, then poured onto ice and neutralized with solid sodium bicarbonate. The organic layer is removed, washed with saturated brine solution, dried over magnesium sulfate and evaporated. Trituration of the resulting residue with ether gives 3-(m-nitrophenyl)-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide-monohydrate; m.p. 150° (d).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].[CH3:14][C:15]([CH3:17])=O>C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>[CH3:14][C:15]1([CH3:17])[O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[C:11](=[O:13])[O:12]1
Reactant: CC(C)=O
Reactant: O=C(O)c1ccc(O)c(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(C(=O)O)ccc2O1
Temperature: 100 °C
Yield: 77 %

Procedure:
A suspension of 4-hydroxyisophtalic acid (Aldrich, 5.0 g, 27.5 mmol) in acetone (10 mL), TFA (30 mL) and TFAA (10 mL) was heated at 100° C. for 24 hrs. The reaction mixture was concentrated under reduced pressure. The residue was taken up with an aqueous solution of HCl (100 mL, 1N) and extracted with EtOAc (3×200 L); The combined organic layers were dried over MgSO4 and the solvents were removed under reduced: pressure. The crude compound was recrystallized in Et2O (50 mL) to give 4.67 g (77%) of the title compound as a beige powder. 1H NMR (DMSO-d6) δ: 8.37 (d J=1.9 Hz, 1H), 8.19 (dd, J=2.2 and 8.7 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 1.72 (s, 6H). HPLC, Rt: 2.40 min (purity: 95.7%).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])(=[O:8])=[O:7])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])(=[O:8])=[O:7]
Reactant: CN(C)C(=O)c1c(S(=O)(=O)NC(C)(C)C)ccn1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution of 5.63 g of 3-[[(1,1-dimethylethyl)amino]sulfonyl]-N,N,1-trimethyl-1H-pyrrole-2-carboxamide in 75 mL of methylene chloride was added 75 mL of TFA. The reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the residue and removed by evaporation to remove residual TFA, affording 4.21 g of the title compound as a gray solid, m.p. 185°-190.5° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.F[C:16]1[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.O>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:16]1[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: Oc1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Oc2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of potassium t-butoxide (12.3 g) in DMSO (100 mL) was added at once 3-chlorophenol (12.86 g). The resulting solution was stirred for 5 minutes at room temperature, then 3-fluoronitrobenzene (12.70 g) was added all at once. The resulting dark mixture was heated at 120° C. for 12 hours, cooled to room temperature then poured into water (700 mL). The resulting mixture was extracted with ether (2×200 mL). The organic fraction was washed with 2N NaOH (100 mL), then with water (100 mL). After drying (MgSO4), the solvent was evaporated and the resulting dark oil was distilled to give 3-(3-chlorophenoxy)nitrobenzene as a yellow oil, b.p. 135-140° C. at 0.05 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH2:18][CH2:19][OH:20])[CH:17]=2)=O)=[C:4]([CH3:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH2:18][CH2:19][OH:20])[CH:17]=2)=[N:34]\[OH:35])=[C:4]([CH3:32])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(CCO)c1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(CCO)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-1-(2-hydroxyethyl)pyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI+): m/z=489.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6](C)[CH3:7])[C:3]([NH2:5])=[O:4].[CH3:10]O.[CH:12](=O)[CH2:13][CH2:14][CH2:15][CH3:16]>O>[CH2:15]([CH:16]1[NH:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:10])[C:3](=[O:4])[NH:5]1)[CH2:14][CH2:13][CH3:12]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: CCCCC=O
Reactant: CO
Solvent: O
Product: CCCCC1NC(=O)C(C)(CCC)N1
Temperature: 70 °C
Yield: 82 %

Procedure:
20.0 g of 2-amino-2,3-dimethylbutyramide (>96%, 0.147 mol.) are dissolved at room temperature in 100 ml of H2O and 50 ml of methanol and mixed with 13.2 g of valeraldehyde (0.152 mol.). The mixture is heated for 2.5 hours at 70° C. The two-phase mixture is extracted three times at room temperature using 200 ml of MIBK each time, and the combined organic phases are concentrated in vacuo. 25.3 g (97.8% (cis/trans mixture: 25:72; no assignment) of a white solid were obtained, corresponding to a yield of 82% of the theoretical yield.
Reaction SMILES: [Mg].BrCCBr.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.C([Mg]Cl)(C)C.[CH2:26]([O:33][C:34](=[O:45])[NH:35][CH:36]([CH3:44])[CH2:37][C:38](N(OC)C)=[O:39])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([C:38](=[O:39])[CH2:37][CH:36]([NH:35][C:34](=[O:45])[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:44])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1
Reactant: CON(C)C(=O)CC(C)NC(=O)OCc1ccccc1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC(=O)OCc1ccccc1
Temperature: 75 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of magnesium turnings (1.55 g; 63.76 mmol) in THF (50 mL) under an atmosphere of N2 was added 1,2-dibromoethane (135 uL). The mixture was heated to 75° C. and 3,5-bis(trifluoromethyl)bromo benzene (4.59 mL; 26.79 mmol) was slowly added to maintain a gentle reflux. The reaction was heated at gentle reflux for 2.5 h and then cooled to room temperature. In a separate flask, isopropyl magnesium chloride (18 mL; 36 mmol) was added dropwise to a stirred solution of benzyl-{3-[methoxy(methyl)amino]-1-methyl-3-oxopropyl}carbamate (Step B; 5 g; 17.86 mmol) in THF (30 mL) at −20° C. The resultant solution was stirred at −20° C. for 40 min prior to dropwise addition of the Grignard solution. The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with 1 N HCl (100 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% acetone/hexanes gradient) to afford benzyl {3-[3,5-bis(trifluoromethyl)phenyl]-1-methyl-3-oxopropyl}carbamate as a white solid. LCMS=434.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.39 (s, 2H), 8.07 (s, 1H), 7.37-7.29 (m, 5H), 5.16-5.04 (m, 3 h), 4.31-4.23 (m, 1H), 4.16-4.10 (m, 1H), 3.19 (dd, J=16.8, 6.5 Hz, 1H), 1.34 (d, J=6.9 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[N:3]=1.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[CH:22]([C:21]([NH:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[N:3]=1)=[O:25])([CH3:24])[CH3:23]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Product: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(NC(=O)C(C)C)n1

Procedure:
This compound was prepared in an analogous manner to Example 9 from 2-amino-6-acetamido-3-(2,3,5-trichlorophenyl)pyrazine (Example 1) and one equivalent isobutyrylchloride (Aldrich). Yield 0.120 g M.p. 230-232° C.