Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1[C@@H]2[CH2:8][C@H:9]([O:34]C(/C=C/C3N=CN(C)C=3)=O)[C@@:10]3(C)[O:14][C@@:13]([O:31]C)(C(CO[C@@H]4OC[C@@H](O)[C@@H](O)[C@@H]4OC(C)=O)=C[C@@H]2[C@@H](C(C)C)CC=1)[CH:12]=[CH:11]3.CCN(CC)CC.CC(OC(C)=O)=[O:57]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][C:9]([CH2:10][C:11]([CH2:12][C:13]([OH:31])=[O:14])=[O:57])=[O:34]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@]12C=C[C@](C)(O1)[C@@H](OC(=O)/C=C/c1cn(C)cn1)C[C@H]1C(C)=CC[C@H](C(C)C)[C@H]1C=C2CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O
Agent: CN(C)c1ccncc1
Agent: CO[C@]12C=C[C@](C)(O1)[C@@H](OC(=O)/C=C/c1cn(C)cn1)C[C@H]1C(C)=CC[C@H](C(C)C)[C@H]1/C=C\2CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Bis-Acetoxy Eleutherobin (2800) and Methyl-Ketal Precursors of Eleuthosides A and B (2900+3000) as illustrated in FIG. 27. To a solution of natural eleutherobin (4) (10.0 mg, 0.015 mmol, 1.0 equivalent), Et3N (6.0 mL, 0.043 mmol, 3.0 equivalents), and 4-DMAP (0.40 mg, 0.0033 mmol, 0.2 equivalents) in CH2Cl2 (0.60 mL) at 0° C. was added Ac2O (1.0 M in CH2Cl2, 0.017 mL, 0.017 mmol, 1.1 equivalents) and the reaction was stirred at the same temperature for 1 hour. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (0.50 mL) and extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated to provide a crude residue which was was purified by flash chromatography (silica gel, 2% MeOH in CH2Cl2) to afford triacetate 2800 (1.8 mg, 16%) along with an inseperable mixture of eleuthosides 2900 and 3000 (7.8 mg, 73%) as well as recovered 1 (0.5 mg, 5%). 2800. Rf=0.44 (silica gel, MeOH-- CH'2Cl2,1:20); [α]D -67.3 (c 1.2, CHCl3); FT-IR (neat) nmax 2962, 1746, 1740, 1644, 1634, 1372, 1226, 1156, 1068, 759, 668, 617 cm-1.
Reaction SMILES: [OH-].[Na+].O1CCCC1.C[O:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=2)[N:15]=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:13]=1)=[O:11].Cl>ClCCl>[C:22]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:13]=[C:12]2[C:10]([OH:11])=[O:9])#[N:23]
Reactant: COC(=O)c1cc(-c2ccccc2)nc2ccc(C#N)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc2nc(-c3ccccc3)cc(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
An aqueous sodium hydroxide solution was added to a tetrahydrofuran (20.0 mL) solution of 6-cyano-2-phenyl-4-quinolinecarboxylic acid methyl ester (0.6354 g, 2.20 mmol) obtained above, and the mixture was stirred at room temperature for 3 hours. To the reaction solution, dichloromethane was added. The mixture was neutralized with 1 N hydrochloric acid, and then washed with water and saturated saline, and dried over anhydrous sodium sulfate. After that, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain the title compound (0.5852 g, 2.13 mmol) as a pale yellow powder.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12]([O:17][C@@H:18]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]3[OH:20])=[N:13][NH:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1)[CH3:2].[C:29](O)(=[O:31])[CH3:30].C(OC(=O)C)(=O)C>O1CCCC1>[C:29]([N:14]1[C:15]([CH3:16])=[C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:12]([O:17][C@@H:18]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]2[OH:20])=[N:13]1)(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)=O)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[(4-ethylthiophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole (0.41 g) in tetra-hydrofuran (10 mL) were added acetic acid (0.11 mL) and acetic anhydride (0.18 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. The resulting precipitated crystal was collected by filtration to give 1-acetyl-4-[(4-ethylthiophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methylpyrazole (0.36 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH:50]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)([CH3:52])[CH3:51]>>[CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:56]6[CH2:57][CH2:58][N:53]([CH:50]([CH3:52])[CH3:51])[CH2:54][CH2:55]6)=[O:36])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: CC(C)N1CCNCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(C(C)C)CC4)cc3)cn2)cc1

