Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1([Br:15])[C:13](=[O:14])[N:4]2[C@@H:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C(N(CC)CC)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C>[Br:15][C:2]1([Br:1])[C:13](=[O:14])[N:4]2[CH:5]([C:10]([O:12][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:11])[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12
Reactant: BrCc1ccccc1
Reactant: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)[C@H]1C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)C1C(=O)OCc1ccccc1
Yield: 85 %

Procedure:
To a stirred solution of 1646 g. of 6,6-dibromo-2,2-dimethyl-(5R)penam-3α-carboxylic acid in 10.1 liters of N,N-dimethylacetamide was added 709 ml. of triethylamine during 10 minutes at ca. 0° C. The temperature was adjusted to 10° C., and 602 ml. of benzyl bromide was added during 4 minutes. To the reaction mixture was then added 941 g. of 4A molecular sieves, and then the reaction mixture was stirred overnight without external cooling. At this point, the reaction mixture was filtered and the filtrate was added to a mixture of 44 liters of ice-water and 14 liters of ethyl acetate. The pH of the aqueous phase was adjusted to 2.0 using 6 N hydrochloric acid, and the layers were separated. The aqueous layer was extracted with further ethyl acetate and the combined ethyl acetate solutions were washed sequentially with 14 liters of saturated, aqueous sodium bicarbonate and 14 liters of saturated, aqueous sodium chloride. The ethyl acetate solution was dried (Na2SO4), and then it was evaporated in vacuo at 25° C. The residue was dissolved in 5.5 liters of isopropyl alcohol at 60° C., and then the isopropyl alcohol solution was cooled slowly with stirring. The solid which precipitated was recovered by filtration, washed with cold isopropyl alcohol and then air dried. This afforded 1777 g. (85% yield) of the title product. The NMR spectrum (CDCl3) showed absorptions at 1.40 (s, 3H), 1.55 (s, 3H), 4.55 (s, 1H), 5.20 (s, 2H), 5.75 (s, 1H) and 7.35 (s, 5H) ppm.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:8][C:9]=1[Cl:10]>CO>[Br:1][CH:12]([CH3:13])[C:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)=[O:14]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(Cl)c(Cl)c1
Solvent: CO
Product: CC(Br)C(=O)c1ccc(Cl)c(Cl)c1
Yield: 95.9 %

Procedure:
51.1 g (0.320 mol) of bromine was added dropwise to a solution of 65.0 g (0.320 mol) of 3′,4′-dichloropropiophenone in 150 g of methanol at a reaction temperature of 58 to 60° C. After the addition was complete, the methanol was evaporated off from the reaction solution under reduced pressure. The resultant concentrate was dissolved in 130 g of toluene and then washed with water (150 ml×3 times). Thereafter, the toluene was evaporated off under reduced pressure, giving 86.6 g (0.307 mol) of crude brown oily 2-bromo-3′,4′-dichloropropiophenone.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][NH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]=3[CH2:25][CH2:26][CH3:27])=[O:19])[CH:12]=2)[C:7]=1[Br:34].[OH-].[Na+].O>CO>[Br:34][C:7]1[C:8]2[C:13](=[CH:12][C:11]([CH2:16][NH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:24]=3[CH2:25][CH2:26][CH3:27])=[O:19])=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[O:5][CH2:4][C:3]([OH:35])=[O:2]
Reactant: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCC(=O)OC)ccc3c2)cnn1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCC(=O)O)ccc3c2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.7 %

Procedure:
A mixture of (1-bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (0.20 g, 0.373 mmol), prepared in the previous step, 1N NaOH (373 μL, 0.373 mmol), 5 mL of water and 60 mL of methanol was stirred at room temperature for 20 h. Starting material was present by TLC. An additional 186 μL (0.186 mmol) of 1N NaOH was added and the reaction stirred at room temperature for 18 h. The reaction was filtered to remove trace solids and acidified with 1N HCl until pH 1 by litmus paper. The methanol was removed under reduced pressure. The solid formed was collected by filtration and dried under reduced pressure to give the title compound (0.13 g, 67%) as an off-white solid, mp 140-145° C.
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4].[Cl:17]CCl.S(Cl)(Cl)=O>CN(C)C=O>[Cl:17][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1O
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O

