Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][OH:33]>C(#N)C>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]([CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:31][CH2:32][OH:33])[CH2:11][CH2:12]1)[C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4]
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N(CC1CCN(CCO)CC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 80 °C
Yield: 56 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (60 mg, 0.184 mmol) in acetonitrile (10 mL) was added potassium carbonate (76 mg, 0.552 mmol) followed by 2-bromoethanol (29.9 mg, 0.239 mmol). The reaction mixture was heated in the seal tube at 80° C. for 4 hours. The reaction mixture was then filtered and evaporated. 2,2,2-Trifluoro-N-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide (40 mg, 0.103 mmol, 55.8% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.07-7.37 (m, 5H), 3.75-3.87 (m, 2H), 3.57-3.66 (m, 1H), 3.49-3.57 (m, 1H), 3.46 (t, J=6.06 Hz, 1H), 3.36-3.41 (m, 3H), 3.19 (t, J=3.79 Hz, 1H), 2.78-3.04 (m, 2H), 2.56-2.76 (m, 1H), 2.48 (ddd, J=3.54, 6.51, 10.17 Hz, 1H), 1.96-2.15 (m, 1H), 1.87 (td, J=2.91, 10.80 Hz, 2H), 1.63 (dt, J=5.24, 10.23 Hz, 1H), 1.39-1.57 (m, 3H); LC-MS Rt=0.76 min; MS (ESI): 371.2 [M++H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[N:7]=1.[CH3:36][N:37]1CCOC[CH2:38]1.ClC(OCC(C)C)=O.CNC.CO>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][CH2:16][C:17]([N:37]([CH3:38])[CH3:36])=[O:19])[N:7]=1
Reactant: CN1CCOCC1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCCCC(=O)O)N2)n1
Agent: CC(C)COC(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCCCC(=O)N(C)C)N2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
A solution of (R,Z)-4-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)butanoic acid (110a, 26 mg, 0.054 mmol) in anhydrous THF was chilled in an ice bath and N-methylmorpholine (9 μL, 0.081 mmol) and isobutyl chloroformate (7.7 μL, 0.060 mmol) were added sequentially. The mixture was stirred under an N2 atmosphere for 20 min. A 33 wt % solution of dimethylamine in methanol (54 μL, 0.11 mmol) was added to the reaction which was subsequently allowed to warm to room temperature with stirring overnight. The THF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with H2O×2 and dried over anhydrous Na2SO4. The ethyl acetate was removed in vacuo and the residue was purified via preparative HPLC to yield (R,Z)-4-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-dimethylbutanamide (98, 6.4 mg, 0.0126 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[NH2:7])[CH3:2].CCN(C1C=CC=CC=1)CC.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:7][C:26](=[O:27])[O:28][CH:29]([CH3:31])[CH3:30])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1ccc(N)cc1OCC
Solvent: c1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CCOc1ccc(NC(=O)OC(C)C)cc1OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
3,4-Diethoxyaniline (1.8 g) and diethylaniline (1.5 g) were dissolved in benzene (20 ml). To the resultant solution was dropwise added isopropyl chloroformate (1.2 g) in 5 minutes under ice-cooling. After being allowed to stand at room temperatue for 3 hours, the reaction mixture was poured into ice-water and extracted with ether. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give crude crystals (2.6 g). Recrystallization from ethanol gave isopropyl N-(3,4-diethoxyphenyl)carbamate (Compound No. 13) (2.3 g) in a yield of 86%. M.P., 100°-100.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[OH:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:31]1([C:22]2[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:2][C:3]4[N:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[O:5][N:4]=4)=[CH:38][CH:37]=3)[N:21]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: ClCc1noc(-c2ccccc2)n1
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1cn(Cc2ccc(OCc3noc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A mixture of 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (307 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-phenyl-1-[4-(5-phenyl-1,2,4-oxadiazole-3-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (651 mg, yield: 89%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: C([O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]([C:20](=[O:28])[CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:18][CH:17]3[CH2:29][CH2:30][CH2:31][N:16]3[CH2:15][C:14]=2[CH:32]=1)(=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]([C:20](=[O:28])[CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:18][CH:17]3[CH2:29][CH2:30][CH2:31][N:16]3[CH2:15][C:14]=2[CH:32]=1
Reactant: [H][H]
Reactant: O=C(Oc1ccc2c(c1)CN1CCCC1CN2C(=O)CCN1CCCC1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCN1CCCC1)N1CC2CCCN2Cc2cc(O)ccc21