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid obtained in Step A in Example 1-D-19 and 1-isopropylpiperazine (30.4 μl, 0.212 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone as a yellow solid (64.4 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-113) as a colorless powder (38.7 mg, 69%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1.O.NN>>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN3C(=O)c4ccccc4C3=O)CC2)c1
Agent: NN
Solvent: O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1

Procedure:
Prepared by Procedure AE and Scheme Y using N-(3-{1-[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)hexyl]-4-piperidinyl}phenyl)-2-methylpropanamide and hydrazine hydrate: ESMS m/e: 346.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O)(=[O:37])[CH3:36]>>[C:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:27]1[CH:26]=[C:25]([C:28]([F:30])([F:31])[F:29])[CH:24]=[CH:23][C:22]=1[O:21][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([CH3:20])[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[C:8]([CH3:33])[CH:9]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: CC(=O)c1ccccc1-c1cc(C(F)(F)F)ccc1Oc1cc(C)cc(Oc2ccc(CCC(=O)O)c(C)c2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-acetyl phenyl boronic acid as in Example 38 to afford 0.032 g (28%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(Cl)CCl.O.O[N:20]1C2C=CC=CC=2N=N1.[OH-].[NH4+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([NH2:20])=[O:13])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(Br)c2cc[nH]c12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)c1ccc(Br)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A mixture of 4-bromo-1H-indole-7-carboxylic acid (10.04 g, 75% purity, 31.2 mmol), EDC (8.96 g, 46.7 mmol), and 1-hydroxybenzotriazole hydrate (7.16 g, 46.7 mmol) in THF (198 mL) and CH2Cl2 (247 mL) was stirred at room temperature for 1 h. The mixture was then bubbled with NH3 gas for 15 min and stirred at room temperature for 4 h. LCMS showed residual starting material, so aqueous ammonium hydroxide (4.85 mL, 125 mmol) was added and the mixture was stirred at room temperature overnight. After 20 h, the mixture was concentrated and partitioned between NaHCO3 (aq) and EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was suspended in EtOAc and the solid was collected by filtration and air-dried to provide the desired product. The filtrates were subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexane (gradient from 20:80 to 50:50) to provide additional desired product for a total of 4.86 g (65% yield) over two steps. LCMS (M−H)−: 237.2, 239.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27](Br)[C:26]([O:30][CH3:31])=[CH:25][C:24]=1[F:32].[Br-].[Cl:35][C:36]1[C:37]([F:44])=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][Zn+].[Cl-].[NH4+]>CN1CCCC1=O.O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([CH2:39][C:38]2[CH:41]=[CH:42][CH:43]=[C:36]([Cl:35])[C:37]=2[F:44])[C:26]([O:30][CH3:31])=[CH:25][C:24]=1[F:32]
Reactant: COC(=O)c1cc(Br)c(OC)cc1F
Reactant: Fc1c(Cl)cccc1C[Zn+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium(0) (6.63 g) and triphenylphosphine (5.98 g) were successively added to 1-methyl-2-pyrrolidinone (350 ml) with stirring at room temperature, and the mixture was stirred for 1 hr. A solution of 5-bromo-2-fluoro-4-methoxybenzoic acid methyl ester prepared in Example 2, Step II, in 1-methyl-2-pyrrolidinone and a solution of 3-chloro-2-fluorobenzylzinc bromide prepared in Example 2, Step I, in tetrahydrofuran were successively added dropwise. After the dropwise addition, the mixture was stirred at 85° C. for 2 hr and cooled. To the reaction mixture were added toluene (560 ml) and 12.5% aqueous ammonium chloride solution (980 ml) and the mixture was stirred. The organic layer was washed successively with 25% aqueous ammonium chloride solution (490 ml), 2% aqueous ethylenediamine solution (490 ml, twice) and 10% brine (490 ml, twice). After the washing, the solvent was concentrated under reduced pressure. Ethyl acetate (105 ml) and heptane (420 ml) were added to the residue to allow recrystallization to give 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl ester (106.8 g, yield 79.4%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[C:12]2[SH:22])=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35]Br)[CH3:30]>CN(C)C=O>[CH2:29]([O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35][S:22][C:12]1[N:11]([CH2:10][C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH:2]=2)[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[N:13]=1)[CH3:30]
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc2c(c1)nc(S)n2Cc1csc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSc1nc2cc(OC)ccc2n1Cc1csc2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 45.3 %

