Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:27][CH2:26]2>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=2)[CH2:29][N:28]([S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)(=[O:34])=[O:35])[CH2:27][CH2:26]4)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: Cc1ccc(S(=O)(=O)N2CCc3cc(Br)ccc3C2)cc1
Product: Cc1ccc(S(=O)(=O)N2CCc3cc(N4CCc5cc(N6CC[C@H](N7CCC[C@@H]7C)C6)ccc5C4)ccc3C2)cc1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 6-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@:9]1([F:26])[C@@H:14]2[C@H:10]1[CH:11]=[CH:12][C@@:13]2([NH2:25])[C:15]([O:17]CC1C=CC=CC=1)=[O:16])=[O:8])C>O.O1CCCC1>[NH2:25][C@@:13]1([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C@@H:10]2[C@H:14]1[C@@:9]2([F:26])[C:7]([OH:8])=[O:6]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C=C[C@@](N)(C(=O)OCc3ccccc3)[C@@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@]1(C(=O)O)C=C[C@@H]2[C@H]1[C@@]2(F)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
Lithium hydroxide hydrate, in an amount of 25 mg, dissolved in 5 mL of water was added to 90 mg of (1R,2S,5R,6R)-2-amino-6-fluoro-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester dissolved in 2 mL of tetrahydrofuran, and the mixture was stirred for 2 hours at room temperature. The solvent was concentrated under reduced pressure. The residue was purified by ion exchange resin (AG 50W-X8 Resin (H type), eluent: water, a 50% aqueous solution of tetrahydrofuran, and a 10% aqueous solution of pyridine), thereby yielding 24 mg of (1R,2S,5R,6R)-2-amino-6-fluoro-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.C([Li])CCC.O>O1CCCC1.CCCCCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:3]=2[CH:4]=1
Reactant: BrCCCCOc1cc(Br)ccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCCCC2
Reaction time: 5 h
Yield: 102.7 %

Procedure:
To a solution of 12.7 g (33 mmol) of 1,4-dibromo-2-(4-bromobutoxy)benzene in 220 mL of anhydrous tetrahydrofuran and 55 mL of hexane under nitrogen cooled in a dry ice/acetone bath was added dropwise 14.5 mL (36.3 mmol, 1.1 equiv) of 2.5M n-butyllithium in tetrahydrofuran, keeping the internal temperature <−70° C. The mixture was stirred with cooling for 30 minutes, then at ambient temperature. After 5 hours, 220 mL of water was added and the layers were separated. The aqueous layer was extracted with 2×160 mL of ether. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 7.7 g of a yellow oil. Purification by flash chromatography (5-20% ethyl acetate in hexanes) gave the product as a yellow oil. MS (m+1)=228.1; 1H NMR (400 MHz, CDCl3) 7.15 (d, 1H, J 2 Hz), 7.09 (m, 1H), 6.99 (d, 1H, J 8 Hz), 4.01 (m, 2H), 2.76 (m, 2H), 1.96 (m, 2H), 1.71 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C@:5]12[CH2:11][C@@H:8]3[CH2:9][C@H:10]1[C@H:6]2[C@@:7]3([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:12]([O:14]C)=[O:13])=[O:4].CO.Cl>O1CCCC1.[OH-].[Na+]>[CH2:20]([O:19][C:17]([NH:16][C@:7]1([C:12]([OH:14])=[O:13])[C@@H:8]2[CH2:11][C@@:5]3([C:3]([OH:4])=[O:2])[C@@H:10]([CH2:9]2)[C@@H:6]13)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@]12C[C@@H]3C[C@H]1[C@H]2[C@@]3(NC(=O)OCc1ccccc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@]1(C(=O)O)[C@H]2C[C@H]3[C@@H]1[C@@]3(C(=O)O)C2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.7 %

Procedure:
A suspension of 2.0 g (5.6 mmole) of (+/−)-(1R*,2R*,3R*,4S*,6S*)-3-benzyloxycarbonylamino-tricyclo[2.2.1.02,6]heptane-1,3-dicarboxylic acid dimethyl ester in a mixture of 30 mL of tetrahydrofuran and 30 mL of 1 N aqueous sodium hydroxide was stirred at room temperature for 24 hours. Because the starting material was unchanged, methanol was added until homogeneity was achieved and the solution was refluxed under nitrogen for 15 hours. The mixture was acidified with concentrated HCl and extracted with ethyl acetate (2×200 mL). The extract was washed with 200 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The resulting residue was recrystallized from ethyl acetate/hexane to give 1.2 g of the title compound as a white solid, m.p. 205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH:25]([C:29]([N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:31])[CH2:26][C:27]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Reactant: C1CCNC1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)N5CCCC5)CC4=O)cc3)CC2)c(C)c1
Yield: 43.5 %