Procedure:
A mixture of 5 g. of 7-benzoyloxy-2,3,5,10,11,11a-hexahydro-10-[3-(1-pyrrolidinyl)propionyl]-1H-pyrrolo[2,1-c] [1,4]benzodiazepine, 250 ml. of ethanol and 2 g. of 10% palladium-on-carbon catalyst is shaken in a Parr hydrogenator under about 3 atmospheres of hydrogen pressure until hydrogen uptake is complete. The catalyst is filtered off and the mother liquor is concentrated and 2,3,5,10,11,11a-hexahydro-7-hydroxy-10-[3-(1-pyrrolidinyl)propionyl]-1H-pyrrolo[2,1-c] [1,4]benzodiazepine is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[O:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[CH:19]=2)[N:8]([CH3:27])[N:7]=1)=[O:5])C.[OH-].[Na+]>CS(C)=O.O>[O:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[CH:19]=[C:18]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[N:8]([CH3:27])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[CH3:11]
Reactant: CCOC(=O)c1nn(C)c(-c2ccccc2-c2cc3ccccc3o2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(=O)O)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Temperature: 45 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A suspension of 0.615 g (1.71 mmol) of 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester in 5.50 ml of DMSO was treated at RT with 0.85 ml (3.41 mmol) of aqueous 1N NaOH. After 2 h, reaction was heated at 45° C. for 30 min. Then it was diluted with chilled water and extracted with Et2O. The water phase was acidified with aqueous 10% KHSO4 and extracted with Et2O (2×). These organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 0.481 g (84%) of 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid as light brown powder. MS: 331.4 (M−H−).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[CH:8][CH:9]=[C:10]([C:11]3[C:12]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=3)[N:4]2[N:3]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:58][C:59]1[CH:64]=[CH:63][C:62]([CH:65]2[CH2:70][CH2:69][N:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:67][CH2:66]2)=[CH:61][CH:60]=1>>[CH3:21][S:18]([N:17]([CH3:22])[C:12]1[C:11]([C:10]2[N:4]3[C:5]([CH:6]=[N:7][C:2]([NH:58][C:59]4[CH:64]=[CH:63][C:62]([CH:65]5[CH2:66][CH2:67][N:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:69][CH2:70]5)=[CH:61][CH:60]=4)=[N:3]3)=[CH:8][CH:9]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:20])=[O:19]
Reactant: CN(c1ncccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ncccc1-c1ccc2cnc(Nc3ccc(C4CCN(CC(N)=O)CC4)cc3)nn12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Into a 8-dram vial, N-[3-(2-Hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-pyridin-2-yl]-N-methyl-methanesulfonamide (56 mg, 0.18 mmol), N,N-Dimethylformamide (0.50 mL, 6.4 mmol), N,N-Diisopropylethylamine (0.0672 mL, 0.386 mmol) and N-Phenylbis(trifluoromethanesulphonimide) (2.77 g, 7.75 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. 2-[4-(4-Amino-phenyl)-piperidin-1-yl]-acetamide (90.0 mg, 0.386 mmol) was added. The reaction was heated at 110° C. for 3 hours. The solvent was removed under vacuum overnight The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were combined and neutralized via polymer bound sulfonic acid column with 2N NH3 in methanol. The filtrate was concentrated to afford 2-[4-(4-{7-[2-(Methanesulfonyl-methyl-amino)-pyridin-3-yl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-phenyl)-piperidin-1-yl]-acetamide as a yellow solid (50 mg, 50%). LCMS (E/I+) 535.16 (M+H). NMR 1H (DMSO-d6)-9.42 (s, 1H), 9.01 (s, 1H), 8.56-8.61 (m, 2H), 7.64-7.69 (m, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.19 (s, 1H), 7.07-7.14 (m, 2H), 6.98 (d, 2H, J=4.63 Hz), 3.13 (s, 3H), 3.00 (s, 3H), 2.84-2.96 (m, 4H), 2.32-2.44 (m, 1H), 2.08-2.19 (m, 2H), 1.64-176 (m, 4H).
Reaction SMILES: [C:1]1(=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[C:2]1=O.[NH2:15][C:16]1[C:21]([N+]([O-])=O)=[CH:20][C:19]([C:25]([F:28])([F:27])[F:26])=[CH:18][C:17]=1[N+:29]([O-])=O.[H][H]>[Pd].C(O)C>[F:26][C:25]([F:27])([F:28])[C:19]1[CH:18]=[C:17]2[C:16](=[CH:21][CH:20]=1)[N:15]=[C:2]1[C:3]3[CH:4]=[CH:5][CH:6]=[C:7]4[C:12]=3[C:11]([C:1]1=[N:29]2)=[CH:10][CH:9]=[CH:8]4
Reactant: Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Reactant: O=C1C(=O)c2cccc3cccc1c23
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1ccc2nc3c(nc2c1)-c1cccc2cccc-3c12
Yield: 50 %