Procedure:
101 mg (0.30 mmol) of 1-((benzothiophene-3-yl)methyl)-5-methoxybenzimidazole-2-thiol were dissolved in 2 ml of dimethylformamide followed by the addition of 62 mg (0.45 mmol) of potassium carbonate and 53 mg (0.40 mmol) of 4-bromobutanoate ethyl ester and heating to 80° C. After 12 hours, the reaction solution was concentrated under reduced pressure and extracted with diethyl ether followed by washing twice with 10 ml of saturated brine and drying with magnesium sulfate. The solvent was then concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 60 mg (0.136 mmol) of 4-(1-((benzothiophene-3-yl)methyl)-5-methoxybenzimidazole-2-ylthio)butanoate ethyl ester (yield: 45%).
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([S:15]([NH:18][C@H:19]([C:27]([OH:29])=O)[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])[CH:9]=[CH:8]2.C(OCC)C.S(Cl)([Cl:37])=O>>[N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([S:15]([NH:18][C@H:19]([C:27]([Cl:37])=[O:29])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])[CH:9]=[CH:8]2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)ccc2c1
Agent: N#N
Solvent: CCOCC
Product: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.5 g of N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry ethyl ether to give N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: BrCC1CCCCC1
Reactant: Oc1cc(F)cc(Br)c1
Product: Fc1cc(Br)cc(OCC2CCCCC2)c1

Procedure:
Alkylation of 3-bromo-5-fluorophenol using (bromomethyl)cyclohexane following the method used in Example 1 gave 1-bromo-3-(cyclohexylmethoxy)-5-fluorobenzene. Yield (1.1 g, 73%): 1H NMR (400 MHz, CDCl3) δ 6.79-6.83 (m, 2H), 6.52 (dt, J=10.4, 2.0 Hz, 1H), 3.70 (d, J=6.0 Hz, 2H), 1.65-1.86 (m, 6H), 1.16-1.34 (m, 3H), 0.97-1.08 (m, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[CH:22]([O:35][C:36]([NH:38][C:39]1[N:47]=[CH:46][N:45]=[C:44]2[C:40]=1[N:41]=[CH:42][N:43]2[CH2:48][C:49](O)=[O:50])=[O:37])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH:22]([O:35][C:36]([NH:38][C:39]1[N:47]=[CH:46][N:45]=[C:44]2[C:40]=1[N:41]=[CH:42][N:43]2[CH2:48][C:49]([N:15]1[CH2:16][CH2:17][N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][C:5]=2[N+:19]([O-:21])=[O:20])(=[O:11])=[O:10])[C:13](=[O:18])[CH2:14]1)=[O:50])=[O:37])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C(O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Agent: Cl
Product: O=C(Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])C(=O)C1)OC(c1ccccc1)c1ccccc1
Yield: 58.4 %

Procedure:
The title compound (805 mg, 58%) was synthesized by reaction of 1-(4-fluoro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (679 mg, 2.0 mmol) with [6-N-(benzhydryloxycarbonyl)-adenin-9-yl]-acetic acid (807 mg, 2.0 mmol) as per the procedure of example 73. 1H NMR (DMSO-d6) δ 10.95 (s, 1H), 8.59 (s, 0.6H), 8.58 (s, 0.4H), 8.47˜8.40 (m, 1H), 8.33 (s, 0.6H), 8.30 (s, 0.4H), 8.26 (m, 1H), 7.88 (m, 1H), 7.53˜7.27 (m, 10H), 6.82 (s, 1H), 5.38 (s, 1.2H), 5.30 (s, 0.8H), 4.56 (s, 0.8H), 4.27 (s, 1.2H), 4.12˜4.06 (m, 2.4H), 3.91˜3.85 (br. m, 1.6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[N:29]=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[CH:26][CH:27]=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[N:29]=4)[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)n1

Procedure:
Example 76 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.0 Hz), 7.83 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.38–7.33 (m, 4H), 6.89 (d, 1H, J=7.6 Hz), 5.68 (br s, 1H), 3.26 (dd, 2H, J=6.0, 12.4 Hz), 2.90 (d, 2H, J=11.6 Hz), 2.58–2.52 (m, 2H), 2.31 (t, 2H, J=6.8 Hz), 1.99 (t, 2H, J=12.0 Hz), 1.85 (d, 2H, J=12.8 Hz), 1.70–1.59 (m, 6H), 1.28 (d, 6H, J=6.8 Hz), 1.01 (dd, 2H, J=3.6, 6.4 Hz); ESMS m/e: 483.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[C:25]2[CH:41]=[CH:42][CH:43]=[CH:44][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[C:25]2[CH:41]=[CH:42][CH:43]=[CH:44][C:24]1=2)=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: CCCCCCC1C(=O)N(NC(=O)[C@@H](N)C(C)C)c2ccccc2-c2ccccc21
Agent: Cl
Product: CCCCCCC1C(=O)N(NC(=O)[C@@H](NC(=O)[C@@H](O)c2cc(F)cc(F)c2)C(C)C)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid. (Example L) and 5-(L-valinyl)-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-V), the title compound was prepared. The product was purified by chromatography (silica, 5% MeOH/CHCl3).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:25]
Reactant: O=C(O)c1ccccc1Br
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: O=C(c1ccccc1Br)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-bromobenzoic acid. MS (ESI) mass calcd. for C23H21BrN4O, 449.34; m/z found, 449.1, 451.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:10]([CH2:19]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:27])CC)C.O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:10]([CH2:19][F:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](c2ccccc2)C1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](CF)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 112.5 %

