Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[CH:5]=1.Cl.[N:17]1([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([N:17]2[CH2:18][CH2:19][N:20]([CH2:2][CH2:3][C:4]3[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[CH:5]=3)[CH2:21][CH2:22]2)=[N:24]1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: CC(=O)Nc1cc(C)c(CCCl)cc1C
Agent: Cl
Product: CC(=O)Nc1cc(C)c(CCN2CCN(c3n[nH]c4ccccc34)CC2)cc1C

Procedure:
N-[4-(2-Chloro-ethyl)-2,5-dimethyl-phenyl]-acetamide (0.142 g, 0.631 mmol) was reacted with 3-piperazin-1-yl-1H-indazole hydrochloride (0.226 g, 0.946 mmol) according to the method outlined in Example 501.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1c(-c2ccc(Cl)cc2)cnn(Cc2ccccc2)c1=O
Temperature: 90 °C
Yield: 83 %

Procedure:
To a solution of 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (20 g, 80 mmol) and 4-chlorophenylboronic acid (15.6 g, 100 mmol) in toluene/EtOH (2:1, 600 mL) at RT under argon was added (Ph3P)4Pd (1.85 g, 1.8 mmol) and 2 M aqueous Na2CO3 solution (160 mL, 320 mmol). The resulting suspension was heated at 90° C. for 16 h with stirring. HPLC/MS indicated about 4% of the 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one still remained. After cooling the reaction mixture to RT, the solution was extracted with CH2Cl2 (2×150 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes/EtOAc to obtain pure title compound, 2-Benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one, (21.7 g, 83%) as a white solid. MS [M+H]+ 327; HPLC retention time=3.85 min.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([O:16]COC)=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[C:12]([O:24]COC)[C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]C)=[O:43])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>>[C:8]([O:7][C:5]([C:4]1[C:12]([OH:24])=[C:13]([C:20]([F:22])([F:23])[F:21])[CH:14]=[C:15]([OH:16])[C:3]=1[CH2:2][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=2)=[CH:33][CH:34]=1)=[O:6])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: COCOc1cc(C(F)(F)F)c(OCOC)c(C(=O)OC(C)(C)C)c1CBr
Product: CC(C)(C)OC(=O)c1c(O)c(C(F)(F)F)cc(O)c1COc1ccc(-c2ccc(CC(=O)O)cc2)cc1
Yield: 17 %

Procedure:
According to a method similar to Example (40-2), Example (8-3) and Example (17-4), from tert-butyl 2-(bromomethyl)-3,6-bis(methoxymethoxy)-5-(trifluoromethyl)benzoate (154 mg, 0.34 mmol) obtained in Example (87-1) and methyl (4′-hydroxy-1,1′-biphenyl-4-yl)acetate (80 mg, 0.33 mmol) obtained in Example (6-2), the title compound was obtained (25 mg, three-step total yield: 17%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[C:11]([Cl:21])[CH:10]=2)[C:3]=1[CH:22]=O.Cl.[OH:25][NH2:26]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[C:11]([Cl:21])[CH:10]=2)[C:3]=1[CH:22]=[N:26][OH:25]
Reactant: CCNC(=O)Nc1ccc(Oc2ncnc(N)c2C=O)cc1Cl
Reactant: NO
Agent: Cl
Product: CCNC(=O)Nc1ccc(Oc2ncnc(N)c2C=NO)cc1Cl

Procedure:
Using the procedure for Example 1, 1-[4-(6-amino-5-formyl-pyrimidin-4-yloxy)-2-chloro-phenyl]-3-ethyl-urea Compound 26b was reacted with hydroxy-amine hydrochloride to provide 1-{4-[6-amino-5-(hydroxyimino-methyl)-pyrimidin-4-yloxy]-2-chloro-phenyl}-3-ethyl-urea Compound 27a.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:21]=O>>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][N:11]([CH3:21])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)CNCC2c1ccc(Cl)cc1
Reactant: C=O
Agent: Cl
Product: COc1ccc2c(c1)CN(C)CC2c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The free base isolated from 1.55 g. of rac.- 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride is shaken with 1.1 ml. of a 35% formaldehyde solution and the mixture is allowed to stand at room temperature for 2 hours. It is hydrogenated over 1 g. of Raney nickel, filtered from the catalyst, the filtrate is evaporated and the residue is crystallized with ethanolic hydrogen chloride, methanol and ether. Recrystallization from methanol-ether gives rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride, m.p. 244°-146°.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20].[OH-].[Na+].CO>O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:12]([N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21]
Reactant: COC(=O)CCCCCCCN(C(=O)c1ccc(Cl)cc1Cl)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(N(CCCCCCCC(=O)O)C(=O)c2ccc(Cl)cc2Cl)cc1