Procedure:
14.2 g of N-(1-hydroxy-2,2,2-trichloroethyl)-2-hydroxybenzamide was mixed with 100 ml of dichloromethane, 7.2 g of thionyl chloride and 0.1 g of N,N-dimethylformamide and the reaction was effected while stirring under reflux for three hours. The solvent was distilled off to obtain N-(1,2,2,2-tetrachloroethyl)-2-hydroxybenzamide (m.p.: 113°-113.5° C.). Without taking this out, 100 ml of dichloromethane and 3.8 g of iso-propyl mercaptan were added thereto and then 4.0 g of pyridine was also added dropwise. After effecting the reaction at room temperature for one hour, water was added thereto, the dichloromethane layer was separated out, dried and concentrated to obtain 16.2 g of N-(1-iso-propylthio-2,2,2-trichloroethyl)-2-hydroxybenzamide as white crystals.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]2[C:8]=1[NH:9][C:10](=[O:26])[N:11]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:1]([CH:3]([NH:6][C:7]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]2[C:8]=1[N:9]([CH3:27])[C:10](=[O:26])[N:11]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCC(CC)Nc1nc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc2c1n(C)c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by methylation of 6-(1-ethyl-propylamino)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one with lithium bis(trimethylsilyl)amide in THF, followed by quenching with methyl iodide. 1H NMR(CDCl3) d 6.98(s,2H), 4.45(d,1H), 4.3(m,1H), 3.7(s,3H), 2.4(s,3H), 2.3(s,3H), 2.1(s,6H), 1.5-1.8(m,4H), 1.0(t,6H), ppm.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:30][O:22][C:21](=[O:23])[CH2:20][O:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH:12]=1
Reactant: O=C(O)COCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)COCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 20 h

Procedure:
35 mg of 2-[2-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]acetic acid was dissolved in 0.4 ml of N,N-dimethylformamide and mixed with 29 mg of cesium carbonate and 50 μl of methyl iodide. It was stirred for 20 hours, then concentrated by evaporation in a vacuum and chromatographed on silica gel.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.CCN(C(C)C)C(C)C.[C:17]([O:21][C:22]([NH:24][C:25]1([CH:31]([OH:35])[C:32](O)=[O:33])[CH2:28][C:27]([F:30])([F:29])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:17]([O:21][C:22](=[O:23])[NH:24][C:25]1([CH:31]([OH:35])[C:32](=[O:33])[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[CH2:28][C:27]([F:29])([F:30])[CH2:26]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Cn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)NC1(C(O)C(=O)O)CC(F)(F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)C(O)C2(NC(=O)OC(C)(C)C)CC(F)(F)C2)n1
Reaction time: 2 h
Yield: 92 %

Procedure:
1-Methyl-1H-pyrazol-3-amine (158 mg, 1.63 mmol) and DIEA (1.08 mL, 6.52 mmol) was added to a solution of (1-tert-Butoxycarbonylamino-3,3-difluoro-cyclobutyl)-hydroxy-acetic acid (1.63 mmol) dissolved in DMF (20 mL). The solution was cooled to 0° C. and after 10 minutes HATU (620 mg, 1.63 mmol) was added. After approximately 2 hours at RT, LC-MS showed product and no starting material and the solvent was removed by rotary evaporation. The crude product was dissolved in 40 mL EtOAc and washed with 25 mL sat. NaHCO3 (aq). The organic phase was dried with Na2SO4, filtered and evaporated to dryness. The crude product was purified on a 25 g silica column on a Biotage Flashmaster, which gave the title product as a white solid (92%). TLC rf: 0.07 in heptane:ethyl acetate 1:1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[N:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])=[CH:18][CH:17]=2)[CH:15]=1.[CH2:30]([N:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:30]([N:37]1[CH2:38][CH:39]=[C:40]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)[CH2:41][CH2:42]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1(C)OB(C2=CCN(Cc3ccccc3)CC2)OC1(C)C
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Br)cc34)nn2)cc1)N1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(C5=CCN(Cc6ccccc6)CC5)cc34)nn2)cc1)N1CCOCC1
Temperature: 150 °C

