Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>CC(N(C)C)=O>[N:64]1([C:20]([C:16]2[CH:15]=[C:14]([O:13][C:12]3[CH:23]=[CH:24][C:9]([NH:8][C:6]4[CH:5]=[C:4]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:3]=[C:2]([NH2:1])[N:7]=4)=[CH:10][CH:11]=3)[CH:19]=[CH:18][N:17]=2)=[O:22])[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)O)c3)cc2)cc(-c2ccccc2)n1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)N4CCOCC4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a solution of 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy} pyridine-2-carboxylic acid (Example 20, 0.15 g, 0.38 mmol) in dry DMA (3 mL) was added HATU (0.14 g, 0.38 mmol) and DIEA (0.15 g, 1.13 mmol). The solution was stirred at rt for 0.5 h, followed by addition of morpholine (0.16 g, 1.88 mmol). The resulting solution was stirred at rt overnight, followed by prep-HPLC separation to give 77 mg (35%) pure product. 1H NMR (DMSO-d6) δ 10.79 (s, 1H), 8.40 (s, 1H), 7.85 (m, 2H), 7.74 (m, 2H), 7.60 (m, 3H), 7.21 (m, 2H), 7.00 (m, 2H), 6.59 (s, 1H), 3.49 (m, 8H); MS ES 469 (M+H)+, calcd 469.
Reaction SMILES: II.[Mg].[CH3:4][N:5]1[CH2:10][CH2:9][CH:8](Cl)[CH2:7][CH2:6]1.CN(OC)[C:14](=[O:27])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=1>BrC(Br)C.O1CCCC1>[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([C:14](=[O:27])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)[CH2:7][CH2:6]1
Reactant: CON(C)C(=O)COc1ccc(NC(C)=O)cc1
Reactant: CN1CCC(Cl)CC1
Agent: CC(Br)Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OCC(=O)C2CCN(C)CC2)cc1
Temperature: 0 °C
Reaction time: 0.01 h
Yield: 47 %

Procedure:
A crystal of iodine was added to 0.45 gm (18.7 mMol) magnesium turnings covered with 6 mL tetrahydrofuran. To this mixture were added 5-6 drops of dibromoethane and the mixture was heated with a heat gun to initiate the reaction. Once the iodine color disappeared, 2 mL (15 mMol) 1-methyl-4-chloropiperidine were added and heating continued for an additional 30 seconds. After the exothermic reaction no longer maintained reflux temperature, the reaction mixture was heated at reflux for 30 minutes and was then cooled to 0° C. To the cold mixture was added the previously prepared N-methyl-N-methoxy 2-(4-acetamidophenoxy)acetamide and the resulting mixture stirred for 30 minutes at 0° C. and then an additional hour after warming to room temperature. The reaction was quenched by the addition of water and the resulting mixture extracted well with ethyl acetate. The combined organic extracts were washed saturated aqueous ammonium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, eluting with dichloromethane containing 5% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 0.90 gm (47%) of the desired ketone.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH:41]([C:43]1[CH:57]=[CH:56][C:46]([O:47][C:48]2[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][N:49]=2)=[C:45]([CH3:58])[CH:44]=1)=O>C1COCC1>[CH3:2][O:3][CH:4]=[CH:41][C:43]1[CH:57]=[CH:56][C:46]([O:47][C:48]2[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][N:49]=2)=[C:45]([CH3:58])[CH:44]=1