Procedure:
As described in example 1(b), the reaction is carried out with 35 g (77 mmol), of 8-[2.4-dichloro-N-(4-methoxyphenyl)-benzamido]-caprylic acid methyl ester, 4 g (0.1 mol) of sodium hydroxide, 150 cc. of methanol and 5 cc. of water. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is further purified chromatographically on silicic acid gel using a mixture of n-hexane and ethyl acetate (2:1) as eluant.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39]>>[Cl:33][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH:30]([CH3:32])[CH3:31])[C:22]([NH:21][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][C:38](=[O:39])[CH2:37][N:36]([CH3:41])[CH3:35])=[O:34]
Reactant: Cc1cccn2cc(-c3ccc(C[C@@H](CN)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12
Reactant: CN(C)CC(=O)O
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CNC(=O)CN(C)C)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12

Procedure:
Following the procedure described above with N-((1S)-2-amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide and N,N-dimethylglycine provided the title product as a white solid. ESMS [M+H]+: 563.2.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[CH:7]([CH:8]=1)[C:6](=[CH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2.N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:34]([CH3:37])([O-:36])=[O:35]>>[CH3:1][C:2]1[CH2:3][CH:4]2[CH:7]([CH:8]=1)[C:6]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH2:37][N+:34]([O-:36])=[O:35])[CH2:5]2
Reactant: CC1=CC2C(=CC(=O)OC(C)(C)C)CC2C1
Reactant: C[N+](=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CC1=CC2C(C1)CC2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 6 h

Procedure:
Tert-butyl 3-methylbicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.21 g, 5.50 mmol) was dissolved in nitromethane (7 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 mL, 6.0 mmol) was added, and the mixture was heated with stirring at 50 to 60° C. for 6 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (1.14 g, 74%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C([BH3-])#N.[Na+]>ClC(Cl)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(C=O)ccc3c2)CC1
Reactant: CC(C)(C)OC(=O)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)CCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
6-hydroxy-2-methylquinoline was treated with cis-4-tert-butylcyclohexanol under Mitsunobu conditions, affording 6-((trans)-4-tert-butylcyclohexyloxy)-2-methylquinoline, which in turn was oxidized with tert-butyl hydrogen peroxide and selenium dioxide in dioxane, providing 6-((trans)-4-tert-butylcyclohexyloxy)-2-formylquinoline. This aldehyde was then treated with t-butyl 3-aminopropionate and sodium cyanoborohydride in dichloroethane to afford t-butyl 3-(((6-((trans)-4-tert-butylcyclohexyloxy)-quinolin-2-yl)methyl)amino)propionate. Treatment with lithium hydroxide in methanol/THF gave the title compound, 3-((6-((trans)-4-tert-butylcyclohexyloxy)quinolin-2-yl)methylamino)propanoic acid.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[C:27]([CH3:29])[CH:28]=1.N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:28]1\[C:23]([NH2:22])=[CH:24][C:25](=[O:30])[CH:26]=[C:27]\1[CH3:29]
Reactant: Nc1c(N)n2n(c1=O)CCC2
Reactant: Cc1cc(N)cc(O)c1
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: CC1=CC(=O)C=C(N)/C1=N\c1c(N)n2n(c1=O)CCC2

Procedure:
0.5 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 3-amino-5-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCOCC1>[C:8]([C:7]1[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][C:4]([N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)=[N:5][C:6]=1[CH3:10])#[N:9]
Reactant: C1CNCCN1
Reactant: Cc1nc(N2CCS(=O)CC2)nc(Cl)c1C#N
Solvent: C1COCCO1
Product: Cc1nc(N2CCS(=O)CC2)nc(N2CCNCC2)c1C#N

