Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[S:11][CH:12]=1.[Cl:24]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>CN(C=O)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Cl:24][C:12]1[S:11][C:10]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[N:9][C:8]=1[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccncc1-c1csc(-c2cccc(C(=O)N(C)C)c2)n1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccncc1-c1nc(-c2cccc(C(=O)N(C)C)c2)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of 3-[4-(4-methylpyridin-3-yl)-1,3-thiazol-2-yl]-N,N-dimethylbenzamide (400 mg) in DMF (2 ml) was added trichloroisocyanuric acid (120 mg) and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with aqueous sodium hydrogen carbonate-ethyl acetate. The organic layer was separated and washed with water, aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1–0:1) for purification to give the title compound (140 mg) as a colorless amorphous compound.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18]>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Yield: 90 %

Procedure:
(S)-2-(oxiran-2-ylmethy)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in acetonitrile (70 mL) respectively, then heated to reflux. Tetra-n-butylammonium bromide (0.55 g, 1.71 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.57 g, yield: 90.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH3:17])[CH3:16])[CH:10]=2)=[CH:4][C:3]=1[N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[O:27]=[C:28]1[NH:32][C:31](=[O:33])[CH:30]([CH2:34][C:35]2[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41](O)=[O:42])=[CH:37][CH:36]=2)[S:29]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[CH3:17][N:15]([CH3:16])[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[CH2:40][O:39][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][CH:30]3[S:29][C:28](=[O:27])[NH:32][C:31]3=[O:33])=[CH:45][CH:44]=2)=[C:3]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:4]=1
Reactant: CN(C)c1cccc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)c1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)c1cccc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)c1
Yield: 97.3 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-dimethylaminophenoxy)phenyl]-N-methylcarbamate (1.00 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.57 g), diethyl cyanophosphonate (0.91 g), triethylamine (0.57 g) and anhydrous tetrahydrofuran (40 ml) and the reaction mixture was purified to give the desired product (1.69 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[Cl:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([O:14][C:13]([Cl:12])([F:22])[F:23])=[CH:16][CH:17]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc(Cl)c(I)c1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 22.2 using 6-chloro-5-iodonicotinic acid and 4-(chlorodifluoromethoxy)aniline to afford an off-white powder. HPLC (Condition 4) tR=6.47 min, UPLC-MS (Condition 3) tR=1.26 min, m/z=456.8 [M−H]−.
Reaction SMILES: C[O:2][C:3]([C:5]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[N:22]=[C:21]([C:23]3[O:31][C:30]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[CH:24]=3)[O:20][N:19]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])[CH3:6])=[O:4].O[Li].O>C1COCC1.O>[C:3]([C:5]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][C:18]2[N:22]=[C:21]([C:23]3[O:31][C:30]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[CH:24]=3)[O:20][N:19]=2)[CH2:15][CH2:16]1)=[O:10])([CH3:6])[CH3:7])([OH:4])=[O:2]
Reactant: COC(=O)C(C)(C)OC(=O)N1CCC(Cc2noc(-c3cc4cnccc4o3)n2)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(OC(=O)N1CCC(Cc2noc(-c3cc4cnccc4o3)n2)CC1)C(=O)O
Reaction time: 16 h

Procedure:
A stirred solution of 4-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylic acid 1-methoxycarbonyl-1-methylethyl ester (Example 72, 43 mg, 100 μmol) in THF-H2O (3:1, 2 mL) was treated with LiOH.H2O (9 mg, 220 μmol). After 16 h, the THF was evaporated in vacuo, then the remainder was diluted with H2O (2 mL), before being washed with EtOAc (2×5 mL). The aqueous phase was neutralised with 1 M HCl, then the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc extracts were dried (MgSO4), filtered, and concentrated to furnish the title compound: RT=2.74 min; m/z (ES+)=415.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)#[N:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:31]([C:29]#[N:30])=[CH:32][CH:33]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)c2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 98.2 %

Procedure:
In a manner similar to the method described in Example 11, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (84.6 mg, 0.20 mmol) was reacted with 4-cyano-benzoic acid (Aldrich, 35.3 mg, 0.24 mmol), in the presence of HATU (72.0 mg, 0.20 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) at rt for 2 hrs to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(4-cyano-benzoyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (108.5 mg, 98.2%). HRMS (ES+) m/z Calcd for C30H25Cl2F2N3O+H [(M+H)+]: 552.1417, found: 552.1416.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10](OC)=[O:11])=[N:8][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:6]1.O.[NH2:25][NH2:26]>CO>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([NH:25][NH2:26])=[O:11])=[N:8][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:6]1
Reactant: NN
Reactant: COC(=O)c1nc(-c2ccccn2)nn1Cc1ccccc1F
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc(-c2ccccn2)nn1Cc1ccccc1F
Temperature: 70 °C