Reactant: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC=Cc1ccc(Oc2ccc(C#N)cn2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Suspend (methoxymethyl)triphenylphosphonium chloride (1.14 g, 3.34 mmol) in THF (11 mL) under N2 and cool the mixture at 0° C., add slowly 0.5M KHMDS in toluene (6.7 mL, 3.34 mmol) and stir at 0° C. for 30 min. Cool the mixture at −78° C. and add a solution of aldehyde from step 1 above (663 mg, 2.78 mmol) in THF (2 mL). Warm the mixture slowly to room temperatures and stir for 1 h. Add water and extract the aqueous layer with Et2O. Dry the organic layer over MgSO4. Eliminate the solvent and purify by flash chromatography on silica gel (eluent: gradient from EtOAc/hexane 10/90 to 20/80) to get the title compound (530 mg, 76%). Electrospray MS M+1 ion=267. 1H-NMR (CDCl3, 300 MHz, mixture of isomers): 8.47-8.45 (m, 2H), 7.92-7.86 (m, 2H), 7.50-7.45 (m, 1H), 7.15-6.93 (m, 5H), 6.14 (d, 1H, J=7.1 Hz), 5.79 (d, 1H, J=13.2 Hz), 5.20 (d, 1H, J=7.1 Hz), 3.78 (s, 3H), 3.68 (s, 3H), 2.11 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]3[C:30]4[C:25](=[N:26][CH:27]=[CH:28][N:29]=4)[N:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[O:31]C)[CH:6]=1)([F:4])[CH3:3].B(Br)(Br)Br.CCCCCC>C(Cl)Cl>[F:4][C:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]3[C:30]4[C:25](=[N:26][CH:27]=[CH:28][N:29]=4)[N:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[OH:31])[CH:6]=1)([F:1])[CH3:3]
Reactant: COc1cc(CCNc2ncnc3nccnc23)ccc1Oc1cc(C(C)(F)F)ccn1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(F)(F)c1ccnc(Oc2ccc(CCNc3ncnc4nccnc34)cc2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of (2-{4-[4-(1,1-difluoroethyl)-pyridin-2-yloxy]-3-methoxyphenyl}-ethyl)-pteridin-4-yl-amine (1.37 g, 3.13 mmol) in CH2Cl2 (15 mL) cooled to 0° C., was added 1M BBr3/hexane (9.4 mL, 9.4 mmol). The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with methanol and concentrated in vacuo. The residue was dissolved in small amount of methanol and poured into aqueous NaHCO3. The hydroxyaryl product precipitated and was collected by suction filtration and washed with H2O. The filter cake was air dried on the filter to yield 2-[4-(1,1-difluoroethyl)-pyridin-2-yloxy]-5-[2-(pteridin-4-ylamino)-ethyl]-phenol (0.76 g), as a light brown solid: 1H NMR (300 MHz, d6-DMSO) δ 9.53 (br s, 1H), 9.45 (s, 1H), 9.12 (s, 1H), 8.91 (d, J=1.5 Hz, 1H), 8.78 (br, 1H), 8.20 (d, J=5.3 Hz, 1H), 7.22 (d, J=5.3 Hz, 1H), 7.08 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.85 (d, J=1.8 Hz, 1H), 6.72 (dd, J=8.1, 1.8 Hz, 1H), 3.84 (dd, J=14.7, 7.4 Hz, 2H), 2.93 (t, J=7.4 Hz, 2H), 1.98 (t, J=19.2 Hz, 3H); ESIMS m/z 425 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:34][C:31]3[S:32][CH:33]=[C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[N:30]=3)=[O:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:7][CH:8]=1
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3nc(-c4ccccn4)cs3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (46 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 39 mg (31%). 1H-NMR: 8.64-8.61 (m, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.03-6.99 (m, 2H), 6.91-6.88 (m, 2H), 3.75, s, 3H), 3.16 (s, 3H).