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (100 mg) described in Example 333 and pyrrolidine (17 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (49 mg) was obtained.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](N)=[O:11])[C:4]=2[NH:3]C=1.NCC(C1C([N+]([O-])=O)=CC=CC=1C(O)=O)=[O:16]>>[NH2:3][C:4]1[C:5]([NH2:1])=[CH:6][CH:7]=[CH:8][C:9]=1[C:10]([OH:11])=[O:16]
Reactant: NCC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: NC(=O)c1cccc2nc[nH]c12
Product: Nc1cccc(C(=O)O)c1N

Procedure:
The method of preparing for benzimidazole-4-amide derivatives of the present invention is as follows: using 2-aminoacetyl-3-nitrobenzoic acid as an initiating raw material, 2-aminoacetyl-3-nitrobenzoic acid in turn is undergoing ammonolysis, Hoffman degradation and reduction, to produce 2,3-diamino benzoic acid; and then condensing 2,3-diamino benzoic acid and aldehydes X—CHO in the presence of catalyst of cupric acetate, to produce benzimidazole-4-carboxylic acid; and then reacting benzimidazole-4-carboxylic acid with thionyl chloride to produce acyl chloride, and then condensing the acyl chloride and an amine NH2—Y, to produce the benzimidazole-4-carboxamide derivative.
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH3:9])[N:3]=1.P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cnc(C)c(O)n1
Product: Cc1cnc(C)c(Cl)n1

Procedure:
The 2-hydroxy-3,6-dimethylpyrazine disclosed by Baxter et al can be reacted with phosphorus oxychloride by the method described in Preparation 13, Step B, to provide 2-chloro-3,6-dimethylpyrazine.
Reaction SMILES: C([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([CH2:15][CH3:16])=[N:9][CH:8]=1)(C)(C)C.[ClH:18]>>[ClH:18].[CH2:13]([C:11]1[C:10]([CH2:15][CH3:16])=[N:9][CH:8]=[C:7]([CH:12]=1)[C:6]([OH:17])=[O:5])[CH3:14]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cnc1CC
Agent: Cl
Product: CCc1cc(C(=O)O)cnc1CC

Procedure:
A solution of 5,6-diethyl-nicotinic acid tert-butyl ester (860 mg, 3.65 mmol) in 6 N aq. HCl (15 mL) is stirred at 65° C. for 3 h before the solvent is evaporated. The residue is dried under HV to give 5,6-diethyl-nicotinic acid hydrochloride (923 mg) as an oil; LC-MS: tR=0.50 min, [M+1]+=180.05.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[CH3:39][O:40][C:41](=[O:53])[C:42]1[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][C:43]=1Br>C1(C)C=CC=CC=1.ClCCl.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]>[CH3:39][O:40][C:41](=[O:53])[C:42]1[CH:43]=[CH:44][C:45]([C:48]([F:49])([F:51])[F:50])=[CH:46][C:47]=1[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1Br
Reactant: C1CCNC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(F)(F)F)cc1N1CCCC1
Temperature: 80 °C
Yield: 30.4 %

Procedure:
To 30 mg (0.0318 mmol) Pd2 dba3, 37.9 mg (0.106 mmol) 2-(dicyclohexyl-phosphino)biphenyl and 315 mg (1.484 mmol) potassium phosphate tribasic under argon at room temperature, was added a solution of 105.2 ul (1.272 mmol) pyrrolidine in 5.5 ml toluene dry, followed by 300 mg (1.06 mmol) 2-bromo-4-trifluoromethyl-benzoic acid methyl ester (CAS: 328-89-2). The reaction mixture was heated at 80° C. overnight. The mixture was cooled to room temperature and diluted with dichloromethane. The suspension was filtered. The filtrate was concentrated in vacuo. The residue was purified on silica (Eluent: heptane/ethyl acetate 0 to 10%) to provide 88 mg (30.4%) of the title compound as an orange oil. MS (m/e): 274.3 (MH+).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[CH:10][N:11]=[CH:12][C:7]=2[C:6]([C:13]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:37])[CH:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:24]C3CCCCO3)[CH:18]=[N:19][CH:20]=2)=[O:14])=[CH:5]1)([CH3:3])[CH3:2].Cl.O1CCOCC1>O1CCOCC1>[OH:24][CH:23]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:22]([NH:21][C:17]1[CH:18]=[N:19][CH:20]=[C:15]([C:13]([C:6]2[C:7]3[CH:12]=[N:11][CH:10]=[N:9][C:8]=3[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)=[O:14])[CH:16]=1)=[O:37]
Reactant: CC(C)n1cc(C(=O)c2cncc(NC(=O)C(OC3CCCCO3)c3ccccc3)c2)c2cncnc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)C(O)c3ccccc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To stirred solution of N-[5-(7-Isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-phenyl-2-(tetrahydro-pyran-2-yloxy)-acetamide (60 mg, 0.12 mmol) (Preparation 237) in dioxane (1 mL) was added dioxane-HCl (1 mL of a 4N solution) at 00° C. The mixture was stirred at room temperature for 2 hours. All the volatiles were removed in vacuo and the solid obtained was triturated with diethyl ether to afford the title compound as a yellowish solid in 78% yield, 42 mg.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>>[CH2:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:22]1[O:24][CH2:23]1
Reactant: ClCC1CO1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Product: CCCCCCCC/C=C\CCCCCCCCOCC1CO1