Procedure:
1.5 g trans-3-hydroxymethyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.41 mmol) were dissolved in 20 ml dichloromethane and 1.31 g of diethylaminosulfurtrifluoride (DAST, 8.1 mmol) in 2 ml dichloromethane were added at 0° C. The reaction mixture was stirred for 72 h at room temperature, further dichloromethane and water were added, the organic phase was separated, dried over magnesium sulphate, filtered and evaporated to dryness to yield 1.7 g of a light yellowish oil. The crude product was purified via silica gel chromatography using n-heptane/ethyl acetate (6:4) as eluent to yield 1.08 g product.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([OH:13])=[O:12])[N:5]2[C:4](=[O:14])[NH:3]1.[CH2:15]=[O:16]>C(O)(C)C>[OH:16][CH2:15][N:3]1[C:2](=[O:1])[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([OH:13])=[O:12])[N:5]2[C:4]1=[O:14]
Reactant: C=O
Reactant: O=C(O)C1C=CCn2c(=O)[nH]c(=O)n21
Solvent: CC(C)O
Product: O=C(O)C1C=CCn2c(=O)n(CO)c(=O)n21
Yield: 44 %

Procedure:
2,3,5,8-Tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid is reacted with formaldehyde in a manner analogous to that described in the preceding paragraph to give in 44% yield 2,3,5,8-tetrahydro-2-hydroxymethyl-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid of melting point 175°-178° C. (from isopropanol). This acid is esterified using diazomethane in ether to give methyl 2-hydroxymethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate of melting point 123°-125° C.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1([CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[CH2:18][CH2:17][NH:16]2)[CH2:14][CH2:13][CH2:12]1.[C:29](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1([CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[CH2:18][CH2:17][N:16]2[CH3:29])[CH2:12][CH2:13][CH2:14]1
Reactant: COc1cc2c(cc1OC)C(C1(c3ccc(Cl)cc3Cl)CCC1)NCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)C(C1(c3ccc(Cl)cc3Cl)CCC1)N(C)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of methyl iodide (1.9 g) in acetone (20 ml) was added dropwise to a stirred suspension of 1-[1-(2,4-dichlorophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4 g prepared as described in Example RC9) and anhydrous potassium carbonate (3.1 g) in acetone (70 ml). The mixture was stirred at ambient temperature for 90 minutes and the solvent removed by evaporation. Water was added and the mixture extracted with ether. The ether layer yielded 1-[1-(2,4-dichlorophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline as an oil. A portion of this oil was characterised by conversion into its 1.5 oxalate salt, m.p. 125°-132° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[F:21].O.[OH-].[Li+]>CO.C1COCC1.O>[F:21][C:5]1[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][C:4]=1[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cc(Nc2ccccc2)c(C(=O)OC)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1F
Temperature: 75 °C

Procedure:
A mixture of 174C (30.0 g, 9.89 mmol) and lithium hydroxide monohydrate (12.5 g, 29.7 mmol) in MeOH (200 mL), THF (200 mL) and water (100 mL) was heated at 75° C. for 0.5 h. HPLC indicated that the reaction was complete. The organic solvents were removed under reduced pressure, and the aqueous residue was diluted with water. The pH was adjusted to 3.0 with 6N aqueous hydrochloric acid which resulted in a precipitate. The solid was collected by vacuum filtration and dried under reduced pressure to provide a quantitative yeild of compound 174D as an orange-yellow solid. HPLC retention time=3.02 min. (Condition B). 1H-NMR (400 MHz, DMSO) δ7.11 (m, 1H), 7.25 (m, 2H), 7.39 (m, 2H), 7.60 (m, 1H), 7.68 (m, 1H), 9.32 (br s, 1H), and 13.55 (br s, 2H).