Reaction SMILES: [F:1][C:2]([CH:5]=[C:6]=[CH:7][C:8]([F:11])([F:10])[F:9])([F:4])[F:3].[O:12]([CH3:14])[Na].O>CO>[C:2]([CH:5]=[C:6]([CH2:7][C:8]([F:9])([F:10])[F:11])[O:12][CH3:14])([F:4])([F:3])[F:1]
Reactant: CO[Na]
Reactant: FC(F)(F)C=C=CC(F)(F)F
Solvent: O
Solvent: CO
Product: COC(=CC(F)(F)F)CC(F)(F)F
Reaction time: 0.25 h
Yield: 88 %

Procedure:
21.1 g (0.12 mol) of bis(trifluoromethyl)allene were added to 20 mL 0.5 N NaOCH3 in methanol (8 mol % relative to allene) over 1 h with water bath cooling, keeping the reaction temperature at 10-20° C. Stirring was continued for 15 min. and the mixture poured into 80 mL cold water. The lower layer was separated and the aqueous portion extracted with 20 mL CH2Cl2. The combined organic layers were washed with 5 mL brine, dried (Na2SO4) and distilled to give 21.9 g (88% yield) of CF3CH=C(OCH3)CH2CF3, boiling point 110-111° C. IR: 1672 cm-1. Major MS fragments: 208 (75.9), 189 (30.2), 158 (31.6), 125 (60.5), 111 (82.4), 91 (100), 31 (91.2). 1H NMR:4.95 (q,1H, J=7.5 Hz), 3.65 (s, 3H), 3.18 (q, 2H, J=9.8 Hz) ppm. 19FNMR: -54.4(d,3 F), -63.9 (t, 3 F) ppm. Anal. Calcd for C6H6F6O: C, 34.61; H, 2.91. Found: C, 34.59; H. 2.85.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:46]=[CH:45][C:25]([O:26][CH2:27][CH:28]([OH:44])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28](=[O:44])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:45][CH:46]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(OCC(O)COc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(OCC(=O)COc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Temperature: 22 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
A solution of 3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxy carbonyl)phenoxy]-2-propanol (2.08 g, 3.25 mmol) in dichloromethane (120 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (5.46 g, 12.9 mmol) and the resulting mixture was stirred at 22° C. for 18 hours. The reaction mixture was then diluted with ethyl acetate, washed with 10% aqueous sodium thiosulfate, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 95:5) gave 1.82 g (88%) of the title material as oil.
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH:5]([CH:7]([N:11]2C(=O)C3=CC=CC=C3C2=O)[C:8]([OH:10])=[O:9])[O:4][N:3]=1.O.NN.C(O)(=O)C>O>[NH2:11][C@@H:7]([C@H:5]1[O:4][N:3]=[C:2]([Cl:1])[CH2:6]1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C(C1CC(Cl)=NO1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CC(=O)O
Solvent: O
Product: N[C@H](C(=O)O)[C@@H]1CC(Cl)=NO1
Reaction time: 7 h
Yield: 58.4 %

Procedure:
To 710 mg (2.3 mmole) of 3-chloro-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid in 15 ml of water is added 260 μl of hydrazine hydrate and the solution stirred at 50° for 7 hours. After cooling, the solution is adjusted to pH 5.5 with acetic acid (80 μl), filtered, and the precipitate washed with 13 ml water. The filtrate is diluted with 200 ml of 2-butanol and allowed to crystallized in the refrigerator for 18 hours. Filtration yielded 240 mg of (αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazole acetic acid; concentrating the mother liquors approximately 15% afforded 50 mg of a second crop of (αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazole acetic acid (71%).
Reaction SMILES: O=C1C2(CCN(C(OC(C)(C)C)=O)CC2)[C:9]2[C:4](=[CH:5][C:6]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=[CH:7][CH:8]=2)[NH:3]1.BrC1C=C[C:36]2[C:41](C)([CH3:42])[O:40][C:39](=[O:44])NC=2C=1>>[CH3:36][C:41]1([CH3:42])[O:40][C:39](=[O:44])[NH:3][C:4]2[CH:5]=[C:6]([B:23]3[O:24][C:25]([CH3:31])([CH3:30])[C:26]([CH3:28])([CH3:29])[O:27]3)[CH:7]=[CH:8][C:9]1=2
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: CC1(C)OC(=O)Nc2cc(Br)ccc21
Product: CC1(C)OC(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc21

Procedure:
Following the procedure described for intermediate 7.33 (Step 2), starting from 7-bromo-4,4-dimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.37 (60 mg), 77 mg of 4,4-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,3]oxazin-2 (4H)-one 7.39 was obtained. LCMS [M+H]+: 304.19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:3]=1.S1C=CC=C1B(O)O.[Br:21]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:21][C:9]1[S:10][CH:11]=[CH:12][C:8]=1[C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1