Procedure:
A suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (100 mg; 0.22 mmol; 1.0 eq.), 1-Benzyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine; hydrochloride (J&W Pharm Lab, 222 mg; 0.66 mmol; 3.00 eq.), Pd2Cl2(PPh3)2(15 mg; 0.02 mmol; 0.1 eq.), potassium carbonate (91 mg; 0.66 mmol; 3.0 eq.) in dioxane (2 mL) and water (1 mL) was degassed with nitrogen flow and heated in MW at 150° C. for 10 min. The reaction mixture was filtered through a celite pad, water was added to the filtrate. Aqueous phase was extracted three times with DCM using separators tubes. Combined organic phases were concentrated under reduced pressure and the crude was purified by flash chromatography on silica (DCM/MeOH, gradient from 100:0 to 90:10) to give the title compound as yellow powder. 1H NMR (300 MHz, DMSO-d6) δ 13.37 (brs, 1H), 9.39 (s, 1H), 8.30 (s, 1H), 8.22-8.10 (m, 2H), 7.76-7.65 (m, 2H), 7.65-7.50 (m, 2H), 7.42-7.31 (m, 4H), 7.31-7.22 (m, 1H), 6.30-6.10 (m, 1H), 3.78-3.50 (m, 8H), 3.47-3.37 (m, 2H), 3.18-3.07 (m, 2H), 2.77-2.56 (m, 4H). HPLC (Condition A): Rt 2.87 min (purity 97.5%). MS (ESI+): 546.4, MS (ESI−): 544.3.
Reaction SMILES: [CH2:1]([C@@H:4]1[C@:12]([C:14]2[C:15]([F:21])=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=2)([CH3:13])[N:11]=[C:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:6]2([CH2:9][CH2:8][CH2:7]2)[S:5]1(=[O:31])=[O:30])[CH:2]=C.C(=O)(O)[O-:33].[Na+].[BH4-].[Na+]>C(Cl)Cl.CO>[Br:20][C:18]1[CH:19]=[C:14]([C@@:12]2([CH3:13])[N:11]=[C:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:6]3([CH2:9][CH2:8][CH2:7]3)[S:5](=[O:31])(=[O:30])[C@@H:4]2[CH2:1][CH2:2][OH:33])[C:15]([F:21])=[N:16][CH:17]=1
Reactant: O=C([O-])O
Reactant: C=CC[C@@H]1[C@@](C)(c2cc(Br)cnc2F)N=C(NC(=O)OC(C)(C)C)C2(CCC2)S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)[C@@H](CCO)S(=O)(=O)C12CCC2
Reaction time: 0.08 h
Yield: 101 %

Procedure:
To a solution of tert-butyl ((6R,7R)-6-allyl-7-(5-bromo-2-fluoropyridin-3-yl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (2.0 g, 3.87 mmol) in DCM (40 mL) and MeOH (10 mL) was added sodium bicarbonate (0.651 g, 7.75 mmol) and the resulting mixture was brought to −78° C. To this mixture was bubbled O3 for 15 min until the starting material was consumed. A stream of oxygen was passed through the solution for 5 min, then solid sodium borohydride (0.293 g, 7.75 mmol) was added to the mixture. The flask was removed from the bath and allowed to reach rt and stirred for 30 min. The mixture was carefully quenched with saturated NH4Cl, water was added and extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated to afford a white solid as tert-butyl ((6R,7R)-7-(5-bromo-2-fluoropyridin-3-yl)-6-(2-hydroxyethyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (2.035 g, 3.91 mmol, 101% yield). LC/MS (ESI+) m/z=541.8 (M+H).
Reaction SMILES: [OH-].[Na+].C([N:6]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Br:21])=[C:16]([CH3:22])[CH:15]=1)[CH2:7][CH2:8][O:9]C(=O)CBr)(=O)C>CCO.C(OCC)(=O)C>[Br:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([NH:6][CH2:7][CH2:8][OH:9])=[CH:15][C:16]=1[CH3:22]
Reactant: CC(=O)N(CCOC(=O)CBr)c1cc(C)c(Br)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(NCCO)cc(C)c1Br
Temperature: 25 °C
Yield: 100.2 %

Procedure:
6 N NaOH (1.5 ml) was added to a solution of bromo-acetic acid 2-[acetyl-(4-bromo-3,5-dimethyl-phenyl)-amino]-ethyl ester (302 mg, 0.74 mmol) in EtOH (6 ml). The reaction solution was heated under reflux overnight, cooled to room temperature and then diluted with ethyl acetate. The organic phase was sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-(4-bromo-3,5-dimethyl-phenylamino)-ethanol (181 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])O[CH:14]=2)=[CH:5][CH:4]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[N:21]([OH:22])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(COc2cn(O)c(CO)cc2=O)cc1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 39.3 g 5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyrone in 600 ml pyridine, was added 52.2 g hydroxylamine hydrochloride, and the mixture was heated at 70°-75° C. for 2.5 hours. The reaction mixture was concentrated to about 100 ml, 100 ml water was added to the concentrate, and the resulting solution was added under ice cooling to a mixture of 75 ml hydrochloric acid and 225 ml water. After adjusting the pH to 2-2.5, stirring was continued under ice cooling for 30 minutes, and the crystals which separated out were collected by filtration, washed with water and dried, giving 16.6 g of 5-p-methoxybenzyloxy-1-hydroxy-2-hydroxymethyl-4-pyridone.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:28])[N:26]=1
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.30 min; [M+H]+=491.0.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.O.[NH2:31][NH2:32]>CN(C=O)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:32][N:31]=2)=[CH:26][CH:25]=1
Reactant: NN
Reactant: COc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 88.5 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (50 mg, 0.13 mmol, prepared in Synthetic Example 15) in DMF (1 ml) was added hydrazine monohydrate (80%, 1 ml, 24.96 mmol, 192 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (44 mg, 89%).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=O)[CH2:8][CH2:7]1)=O)C.[CH2:23]([O:25]C(N1CCC(C(C(OCC)=O)N)(C2C=CC=CC=2C)CC1)=O)C.C(O)(=O)CO.N>Cl>[OH:25][CH2:23][C:13]1[N:12]([CH:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)[C:16]2[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=1
Reactant: CCOC(=O)C(N)C1(c2ccccc2C)CCN(C(=O)OCC)CC1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cccc(C)c32)CC1
Agent: Cl
Agent: N
Agent: O=C(O)CO
Product: Cc1cccc2nc(CO)n(C3CCNCC3)c12
Temperature: 100 °C
Reaction time: 72 h
Yield: 41 %