Procedure:
Acenaphthenequinone, 9.1 g. (0.05m), and 10.3 g. (0.05m) of 4-amino-3-nitrobenzotrifluoride were hydrogenated at room temperature in 125 ml. of 2B ethanol with 2.5 g. of palladium-on-carbon (5 percent) at 50 psi. After 4 hours three equivalents of hydrogen were absorbed and the temperature rose to 40° C. The catalyst was filtered and the filtrate was diluted with 1.2 l. of ethanol. The reaction was completed by refluxing the ethanolic solution for about 1 hour. The precipitated product was collected to yield about 8 g. (50 percent yield) of 9-(trifluoromethyl)acenaphtho[1,2-b]quinoxaline, mp = 185°-186° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:22])=[C:5]([C:18](OC)=[O:19])[C:6]([C:14](OC)=[O:15])=[N:7]2.O.[NH2:24][NH2:25]>C(O)C>[Br:1][C:2]1[C:3]2[C:4]([OH:22])=[C:5]3[C:18](=[O:19])[NH:25][NH:24][C:14](=[O:15])[C:6]3=[N:7][C:8]=2[CH:9]=[C:10]([CH2:12][CH3:13])[CH:11]=1
Reactant: NN
Reactant: CCc1cc(Br)c2c(O)c(C(=O)OC)c(C(=O)OC)nc2c1
Solvent: O
Solvent: CCO
Product: CCc1cc(Br)c2c(O)c3c(=O)[nH][nH]c(=O)c3nc2c1

Procedure:
To a mixture of dimethyl 5-bromo-7-ethyl-4-hydroxyquinoline-2,3-dicarboxylate (1.0 g, 2.7 mM,) in ethanol (25 mL) was added hydrazine hydrate (0.68 g, 14 mM). The resulting mixture was concentrated at 30° C. using a rotary evaporator and the residue was diluted with another portion of ethanol (25 mL) and similarly concentrated at 30° C. The residue was suspended in ethanol and filtered to separate the title compound (0.82 g, 82%) as a light yellow solid. Recrystallization of a portion of this material from dimethylsulfoxide/ethanol provided an analytical sample of the title compound as a light yellow crystalline solid, mp 335°-340° C. (dec).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[OH-].[Na+].[CH2:17](Cl)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20]>CO>[F:14][C:2]([F:13])([F:1])[C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([S:10][CH2:17]/[CH:18]=[C:19](\[CH3:20])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[N:9][C:5]=2[CH:4]=1
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CSc1nc2cc(C(F)(F)F)ccc2[nH]1
Yield: 31 %

Procedure:
To a solution of 5-trifluoromethyl-2-mercaptobenzimidazole (1.09 g, 5 mmol) (Senn-Bilfingen, J., DE 3240298(1983)) in methanol (10 mL) was added 2N aqueous sodium hydroxide (6 mmol) and geranyl chloride (0.86 g, 5 mmol). The resultant solution was stirred for 48 hours at ambient temperature, evaporated in vacuo, dissolved in methylene chloride, washed with saturated sodium chloride, and dried over sodium sulfate. Evaporation of the solvent gave an oil which was flash chromatographed (5% MeOH (CH2Cl2) in Merck Kieselgel) and treated with charcoal. Evaporation of the solvent gave an off-white solid of the title compound (550 mg). m.p. 106°-108° C. NMR (CDCl3)δ7.83(m,1H), 7.57(m,2H), 5.43(d, J=7 Hz,1H), 5.2(m,1H), 4.03(d,J=7Hz,2H), 2.0(m,4H), 1.70(s,3H), 1.67(s,3H), 1.65(s,3H).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
Tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (3.10 mmol, 1 g) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum and purified by SCX chromatography to afford the title compound (600 mg). MS (ESI) m/z 223.3 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11]COC)=[CH:9][N:10]=1)[CH:6]=[O:7].Cl.[C:16]([O-])([O-])=[O:17].[K+].[K+].C1[CH2:26][O:25][CH2:24]C1>O>[OH:11][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH2:1][CH2:24][O:25][CH3:26])=[N:10][CH:9]=1.[OH:11][C:8]1[CH:9]=[N:10][C:3]([O:2][CH2:1][CH2:24][O:25][CH3:26])=[C:4]([CH:5]=1)[CH:16]=[O:17]
Reactant: C1CCOC1
Reactant: COCOc1cnc(OC)cc1C=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COCCOc1cc(C=O)c(O)cn1
Product: COCCOc1ncc(O)cc1C=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 60 %
Yield: 11 %