Reactant: Clc1ccnc(-c2ccsc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: OB(O)c1cccs1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccnc(-c2ccsc2Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-2-thiophen-3-yl-pyridine (755 mg, 3.9 mmol), prepared from 2-thiopheneboronic acid via the method outlined in Example 26, Step A, and N-bromosuccinimide (712 mg, 4 mmol) in DMF (6 mL) was stirred at room temperature for 8 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated to yield a residue. The residue was recrystallized from EtOH to yield 2-(2-bromo-thiophen-3-yl)-4-chloro-pyridine as a solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[N:13][N:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[CH:15]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:30]([OH:33])[C:31]#[CH:32]>N1CCCC1.C(Cl)Cl.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>[N:24]1([C:22]([C:19]2[CH:18]=[CH:17][C:16]([N:14]3[CH:15]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([C:32]#[C:31][CH2:30][OH:33])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=[N:13]3)=[CH:21][CH:20]=2)=[O:23])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: C#CCO
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4cc(Br)ccc34)nn2)cc1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4cc(C#CCO)ccc34)nn2)cc1)N1CCOCC1
Temperature: 80 °C
Yield: 28.3 %

Procedure:
A mixture of {4-[4-(6-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (150 mg; 0.33 mmol; 1.0 eq.), propargyl alcohol (39 μl; 0.66 mmol; 2.0 eq.) and Pd(PPh3)4 (19 mg, 0.02 mmol, 0.05 eq.) in pyrrolidine (1.5 mL) was heated O/N at 80° C. in a sealed tube. The reaction mixture was then diluted with DCM and washed with a saturated solution of NH4Cl (three times) and brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave the title compound as a beige solid (40 mg, 28%). 1H NMR (300 MHz, DMSO-d6-d6): 13.50 (brs, 1H), 9.42 (s, 1H), 8.34 (dd, J=8.5 Hz, 1.0 Hz, 1H), 8.15 (d, J=8.6 Hz, 2H), 7.70-7.67 (m, 3H), 7.28 (dd, J=8.5 Hz, 1.0 Hz, 1H), 5.40 (t, J=6.0 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 3.64 (m, 6H), 3.47 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[F:26])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[F:26])=[N:28][OH:29])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(C(F)(F)F)cc1F)C1CCN(Cc2ccccc2)CC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccc(C(F)(F)F)cc1F)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
A mixture of (1-benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone (5.0 g, 13.66 mmol), hydroxylamine hydrochloride (1.1 g, 16.39 mmol) and pyridine (50 mL) was stirred at room temperature overnight when the mixture was distilled to remove pyridine (35 mL). The solid residue was washed with heptane then ether. The resulting solid was partitioned between a saturated solution of NaHCO3 and EtOAc. The organic layer was dried (MgSO4), filtered and evaporated. The solid residue was washed with 3:1 heptane/EtOAc and dried under vacuum to obtain 2.1 g (40%) of the desired product as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH3:9])[O:6][CH:7]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[CH2:8]([C:5]1[O:6][CH:7]=[C:3]([CH2:2][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[N:4]=1)[CH3:9]
Reactant: CCOP(OCC)OCC
Reactant: CCc1nc(CCl)co1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(Cc1coc(CC)n1)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
A mixture of 4-chloromethyl-2-ethyl-1,3-oxazole (3.26 g), triethyl phosphite (8.19 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v), ethyl acetate, then ethyl acetate-ethanol (10:1, v/v) to give diethyl [(2-ethyl-1,3-oxazol-4-yl)methyl]phosphonate as a colorless oil (3.86 g, yield 70%).
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:35](O)[CH3:36]>O1CCCC1>[CH2:35]([CH:18]([O:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:11]([NH:10][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:32])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([OH:21])=[O:20])[CH3:36]
Reactant: CCO
Reactant: CCOC(=O)COc1ccc(CC(NS(=O)(=O)c2ccc(C)cc2)c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(CC(NS(=O)(=O)c2ccc(C)cc2)c2cccnc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-[2-(4-toluene sulfonamido)-2-(3-pyridyl)ethyl]phenoxyacetate (90 mg) was dissolved in 2 ml of ethanol and 2 ml of tetrahydrofuran, followed by addition of 0.30 ml of aqueous 2N sodium hydroxide solution, and stirred at room temperature for one hour. The solvent was concentrated under reduced pressure, and neutralized with 2N hydrogen chloride. Then, the crystalline deposited was taken out by filtration, to yield 80 mg of ethyl 4-[2-(4-toluene sulfonamido)-2-(3-pyridyl)- ethyl]phenoxyacetic acid.