Procedure:
2.7 gm (0.01 mol) of 4-chloro-5-cyano-6-methyl-2-(1-oxido-thiomorpholino)-pyrimidine (m.p. 251°-253°C, obtained from 5-cyano-2,4-dichloro-6-methyl-pyrimidine and thiomorpholine-1-oxide in acetone while cooling) were refluxed with a solution of 8.6 gm (0.1 mol) of piperazine in 80 ml of dioxane for about 30 minutes. The major part of the solvent was distilled off in vacuo, the residue was dissolved in about 80 ml of water, and a small quantity of 8 N sodium hydroxide was added, whereby the reaction product was first obtained as greasy, but soon solidifying precipitate. The product was suction-filtered off, washed with water and dried. Yield: 2.8 gm (87% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.P(Cl)(Cl)([Cl:14])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:14][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
3-Chloro-2-hydroxy-5-nitropyridine (4.8 g) was added to phosphorus oxychloride (11 ml) and phosphorus pentachloride (4.45 g) and the mixture refluxed overnight. The mixture was then cooled to room temperature and evaporated under reduced pressure. Iced water was added to the mixture and a solid product formed. The solid was removed by filtration, washed with water and air-dried to give 2,3-dichloro-5-nitropyridine (3.94 g).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:21])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:3][N:4]([CH3:21])[C:5]1[CH:10]=[C:9]([O:11][S:23]([CH3:22])(=[O:25])=[O:24])[CH:8]=[CH:7][C:6]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)c1cc(O)ccc1-c1nc2ncccc2[nH]1
Agent: Cl
Product: CN(C)c1cc(OS(C)(=O)=O)ccc1-c1nc2ncccc2[nH]1

Procedure:
Prepared analogously to Example 56 from 2-(2'-dimethylamino-4'-hydroxy-phenyl)-imidazo[4,5-b]pyridine dihydrochloride and methanesulfonyl chloride. The product was purified over silica gel column [eluant: first methylene chloride, then methylene chloride/ethanol (50:1)].
Reaction SMILES: O[C:2]1[C:3]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.P(Br)(Br)([Br:29])=O.C(=O)(O)[O-].[Na+].C(Cl)Cl>C1(C)C=CC=CC=1>[Br:29][C:2]1[C:3]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)c(C(=O)Nc3ccccc3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cnc(Br)c(C(=O)Nc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 120.8 %

Procedure:
A solution of 3-hydroxy-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide (84.3 mg, 0.1712 mmol) in toluene (3.000 mL) was treated with POBr3 (196.3 mg, 0.6848 mmol) and the resultant mixture was heated to 100° C. for 16 hours. The reaction mixture was allowed to cool to ambient temperature and treated with sodium bicarbonate/DCM. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to give the impure desired product as a yellow solid (89.4 mg, 95% Yield). MS (ES+) 433.88.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH2:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](OCC)(=[O:26])[CH2:22][C:23]([CH3:25])=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:21](=[O:26])[CH:22]=[C:23]([CH3:25])[C:13]3[C:12](=[O:14])[N:11]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:10][C:9]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(Nc2cccc(Cl)c2)=NN1c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2cccc(Cl)c2)c2[nH]n(-c3ccccc3)c(=O)c12
Yield: 28.5 %