Procedure:
To a solution of methyl 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate I-35 (115 mg, 0.368 mmol) in methanol (2 mL) was added hydrazine hydrate (72 μL, 1.5 mmol). The solution was heated to 70° C. for 3.5 h, at which point the solvent was removed in vacuo to give 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbohydrazide C as a white solid. To the crude solid (17 mg, 0.054 mmol) suspended in ethyl acetate (600 μL) was added acetic formic anhydride (0.03 mL, taken from a 2:1 (molar ratio) of formic acid to acetic anhydride, allowed to age 2 h prior to addition). After stirring for 1.25 h, the solution was diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were dried over MgSO4, filtered, and the solvent was removed in vacuo to give the crude intermediate D that was carried on without further purification. To the crude solid was added phosphoryl chloride (237 μl, 2.54 mmol) and the solution was heated to 60° C. for 6.5 h. The solution was diluted with ethyl acetate (75 mL) and saturated aqueous sodium bicarbonate (75 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were washed with brine (50 mL), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (20-95% ethyl acetate in hexanes) gave 2-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)-1,3,4-oxadiazole I-42 (7.5 mg, 0.023 mmol, 42% yield for three steps) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:19])([F:18])[CH2:16][O-:17]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [O-]CC(F)(F)F
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)c([N+](=O)[O-])c1

Procedure:
In a first reaction step, 1-chloro-2,4-dinitrobenzene (II) is reacted with 2,2,2-trifluoroethanolate to form 1,3-dinitro-4-(2',2',2'-trifluoroethoxy)-benzene (III) according to the following reaction: ##STR2## For obtaining this reaction, 4.0 g (0.17 mole) sodium is completely dissolved in 100 ml 2,2,2-trifluoroethanol. Thereafter, 21.5 g (0.11 mole) of finely powdered 1-chloro-2,4-dinitrobenzene is added to the solution. The mixture is then heated under reflux for 3 hours and the excessive trifluoroethanol is distilled off under normal pressure. The remaining oil is dissolved in 210 ml ethanol. Through addition of 170 ml water, the reaction product III is precipitated in a crystalline form. It is sucked off, washed with a water-ethanol mixture (1:1) and then dried over CaCl2. The yield of 1,3-dinitro-4-(2',2',2'-trifluoroethoxy)-benzene is 27.0 g (0.1 mole 95% relative to the use 1-chloro-2,4-dinitrobenzene). The substance has a melting point of 76°-77° C.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:28][CH2:27][CH2:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:29]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)NCC2
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(c1ccccc1)N(CCCCCCCC(=O)NOCc1ccccc1)CC2

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.3 g, 1.1 mmol) was reacted with 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.32 g, 1 mmol) in the presence of potassium carbonate (0.14 g, 1 mmol) and DMF as solvent to give 8-(6,7-dimethoxy-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid benzyloxyamide as an amorphous solid (yield 0.12 g, 23%; purified by column chromatography using silica gel and ethyl acetate: heptane=1:1 as an eluent). MS (M+H+)=517.
Reaction SMILES: [C:1]1([CH:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][NH:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(Cl)Cl.N1C=CC=CC=1>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:10]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:18])[NH:9]1)=[O:25]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C1NNC(c2ccccc2)C1c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1NN(C(=O)c2cccc(C(F)(F)F)c2)C(c2ccccc2)C1c1ccccc1
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A solution of 4,5-diphenyl-3-pyrazolidinone (2.0 g, 8.4 mmol) in 50 mL CH2Cl2 and 5 mL pyridine was treated dropwise with a solution of 3-trifluoromethylbenzoylchloride (1.4 g, 8.4 mmol) in 25 mL CH2Cl2 and stirred overnight. The mixture was washed with 1N HCl, dried over Na2SO4, evaporated, and the product isolated by chromatography (preparative HPLC) as 840 mg (24%) purple foam:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([C:21]([F:20])([F:30])[F:31])[CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cccc(C(F)(F)F)c1
Yield: 80 %

Procedure:
The compound prepared in Example 3 was reacted with 3-trifluoromethyl-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 80%).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][NH2:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(C)(C)C>Cl>[NH2:18][CH2:17][C@@H:8]([CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:7][C:6]([OH:19])=[O:5]
Reactant: CCCCC[C@@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Agent: Cl
Product: CCCCC[C@@H](C)C[C@H](CN)CC(=O)O

Procedure:
Compound 161 (1.20 g, 4.44 mmol) was heated to 50° C. in 3N HCl (30 mL) for 4 hours. The solvent was evaporated, and the oil washed with toluene, and evaporated. The crude material was passed through an ion exchange column (Dowex 50WX8-100, strongly acidic) eluting with water, then 0.5N NH4OH. Isolate (3S,5R)-3-aminomethyl-5-methyl-decanoic acid as a white solid (0.725 g, 75%): mp=174-175° C.; 1H NMR (400 MHz, CDCl3) δ2.83 (dd, J=12.69, 4.88 Hz, 1H), 2.70 (dd, J=13.1, 7.45 Hz, 1H), 2.08 (d, J=6.59 Hz, 2H), 1.98 (m, 1H), 1.28-1.20 (m, 1H), 1.19-1.09 (m, 2H), 0.99-0.91 (m, 2H), 0.66 (m, 6H); MS (APCI) m/z 215 (M+, 10%), 174 (M+−41, 100%); [α]D=−5.7 (cl.025 in H2O).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].O[CH:18]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:25][C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2>C(O)C.C(O)(=O)C>[Br:16][C:14]1[CH:13]=[CH:12][C:3]([C:4]([CH:6]([CH:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[O:25][C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])=[C:2]([CH3:1])[CH:15]=1
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C(=O)c1ccc(Br)cc1C)C1c2ccccc2Oc2ccccc21