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]2=[N:16][CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](=[O:20])[N:6]2[CH2:5]1)[CH:2]=[CH2:3]>CC1C=CC(C(C)C)=CC=1.[Pd].C(Cl)Cl>[CH3:15][O:14][C:10]1[CH:9]=[C:8]2[C:13]([C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]3[C:19](=[O:20])[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=[C:7]32)=[CH:12][CH:11]=1
Reactant: C=CCC1Cn2c(ncc(C(=O)OCC)c2=O)-c2cc(OC)ccc21
Agent: [Pd]
Solvent: ClCCl
Solvent: Cc1ccc(C(C)C)cc1
Product: CCCc1cn2c(=O)c(C(=O)OCC)cnc2c2cc(OC)ccc12
Yield: 62.6 %

Procedure:
A mixture of ethyl (±)-7-allyl-6,7-dihydro-10-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (190 mgs.) in p-cymene (5 ml.) containing 10% palladium on carbon (50 mgs.) was refluxed for 4 hours. The mixture was cooled, diluted with methylene chloride and filtered to remove the catalyst. The filtrate was evaporated to dryness in vacuo and the residue recrystallized from ethanol, with charcoal treatment, to give yellow needles of title product (119 mgs., 63%), m.p. 187°-188°.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]1[N:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=1)=[O:6])[CH3:3].Cl.[NH2:25][OH:26].N1CCCCC1>CS(C)=O>[CH3:21][C:19]([CH3:22])([O:18][C:16]([N:7]([C:5]([O:4][C:2]([CH3:23])([CH3:3])[CH3:1])=[O:6])[C:8]1[N:9]=[CH:10][C:11]([C:14](=[NH:15])[NH:25][OH:26])=[N:12][CH:13]=1)=[O:17])[CH3:20]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(C#N)cn1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(C(=N)NO)cn1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 55.2 %

Procedure:
A solution of 5-[[bis[(1,1-dimethylethoxy)carbonyl]]amino]-2-pyrazinecarbonitrile (305.7 mg, 0.954 mmol) in dimethyl sulfoxide (5.8 mL) was treated with hydroxylamine hydrochloride (333.8 mg, 4.804 mmol) and piperidine (0.50 mL, 5.050 mmol). The reaction was stirred at 25° C. for 50 min and then was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/3 ethyl acetate/hexanes) afforded the 5-[[bis[(1,1-dimethylethoxy)carbonyl]]amino]-N-hydroxy-2-pyrazinecarboximidamide as a white solid (186.2 mg, 55%): mp 185–186° C.; (ES)+-HRMS m/e calcd for C15H23N5O5 (M+H)+ 354.1772, found 354.1775.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1N.S(=O)(=O)(O)[OH:11].S(O)(O)(=O)=O.BrC1C=CC(Br)=CC=1N>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1[OH:11]
Reactant: O=S(=O)(O)O
Reactant: Nc1cc(Br)ccc1Br
Solvent: Cc1ccccc1C
Product: Oc1cc(Br)ccc1Br

Procedure:
61.6 Grams of 2,5-dibromoaniline and 250 g of 75% aqueous sulfuric acid solution were charged into a ceramic ball mill having one liter capacity. A suspension of fine particles of 2,5-dibromoaniline sulfate was prepared by a method similar to that described in Example 5. The suspension was transferred into a beaker having one liter capacity. The ceramic ball mill used was washed with 120 g of 75% aqueous sulfuric acid solution and the washings were transferred into the beaker. Diazotization of 2,5-dibromoaniline sulfate in the form of suspension of fine particles was carried out by a method similar to that described in Example 5 except that 18.2 g of sodium nitrite powder was added. Hydrolysis of 2,5-dibromobenzenediazonium sulfate was carried out by a method similar to that described in Example 5. A xylene layer was isolated from the hydrolyzed product and a crude product of 2,5-dibromophenol was obtained after the xylene was removed by distillation. The crude product of 2,5-dibromophenol was steam distilled by introducing superheated steam. After the distillate was cooled, crystallized 2,5-dibromophenol thus formed was obtained by filtration and dried. 47.3 Grams of 2,5-dibromophenol having melting point of 71°-74° C was obtained. The yield was found to be 85.0%.