Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:7][C:6](/[CH:8]=[N:9]/[O:10][CH3:11])=[N:5][NH:4][C:3]1=[O:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>CCO.Cl>[CH3:11][O:10]/[N:9]=[CH:8]/[C:6]1[CH2:7][N:2](/[N:1]=[CH:19]/[C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[C:3](=[O:12])[NH:4][N:5]=1
Reactant: O=Cc1cccnc1
Reactant: CO/N=C/C1=NNC(=O)N(N)C1
Agent: Cl
Solvent: CCO
Product: CO/N=C/C1=NNC(=O)N(/N=C/c2cccnc2)C1
Temperature: 60 °C

Procedure:
To a solution of 4-amino-6-[(E)-methoxyiminomethyl]-2,5-dihydro-1,2,4-triazin-3-one (2.57 g, 15.0 mmol) in EtOH was added pyridine-3-carbaldehyde (1.41 mL, 15.0 mmol), followed by addition of 1 drop conc. HCl. The mixture was heated to 60° C. for 3 h and then allowed to cool to room temperature. After addition of silica gel, the reaction mixture was evaporated and purified by flash chromatography (5% MeOH/CH2Cl2) to give compound I-001 as a white solid. LCMS (Method H) RT 0.97 min. [M+H]+ 261. M.p. 237-238° C.
Reaction SMILES: [OH:1][NH:2][N:3]=[CH:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13](=[O:34])[C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:33])[C@@H:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:7][CH2:6]1.[CH3:35]O[NH3+].[Cl-]>CN1CCCC1=O.CCOCC>[CH3:35][O:1][NH:2][N:3]=[CH:4][N:5]1[CH2:6][CH2:7][CH:8]([CH2:11][NH:12][C:13](=[O:34])[C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:33])[C@@H:20]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:9][CH2:10]1
Reactant: CO[NH3+]
Reactant: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC1CCN(C=NNO)CC1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CONN=CN1CCC(CNC(=O)[C@@H]2CCCN2C(=O)[C@@H](Cc2ccccc2)NS(C)(=O)=O)CC1
Temperature: 130 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a stirred solution of Example 3 Part D aminonitrile (0.34 g, 0.74 mmol) in 3.0 mL of 1-methyl-2-pyrrolidinone was added methoxyamine.HCl (0.18 g, 216 mmol). This reaction solution was immersed into a 85° C. oil bath. The bath temperature was slowly raised up no 130° C. in 80 min. The reaction solution was stirred at 130° C. for 2 h and cooled to room temperature. The solution was diluted with 30 mL of ether and the solution was decanted. The remaining oily residue was purified by preparative HPLC to give 250 mg (51%) of title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]3[CH2:13][CH2:12][CH2:11][C:8]=3[C:9](=[O:10])[N:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:1]3[C:5]4=[N:6][C:7]5[CH2:13][CH2:12][CH2:11][C:8]=5[C:9](=[O:10])[N:4]4[CH:3]=[CH:2]3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: O=c1c2c(nc3[nH]ccn13)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccn3c(=O)c4c(nc23)CCC4)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,6,7,8-tetrahydro-5H-cyclopent[d]imidazo[1,2-a]pyrimidin-5-one (0.345 g, 1.967 mmol) and 4-(4-chlorobenzoyl)benzyl bromide (0.0650 g, 2.10 mmol) in DMF (15.0 ml)-DMSO (5 ml) was added potassium carbonate (0.30 g, 2.17 mmol) and the mixture was stirred at room temperature overnight. The solvent was then distilled off and the residue was purified by preparative TLC (methylene chloride: methanol=20:1) to provide a colorless amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6](OS(C(F)(F)F)(=O)=O)[C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2]
Reactant: COc1ccc2ccc(C#N)cc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2ccc(C#N)cc2c1-c1ccccc1
Temperature: 100 °C
Yield: 101.1 %

Procedure:
Under nitrogen atmosphere, 1.2 g of 2-cyano-7-methoxy-8-trifluoromethanesulfonyloxynaphthalene, 0.66 g of phenylboronic acid, 0.12 g of tetrakis triphenylphosphine palladium and 1.5 ml of triethyl- amine were suspended in 20 ml of anhydrous N, N-dimethylformamide. The resulting suspension was stirred under heating at 100° C. for 1.5 hours and cooled to room temperature by allowing to stand. A saturated aqueous solution of ammonium chloride was added to the resulting reaction mixture, followed by the extraction with ethyl acetate (50 ml×2). The organic layers were combined, washed with brine, died over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography to give 0.95 