Procedure:
A solution of ethyl 2-methyl-4-bromobenzoylacetate (18.5 g, 65.0 mmol) was heated at 60° C. with 9-hydroxyxanthene (14.2 g, 71.5 mmol) in ethanol-acetic acid (1:1, 200 ml) for 40 h. The product was isolated as in Example 1 (iii), except the aqueous phase was extracted with diethyl ether. The crude product was purified on flash silica eluting with hexane-dichloromethane (3:2 then 1:1) to give ethyl 2-(4-bromo-2-methylbenzoyl)-2-(9H-xanthen-9-yl)acetate as an oil.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][N:12]1[CH2:13][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][C:11]1=[O:14])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: O=C1CC(c2ccc(Cl)cc2)CN1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CN1CC(c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13 g (565 mmol) of sodium are added in portions to 410 ml of ethanol. After it has dissolved completely, 107 g (545 mmol) of 4-(p-chlorophenyl)-2-oxopyrrolidine are added, the whole is stirred at room temperature for 2 hours, concentrated to dryness by evaporation under reduced pressure and dried overnight at 100° under reduced pressure. The resulting sodium 4-(p-chlorophenyl)-2-oxopyrrolidine is made into a slurry in 340 ml of toluene, and a solution of 63.7 ml (95.9 g; 574 mmol) of bromoacetic acid ethyl ester is added dropwise, while stirring, at 20° to 25°. The whole is stirred for a further 16 hours, concentrated to dryness by evaporation under reduced pressure at approximately 70° and partitioned between 300 ml of water and 600 ml of ethyl acetate. The organic phase is separated off, washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness by evaporation under reduced pressure. 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid ethyl ester is obtained which, for purification, is distilled under reduced pressure; b.p.=176°-178° at 0.02 torr (0.027 mbar).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@@H:22]1[C:27](O)=[O:28])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:27]([C@H:22]2[CH2:23][NH:24][CH2:25][CH2:26][N:21]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:28])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
1-Benzylpiperazine (2.7 ml) and (2R)-1-BOC-piperazine-2-carboxylic acid (3.571 g) were suspended in DMF (150 ml) and stirred at 0° C. Triethylamine (4.33 ml) was added followed by PyBOP reagent (8.08 g). The mixture was allowed to warm to room temperature overnight, concentrated to approximately a third of the volume in vacuo and partitioned between brine (75 ml) and ethyl acetate (2×200 ml). Combined organic extracts were treated with saturated aqueous sodium bicarbonate (75 ml) and brine (75 ml), dried (sodium sulphate), concentrated in vacuo using high vacuum to remove DMF traces and purified by chromatography eluting with 0-15% methanol/dichloromethane. This gave tert-butyl (2R)-2-[(4-benzylpiperazin-1-yl)carbonyl]piperazine-1-carboxylate as a white glass (5.01 g).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[N:36]1([C:42]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[O:17][C:18]5[C:23]([C:24](=[O:26])[CH:25]=4)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=5[N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)N5CCOCC5)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 431 and commercially available morpholine-4-carbonyl chloride (Aldrich) via the parallel synthesis described above. MS−base peak at m/z=591 by positive ion CI.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].CN1CCCC1=[O:31].[OH-].[Na+].O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:31])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a 25 mL volume three-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-39) (1.71 g), N-methyl-2-pyrrolidone (3.1 ml), and 27 w/w % of aqueous sodium hydroxide solution (2.99 g) were added, and stirred at 70° C. for 6 hours. To the mixture was added water (4.0 ml) and toluene (4.6 ml), and then the organic layer was removed. To the resulting aqueous layer, 35 w/w % of hydrochloric acid was added to adjust to pH to less than 1. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 1.23 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:5]=1/[CH:18]=[CH:19]/[CH:20]([OH:29])[CH2:21][C:22](=[O:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl>C(O)C.O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:5]=1/[CH:18]=[CH:19]/[CH:20]([OH:29])[CH2:21][CH:22]([OH:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1-c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1-c1ccc(F)cc1

Procedure:
Sodium tetrahydridoborate (1.55 g, 41.1 mmole) is added with stirring to a cooled solution (5° C.) of methyl (E)-7-(2,4-dichloro-6-(4-fluorophenyl)phenyl)-5-hydroxy-3-oxo-6-heptenoate (82.3 mmole) in ethanol (200 ml) at a rate sufficient to maintain the internal temperature at 15°-20° C. The resulting solution is stirred with ice-bath cooling for 15 min. and then acidified with 6 N hydrochloric acid. The resulting mixture is diluted with water (500 ml) and extracted with ether (3×250 ml). The organic extracts are combined, washed with brine (4×100 ml), dried over magnesium sulfate and filtered. The filtrate is evaporated in vacuo, leaving the title compound as an oil.