Procedure:
To 5.7 g of 3-(3-chlorophenylamino)-1-phenyl-2-pyrazolin-5-one were added 2.8 g of ethyl acetoacetate and 40 ml of acetic acid and the mixture was heated while refluxing for 6 hours. The precipitated crystals were filtered and washed with isopropyl alcohol to obtain 2 g of 7-(3-chlorophenyl)-4-methyl-2-phenylpyrazolo[3, 4-b]pyridine-3,6-dione (melting point: 278° to 282° C.). A solution was prepared by adding 24 ml of methanol and 1.12 ml of triethylamine to 1.4 g of the crystals obtained above, 1.13 g of 1,7-diphenyl-1,7-diaza-1,3,5-heptatriene hydrochloride were added to this solution, and then 0.75 ml of anhydrous acetic acid was added with stirring at room temperature for one hour. The precipitate thus formed was filtered and washed with methanol, followed by drying to obtain 5-[5-(N-acetylanilino)-2, 3-pentadienylidene]-7-(3-chlorophenyl)-4-methyl-2-phenylpyrazolo[3, 4-b]pyridine-3,6-dione. 30 ml of N,N-dimethylformamide and 0.32 g of 8-(3-chlorophenyl)-4-methyl-2-phenylpyrazolo[3, 4-b]pyridine-3,6-dione were added to 0.5 g of this product, and the solution was stirred at 50° C. for 2 hours. After filtering the reaction solution, ethyl acetate in an amount of ten times by volume was added while stirring to precipitate crystals. The obtained crystals were dissolved again in a small amount of N,N-dimethylformamide, and then ethyl acetate in an amount of ten times by volume was added to precipitate crystals, followed by filtering, washing with ethyl acetate and drying to obtain 0.4 g of Compound 4. Melting point: 300° C. or higher.
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[C:17]([C:21]#[C:22][CH2:23][CH:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32]C)=O)[CH2:26][CH2:25]4)[N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:34])[C@@H:7]1[OH:35])=[O:5].CO.[NH3:38]>>[CH2:2]([NH:3][C:4]([CH:6]1[CH:7]([OH:35])[CH:8]([OH:34])[CH:9]([N:11]2[CH:12]=[N:13][C:14]3[C:15]2=[N:16][C:17]([C:21]#[C:22][CH2:23][CH:24]2[CH2:25][CH2:26][CH:27]([C:30](=[O:32])[NH2:38])[CH2:28][CH2:29]2)=[N:18][C:19]=3[NH2:20])[O:10]1)=[O:5])[CH3:1]
Reactant: N
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(C#CCC4CCC(C(=O)OC)CC4)nc32)[C@H](O)[C@@H]1O
Solvent: CO
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(C#CCC4CCC(C(N)=O)CC4)nc32)C(O)C1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
To a sealed tube containing 10 mL of saturated MeOH/NH3 solution was added 5 mg (0.01 mmol) of ATL146e. The flask was sealed and allowed to stir at 25° C. for 48 hours. The vessel was cooled to 0° C., opened, and the ammonia removed by bubbling N2 for 1 hour. The remaining solvent was then removed in vacuo to yield 4.0 mg (83%) of JR3055 as a white solid after the residue was purified by RP-HPLC. 1H NMR (CD3OD-d4) δ 8.41 (s, 1H), 5.98 (d, J=7.2 Hz, 1H), 4.65 (dd, J=7.3 Hz, 4.8 Hz, 1H), 4.41 (d, J=2.0 Hz, 1H), 4.28 (dd, J=4.6 Hz, 2.0 Hz, 1H), 3.35 (m, 2H), 2.37 (d, J=6.4 Hz, 2H) 2.10 (m, 1H), 1.90 (m, _H), 1.53 (m, _H_), 1.23 (m, _H), 1.12 (t, J=7.3 Hz, 3H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 472.3 (MH+, 100), 299.4 (10).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:47]1[C:55]2[C:50](=[CH:51][C:52]([C:56]3[N:60]=[CH:59][N:58](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:57]=3)=[CH:53][CH:54]=2)[C:49]([C:80]2[CH:81]=[C:82](O)[CH:83]=[CH:84][CH:85]=2)=[N:48]1.Cl>O1CCCC1>[NH:57]1[C:56]([C:52]2[CH:51]=[C:50]3[C:55](=[CH:54][CH:53]=2)[NH:47][N:48]=[C:49]3[C:80]2[CH:85]=[C:84]([CH:83]=[CH:82][CH:81]=2)[O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[N:60][CH:59]=[N:58]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C1CCCN1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCN1CCOc1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 29.9 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 1-(2-hydroxyethyl)pyrrolidin-2-one (0.299 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6N hydrochloric acid (25 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6N sodium hydroxide (25 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica pretreated with 2% triethylamine/ethyl acetate followed by 0–15% methanol/ethyl acetate. The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (0.0768 g, 30% yield). 1H NMR (CD3OD) δ 13.41 (br s, 1H), 8.65 (s, 1H), 8.10 (d, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 7.50 (m, 2H), 7.05 (m, 1H), 4.20 (t, 2H), 3.60 (t, 2H), 3.50 (t, 2H), 2.25 (t, 2H), 1.95 (m, 2H). ES-MS (m/z) 389 [M+1]+
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[NH2:26][OH:27].Cl>N1C=CC=CC=1>[N:26](=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:27]
Reactant: NO
Reactant: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=NO

Procedure:
A stirred solution of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (5.48 g., 0.015 mole) and hydroxylamine hydrochloride (3.2 g., 0.045 mole) in pyridine (60 ml.) is heated at 95°C. on a steam bath for 36 hours then poured into aqueous hydrochloric acid affording (1-hydroximino-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[CH2:11]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3][CH:2]1[NH:1][C:23]([NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: NC1CCN2CCc3ccccc3C2C1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)NC1CCN2CCc3ccccc3C2C1
Reaction time: 18 h

Procedure:
To 2-amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine (0.436 g) stirred at room temperature in benzene (50 ml) was added phenyl isocyanate (0.290 g, 5% excess) in benzene (25 ml). After stirring for 18 hours, the title compound was filtered off as a white solid (0.621 g) which was converted in ethanolic hydrogen chloride to the hydrochloride (0.654 g), m.p. 210.1° C. C20H23N3O.HCl.H2O requires C, 63.90; H, 6.97; N, 11.18% Found: C, 63.72; H, 6.87; N, 11.10%.