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13](C)[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1C=C2N(C3C=CC=CC=3Cl)CC3(CCN(C)CC3)C2=CC=1.Cl[C:56]([O:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:57].CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([C:56]([O:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)=[O:57])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Oc1ccccc1)N1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.8 g of 6-chloro-1-(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine], free base of Example 28, and 0.5 g of phenyl chloroformate in 20 ml of methylene chloride is stirred at ambient temperature for 16 hours. Thereafter, the mixture is successively washed with 10% sodium hydroxide, washed with water, dried and concentrated under vacuum leaving a brownish oil. The oil is passed through an alumina column, ether eluant, providing a colorless gum of 6-chloro-1-(2-chlorophenyl)-1'-phenoxycarbonylspiro[indoline-3,4'-piperidine]. IR and NMR spectra confirm the assigned structure.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][N:24]1[CH2:27][CH:26]([NH2:28])[CH2:25]1>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:28][CH:26]2[CH2:27][N:24]([CH3:23])[CH2:25]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CN1CC(N)C1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CN(C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared similarly to that described in Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 75 mg, 0.135 mmol), 1-methylazetidin-3-amine (87 mg, 0.405 mmol), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high-throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(2-methyl-3-((1-methyl-3-azetidinyl)amino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (MeOH-d4) δ: 7.80-7.85 (m, 1H), 7.63-7.68 (m, 1H), 7.36-7.42 (m, 1H), 6.93 (s, 1H), 3.59-3.65 (m, 2H), 3.22-3.26 (m, 2H), 3.11-3.14 (m, 1H), 2.97-3.04 (m, 2H), 2.59 (s, 3H), 2.01 (s, 3H). m/z (ESI, +ve) 363.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Na].[CH3:23][OH:24]>O>[CH3:23][O:24][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nn2)CC1
Agent: [Na]
Solvent: O
Product: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)nn1
Temperature: 120 °C
Yield: 75 %

Procedure:
tert-Butyl [1-(6-chloropyridazin-3-yl)piperidin-4-yl]carbamate (0.50 g, 1.60 mmol) was dissolved in dry MeOH (15 ml) and sodium metal (0.073 g, 3.20 mmol) dissolved in MeOH (5 ml) was added. The reaction mixture was heated at in a microwave reactor at 120° C. for 4 h. The mixture was diluted with water (500 ml) and extracted with EtOAc (200 ml). The organic phase was dried (Na2SO4), filtered and evaporated to yield the title compound (0.37 g, 75%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:20])[CH2:18]C)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:21]1[C:22]2[S:35][CH:34]=[CH:33][C:23]=2[N:24](C(OC(C)(C)C)=O)[N:25]=1)=O)(C)(C)C.C[Mg]Br.O1CC[CH2:41][CH2:40]1>>[NH:24]1[C:23]2[CH:33]=[CH:34][S:35][C:22]=2[C:21]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([C:17]([OH:20])([CH2:40][CH3:41])[CH3:18])=[CH:14][CH:15]=3)=[N:25]1
Reactant: C1CCOC1
Reactant: CCC(=O)c1ccc2c(c1)cc(-c1nn(C(=O)OC(C)(C)C)c3ccsc13)n2C(=O)OC(C)(C)C
Agent: C[Mg]Br
Product: CCC(C)(O)c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-propionyl-indole-1-carboxylic acid tert-butyl ester [450 mg, 0.908 mmol, Intermediate (15)] in anhydrous tetrahydrofuran (25 mL) that is cooled to −78° C. is added methylmagnesium bromide (1M in tetrahydrofuran, 3 mL) via syringe under nitrogen. After stirring for 30 minutes cooling bath is removed and brought the reaction to room temperature. The reaction is cooled to −78° C. then additional 5 mL of methyl magnesium bromide is added. After 30 minutes, the cooling bath is removed and reaction temperature is brought to room temperature. After 4 hours, it is quenched by the addition of saturated ammonium chloride (6 mL). After stirring for 10 minutes, water (20 mL) is added and extracted three times with ethyl acetate (40 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate. Purification by chromatography (35 g silica gel cartridge, 1:1 ethyl acetate /heptane) afforded 2-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-butan-2-ol [148 mg, 52%, Example 32 ] as a white solid; 1H NMR [(CD3)2SO)]: δ 13.204 (1H, s), 11.402 (1H, s), 7.743 (1H, d), 7.595 (1H, s), 7.333-7.192 (3H, m), 6.598 (1H, s), 4.658 (1H, s, OH), 1.728 (2H, q), 1.461 (3H, s), 0.702 (3H, t); LC/MS: 312 (M+H).