Procedure:
The 1-Ethoxycarbonyl-4-(1,3-dihydro-7-methyl-2H-benzimidazol-2-on-1-yl)piperidine (40 mg) obtained in Reference Example 11, (d) was dissolved in 5 N aqueous hydrochloric acid (0.8 ml), added with glycolic acid (16 mg) and stirred at 100° C. for 3 days. The reaction mixture was made alkaline by addition of aqueous ammonia and extracted twice with dichloromethane (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 14.4 mg of the title compound. Yield: 41%.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([C:22]([O:24][CH3:25])=[O:23])[CH3:21])=[N:15][CH:16]=[N:17][CH:18]=1.[ClH:44]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH:20]([C:22]([O:24][CH3:25])=[O:23])[CH3:21])=[N:15][CH:16]=[N:17][CH:18]=1
Reactant: Cl
Reactant: COC(=O)C(C)Oc1ncncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)C(C)Oc1ncncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
Isoamyl nitrite is added to a mixture of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine, copper(I) chloride, copper(II) chloride and acetonitrile dropwise at room temperature, and the mixture is stirred for 1 hour. This reaction solution is poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine [present compound 4-2].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:9][CH:8]=1)=[O:6])[CH3:2].[CH:22](OCC)(OCC)OCC>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[N:20]=[CH:22]2)=[CH:11][CH:12]=1)=[O:6])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(=O)c1ccc(Nc2ncccc2N)cc1
Product: CCOC(=O)C(=O)c1ccc(-n2cnc3cccnc32)cc1

Procedure:
A solution of [4-(3-amino-pyridin-2-ylamino)-phenyl]oxo-acetic acid ethyl ester (195 mg, 0.547 mmol) in triethyl orthoformate (5 mL) is heated at 144° C. for 5 h. The reaction mixture is left in the fridge over night and then refluxed for additional 5 h. The solvent is removed and the product is purified by reverse phase MPLC with ACN/water to afford (4-imidazo[4,5-b]pyridine-3-yl-phenyl)-oxo-acetic acid ethyl ester. ES-MS: 296.10 [M+H]+; tR=1.4 min (System 2).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7])=O.Cl.[NH2:19]O>C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7])#[N:19]
Reactant: NO
Reactant: COc1c(C=O)cc(C(=O)O)cc1C(F)(F)F
Agent: Cl
Solvent: O=CO
Product: COc1c(C#N)cc(C(=O)O)cc1C(F)(F)F
Yield: 27.2 %

Procedure:
3-formyl-4-methoxy-5-trifluoromethylbenzoic acid (58.04 g) was dissolved in formic acid (290 mL), and hydroxylamine hydrochloride (17.07 g) was added to the solution, and the mixture was refluxed for 19 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (15.62 g) as a brown solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=3)[CH2:4]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(C)cc1)C2
Reaction time: 20 h

Procedure:
6.0 g (21.1 mmol) of methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate hydrochloride are suspended in 60 ml of chloroform and 5.0 g (25.3 mmol) of p-toluenesulphonyl chloride are added. 5.1 g (50 mmol) of triethylamine are added, with vigorous stirring, a clear solution being formed. After 20 hours at room temperature, the mixture is washed with water, the chloroform solution is evaporated and the residue is recrystallised from methanol.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([C:15]([N+:18]([O-:20])=[O:19])=[N:16][OH:17])[CH2:12][N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:9]=2[CH:28]=1>CCOCC.O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([C:15]([N+:18]([O-:20])=[O:19])=[N:16][O:17][CH3:3])[CH2:12][N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:9]=2[CH:28]=1
Reactant: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CON=C(C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of diazomethane in ether was added to a suspension of 6 g (0.0163 mole) of 7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine in 100 ml of tetrahydrofuran. After sitting at room temperature for 1 hr the excess diazomethane was destroyed by addition of glacial acetic acid. The solvent was evaporated under reduced pressure and the residue was passed over 100 g of silica gel using methylene chloride. Crystallization from ether/hexane gave light yellow crystals with mp 130°-133° C.