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (1.27 g, 5.29 mol) in THF (5 mL) was added HCl (3 N, 4 mL). The reaction was stirred at 50° C. for 1 h, cooled to rt, and diluted with water (5 mL). The mixture was neutralized to pH 7-8 with solid K2CO3 and the aqueous layer was extracted with EtOAc (100 mL) twice. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes to give 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (630 mg, 60%) and 5-hydroxy-2-(2-methoxyethoxy)nicotinaldehyde (120 mg, 11%). Data for 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde: 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 9.50 (s, 1H), 8.07 (s, 1H), 7.02 (s, 1H), 4.51-4.39 (m, 2H), 3.81-3.72 (m, 2H), 3.47 (s, 3H). LRMS (M+H+) m/z 198.1. Data for and 5-hydroxy-2-(2-methoxyethoxy)nicotinaldehyde: 1H NMR (400 MHz, CDCl3) δ 10.3 (s, 1H), 7.99 (d, J=3.2 Hz, 1H), 7.58 (d, J=3.2 Hz, 1H), 7.18-7.07 (br, 1H), 4.54 (dd, J=5.4, 3.7 Hz, 2H), 3.84 (dd, J=5.4, 3.7 Hz, 2H), 3.49 (s, 3H). LRMS (M+H+) m/z 198.1
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10]C(C#N)=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].O.[C:18]([OH:21])(=[O:20])[CH3:19]>>[CH:1]([C:4]1[CH:11]=[CH:10][C:19]([C:18]([OH:21])=[O:20])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)c1ccc(C#N)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Yield: 73 %

Procedure:
The product of Example 431B (1.746 g, 9.1798 mmol) dissolved in a 2:1:1 v/v/v mixture of water/acetic acid/concentrated sulfuric acid (24 mL) was heated at reflux for 3 days. The reaction was cooled, poured onto ice water (80 mL) and adjusted to pH12 with 6N aqueous sodium hydroxide. The reaction was washed with ethyl ether (3×50 mL). The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and extracted with ethyl ether (2×75 mL). The ethereal extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. The residue was co-concentrated with methylene chloride (5 mL)/hexanes (100 mL) three times and dried on high vacuum to afford the title compound as an off-white solid (1.402 g, 6.702 mmol, 73%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.23 (d, J=6.62 Hz, 6 H) 2.88-3.23 (m, 1 H) 7.66 (dd, J=8.09, 1.84 Hz, 1 H) 7.80 (d, J=7.72 Hz, 1 H) 7.83 (d, J=1.47 Hz, 1 H) 13.70 (br s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[OH:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:40]3[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][OH:34])[CH2:38][CH2:39]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCN(CCO)CC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and 1-(2-hydroxyethyl)piperazine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C26H38N7O5SF2 [(M+H)+] 598.2618, observed 598.2624.
Reaction SMILES: O[C:2]1([OH:20])[C:10](=[O:11])[C:9]2[C:4](=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19].[Se]=O.FC(F)(F)C(O)=O.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1)([CH3:32])[CH3:31]>O1CCOCC1.CC(O)=O>[OH:20][C:2]1([C:36]2[CH:37]=[CH:38][C:33]([CH:30]([CH3:32])[CH3:31])=[CH:34][C:35]=2[O:39][CH3:40])[C:10](=[O:11])[C:9]2[C:4](=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19]
Reactant: COc1cccc(C(C)C)c1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c2c1C(=O)C(O)(O)C2=O
Agent: O=[Se]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2c(NC(C)=O)ccc([N+](=O)[O-])c2C1=O
Reaction time: 12 h
Yield: 19.7 %

Procedure:
N-(2,2-dihydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (1.50 g, 6.4 mmol) was completely dissolved in anhydrous dioxane (15 ml). This solution was added with selenium oxide (1.56 g, 14.0 mmol) and AcOH (1.5 ml). The reaction mixture was heated for 12 hrs under reflux. After filtration at high temperature, the filtrate was concentrated to afford 1.79 g (100%). A trifluoroacetic acid solution of the resulting product was added with isopropyl-3-methoxy benzene (962 mg, 6.4 mmol) followed by stirring for 12 hours. The resulting product was extracted with ethyl acetate, and concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:1) to afford the title compound (0.52 g, 20%).
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(O)O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:29]=[N:30][C:31]([CH3:35])=[C:32](Br)[CH:33]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:33]=[C:32]([C:4]5[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=5)[C:7]([OH:9])=[O:8])[C:31]([CH3:35])=[N:30][CH:29]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1cccc(C(=O)O)c1

Procedure:
3-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-methylpyridin-3-yl)benzoic acid was prepared from 3-boronobenzoic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.