Reaction SMILES: C([C:3]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:5]=[CH:6][N:7](C)[CH3:8])#N.[ClH:16].O.[OH-].[Na+]>C(O)(C)C>[Cl:16][N:7]1[CH:6]=[CH:5][CH:4]=[C:3]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH2:8]1
Reactant: Cl
Reactant: CC(C)S(=O)(=O)C(C#N)=CC=CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)S(=O)(=O)C1=CC=CN(Cl)C1
Reaction time: 20 h
Yield: 51.5 %

Procedure:
The 1-cyano-1-isopropylsulphonyl-4-dimethylamino-1,3-butadiene (34 g, 0.15 mol) obtained in (a) above was dissolved in isopropanol (350 ml). The solution was then heated to reflux and saturated with dry hydrogen chloride. After about 20 hours, the solution was cooled and poured into water and crushed ice. This solution was then neutralised with sodium hydroxide solution and extracted with toluene (5×100 ml). The combined extracts were then evaporated and the remaining brown syrup purified over silica using 1:1 toluene:ethyl acetate as eluant to leave an oil which yielded 7 g 1-chloro-3-isopropylsulphonylpyridine as yellow crystals, m.pt. 82°-84° C., after stirring with petroleum ether. Yield: 51.5% of the theoretical.
Reaction SMILES: O[N:2]=[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)[CH2:21][CH2:20]2)=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6](O)=[O:7].[H][H]>[Ni].CO>[CH3:31][C:27]1[CH:26]=[C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][C:12]3[CH:11]=[CH:10][C:9]([CH:3]4[NH:2][C:6](=[O:7])[CH2:5][CH2:4]4)=[CH:14][CH:13]=3)[CH2:24][CH2:23]2)[CH:30]=[CH:29][CH:28]=1
Reactant: [H][H]
Reactant: Cc1cccc(N2CCN(CCCCc3ccc(C(CCC(=O)O)=NO)cc3)CC2)c1
Agent: [Ni]
Solvent: CO
Product: Cc1cccc(N2CCN(CCCCc3ccc(C4CCC(=O)N4)cc3)CC2)c1
Yield: 71.4 %

Procedure:
To 9.7 g of 4-hydroxyimino-4-[4-(4-(4-(3-methylphenyl)piperazin-1-yl)butyl)phenyl]butyric acid and 5 g of Raney nickel, 300 ml of methanol is added, and stirred for 9 hours in 70 atm hydrogen gas at 120° C. in an autoclave. After the completion of the reaction, the catalyst is removed by filtration, and the solvent is distilled off under reduced pressure. The resulting oily substance is purified by silica gel column chromatography and recrystallized from ethyl acetate to give 6.4 g of 5-[4-(4-(4-(3-methylphenyl)piperazin-1-yl)butyl)phenyl]pyrrolidin-2-one having a melting point of 114° to 116° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.C([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)(=O)C.[OH-].[Na+].O>C(O)C>[OH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Reactant: CC(=O)OCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc2nc(SCCCCCO)[nH]c2c1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
2.46 g of 5-methyl-2-mercaptobenzimidazole and 3.4 g of 5-bromopentyl acetate were dissolved in 30 ml of ethanol and the mixture was refluxed with stirring under heating for 7 hours. After cooling to room temperature, the reaction mixture was added with was 22.5 ml of 2 N sodium hydroxide solution and stirred at room temperature for 1 hour, and then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=95:5) to obtain 3.04 g of the title compound as pale yellow oil (yield: 81%).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[C:18]([CH:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:22](OCC)=[O:23])(=O)[CH3:19].P(Cl)(Cl)(Cl)=O>>[OH:10][C:9]1[CH:11]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:6]=[C:7]2[C:8]=1[C:18]([CH3:19])=[C:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:22](=[O:23])[O:12]2
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCC(C)C(C)c1cc(O)c2c(C)c(CCC(=O)OCC)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 288 h

Procedure:
A mixture of 262 g. (1.109 mole) of 5-(3-methyl-2-octyl)resorcinol, 283 g. (1.23 mole) of diethyl α-acetylglutarate, and 170 g. (1.11 mole) of phosphorus oxychloride protected from atmospheric moisture is stirred at room temperature for 12 days. The mixture is taken up in benzene-ether and the solution is washed several times with water, aqueous sodium bicarbonate, water and dried over anhydrous magnesium sulfate. After removal of the solvent, 441 g. of an oil is obtained, which solidifies on standing.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:30])[CH:14]([NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([Cl:28])[CH:22]=1)[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][CH:14]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:13]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:30])=[O:29])=[CH:22][C:23]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)C(NC(=O)c1ccc(N)c(Cl)c1)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
To a solution of 4 (15.9 g, 36.3 mmol) in CH2Cl2 (30 mL) was added TFA (trifluoroacetic acetic acid) (30 mL) and the solution stirred at room temperature for 3 hours under N2. The reaction was transferred to a beaker (1 L) and diluted with CH2Cl2 (60 mL). To the solution at 0° C. was added solid NaHCO3 (39 g, 46 mmol) and stirred for 15 minutes'before partitioning between EtOAc (300 mL) and H2O (300 mL). After extraction the aqueous layer was acidified to pH 4-5 and extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated to dryness to give 5 as a white solid (14.0 g, quantitative yield): 1H-NMR (500 MHz, CDCl3) δ1.08 (s, 9H), 1.97-2.22 (m, 3H), 2.29-2.41 (m, 1H), 3.71-3.78 (m, 1H), 3.90-3.98 (m, 1H), 4.55-4.62 (m, 1H), 4.86 (d, 1H), 6.64 (d, 1H), 6.74 (d, 1H), 7.53 (d, 1H), 7.74 (s, 1H). Analytical HPLC (cyano column): 8.24 min. LC-MS (ES+) m/e=382.4 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[CH2:12][C:13]1[C:14](=[O:43])[NH:15][C:16](=[O:42])[N:17]([CH2:19][O:20][CH:21]([CH2:32][O:33]C(=O)C2C=CC=CC=2)[CH2:22][O:23]C(=O)C2C=CC=CC=2)[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[CH2:12][C:13]1[C:14](=[O:43])[NH:15][C:16](=[O:42])[N:17]([CH2:19][O:20][CH:21]([CH2:32][OH:33])[CH2:22][OH:23])[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCC(COC(=O)c1ccccc1)OCn1cc(Cc2cccc(OCc3ccccc3)c2)c(=O)[nH]c1=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1[nH]c(=O)n(COC(CO)CO)cc1Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 1.0 g of 3b prepared as above in 35 ml of EtOH there was added 33 ml of 2N NaOH and the reaction mixture stirred overnight at room temperature. The solution was neutralized with HCl or alternatively with Dowex 50 (H+), filtered, and the resin washed thoroughly with aqueous alcohol. After evaporation of the combined filtrates, the residue was passed through a silica gel column and the product eluted with methylene chloride-methanol (15:1) to yield 0.45 g of 4b. It was recrystallized with some difficulty from methylene chloride, M.p. 113° C. UV(pH 1): λ max 266 nm (10,600); (pH 11): λ max 267 nm (7700). NMR(CHCl3): δ 3.53-3.69 (m, 7H, CH2 at C5, CH2OH and tert. H overlap), 5.02 (s, 2H, CH2 of OBzl), 5.20 (s, 2H, CH2 at N1 ), 6.80-7.44 (m, 10H, ArH and C6 -H overlap).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[NH:8][NH:9][C:10](=[O:12])[CH:11]=2)=[CH:3][CH:2]=1.[Mg].[CH3:20]I.Cl>C1COCC1>[C:1]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH3:20])[CH2:11][C:10](=[O:12])[NH:9][NH:8]2)=[CH:3][CH:2]=1
Reactant: O=c1cc(-c2ccc(-c3ccccc3)cc2)[nH][nH]1
Reactant: CI
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(c2ccc(-c3ccccc3)cc2)CC(=O)NN1

Procedure:
A solution of 23.6 g of 3-(4-biphenylyl)-pyrazolin-5-one [obtainable from 3-(4-biphenylyl)-3-oxopropionic acid ethyl ester and hydrazine] in 400 ml of THF is added dropwise, while stirring and cooling, to a Grignard solution prepared from 4.8 g of magnesium and 28.4 g of methyl iodide in 800 ml of absolute THF. After stirring for 2 hours at 10°-25°, the mixture is decomposed with ice and dilute hydrochloric acid and worked up in the usual manner to give 3-(4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 191°-192°.
Reaction SMILES: [H-].[Na+].Br.Cl[C:5]1[C:6]2[CH2:17][CH2:16][CH2:15][C:7]=2[C:8]2[N:9]([C:11]([NH2:14])=[N:12][N:13]=2)[N:10]=1.[CH3:18][CH2:19][CH:20]([OH:23])[CH2:21][CH3:22]>CN(C=O)C>[CH2:19]([CH:20]([O:23][C:5]1[C:6]2[CH2:17][CH2:16][CH2:15][C:7]=2[C:8]2[N:9]([C:11]([NH2:14])=[N:12][N:13]=2)[N:10]=1)[CH2:21][CH3:22])[CH3:18]
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCC3
Reactant: CCC(O)CC
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn2c(N)nnc2c2c1CCC2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Pentanol (20 ml) was initially charged under argon, admixed with sodium hydride (991 mg) and stirred at 50° C. for 1 h. Subsequently, 6-chloro-8,9-dihydro-7H-cyclopenta[d][1,2,4]-triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.017, 2.0 g), dissolved in 3-pentanol (20 ml) and DMF (100 ml), was slowly added dropwise within 1 h. After stirring for 1 h, the mixture was concentrated, and the residue was admixed with water and extracted four times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using a 40 g silica gel cartridge (dichloromethane-methanol gradient 0-10% in 50 min). The clean product fractions were combined and dried. 1.04 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])=[CH:14][C:13]1=[O:29])[C:5]([O:7][CH3:8])=[O:6].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:30][C:14]1[C:13](=[O:29])[N:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[Cl:1])[C:17]([CH3:18])=[CH:16][C:15]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
Methyl 3-chloro-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (from step 2) (2.60 g, 6.21 mmol) was taken up in CH2Cl2 (20 ml). N-bromosuccinimide (1.11 g, 6.21 mmol) was added and the mixture stirred at room temperature for 4 hours. The CH2Cl2 is removed in vacuo and the residue is taken up in CH3CN. The resulting precipitate is collected on a filter pad and washed with CH3CN to yield a white solid (0.75 g, 24%). 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J=1.88 Hz, 1H), 8.06 (dd, J=8.19, 1.75 Hz, 13H), 7.59 (app q, J=8.46 Hz, 1H), 7.33 (d, J=8.19, 1H), 6.96 (dt, J=8.06, 1.21 Hz, 1H), 6.89-6.84 (m, 1H), 6.13 (s, 1H), 5.26 (s, 2H), 3.95 (s, 3H), 1.95 (s, 3H). ES-HRMS m/z 497.9892 (M+H calcd for C22H16BrClF2NO4 requires 497.9914).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:25]1([CH3:33])[CH:30]=[CH:29][CH:28]=[C:27]([Mg]Br)[CH:26]=1>O1CCCC1>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([C:5]([C:27]2[CH:26]=[C:25]([CH3:33])[CH:30]=[CH:29][CH:28]=2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc([Mg]Br)c1
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2cccc(Cl)c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloro-2-nitrobenzoic acid (2.5 g, 12.40 mmol) in tetrahydrofuran (50 mL) was treated with oxalyl chloride (1.194 mL, 13.64 mmol) followed by DMF (0.096 mL, 1.240 mmol). The reaction mixture was stirred at room temperature for 2 hrs. After cooling to 0° C., a 1M solution of m-tolylmagnesium bromide (24.81 mL, 24.81 mmol) was added. After 1 hr another portion of m-tolylmagnesium bromide (24.81 mL, 24.81 mmol) was added. After 1 hour, the reaction mixture was partitioned between ethyl acetate (200 mL) and 1N HCl (150 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=ethyl acetate/heptane, REDISEP® SiO2 120 g) to provided Intermediate A-18A (0.700 g, 21%). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, J=8.1, 1.1 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.71 (dd, J=7.7, 1.1 Hz, 1H), 7.66-7.54 (m, 3H), 7.52-7.46 (m, 1H), 2.40 (s, 3H).