Procedure:
reacting oleyl alcohol with epichlorohydrin in a molar ratio of 1:1 to give oleyl glycidyl ether,
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18]C)=O)=[C:8]2[C:20](=[O:28])[N:21]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH3:22])=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([OH:18])=[C:23]([C:24]([O:26][CH3:27])=[O:25])[N:21]([CH3:22])[C:20](=[O:28])[C:8]2=3)=[CH:29][CH:30]=1
Reactant: COC(=O)CN(C)C(=O)c1c(C(=O)OC)c2ccccc2n1Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
An ice cold solution of methyl 1-(4-fluorobenzyl)-2-((2-methoxy-2-oxoethyl)(methyl)carbamoyl)-1H-indole-3-carboxylate (3 g, 7.27 mmol) in N,N-Dimethylformamide (DMF) (36.4 ml) was treated with NaH (0.378 g, 9.46 mmol). After 1 h, the reaction mixture was cooled to 0° C. and slowly quenched with H2O. The mixture was extracted with EtOAc and the organic layer washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by ISCO (0-3% DCM/MeOH) to afford methyl 9-(4-fluorobenzyl)-4-hydroxy-2-methyl-1-oxo-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylate (1.1 g, 2.89 mmol, 39.8% yield) as an orange solid. LCMS (m/z) ES+=381 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH:15](I)([CH3:17])[CH3:16]>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:15]([CH3:17])[CH3:16]
Reactant: Oc1ccccc1Br
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)Oc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepare a stirred mixture of ortho-bromo-phenol (25.951 g, 17.4 mL, 0.15 mole) and potassium carbonate (20.70 g, 0.16 mole) in 175 mL isopropanol at ambient temperature under argon. Slowly add isopropyl iodide (22.2 g, 16.00 mL), heat at reflux and stir the mixture overnight. Cool to ambient temperature then filter, condensing the filtrate on a rotary evaporator. Dissolve the residual oil in diethyl ether (300 mL) and twice extract with 100 mL 50% sodium hyroxide. Separate, wash with brine and concentrate on a rotary evaporator to give a pale yellow liquid. Distill on the Kugelrohr (0.05 mm, 100°-120° C.) to obtain the title compound as an oil. (24.21 g, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH:13]1[C:18]([CH:19]=O)=[CH:17][C:16]2[O:21][CH2:22][O:23][C:15]=2[CH:14]=1.Cl>CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[CH:19][C:18]1[CH:13]=[CH:14][C:15]3[O:23][CH2:22][O:21][C:16]=3[CH:17]=1)[CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Solvent: CO
Product: O=C1C(=Cc2ccc3c(c2)OCO3)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 89.8 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and piperonal 1.11 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 0.5 hours and cooled to room temperature, and the precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 1.63 g.
Reaction SMILES: N[C@H](C(N[C@H](C(N[C@H]([C:20]([NH:22][C@H](C(O)=O)C)=[O:21])CC(C)C)=O)C)=O)CC(C)C.[CH:28]1[C:33]([C:34]([NH:36][C@H:37]([C:43]([OH:45])=[O:44])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:35])=[CH:32][CH:31]=[C:30]([NH:46][CH2:47][C:48]2[CH:49]=[N:50][C:51]3[N:57]=[C:56]([NH2:58])[N:55]=[C:54]([NH2:59])[C:52]=3[N:53]=2)[CH:29]=1.C1([N:66]=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH:32]1[C:33]([C:34]([NH:36][C@H:37]([C:43]([OH:45])=[O:44])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:35])=[CH:28][CH:29]=[C:30]([NH:46][CH2:47][C:48]2[CH:49]=[N:50][C:51]3[N:57]=[C:56]([NH2:58])[N:55]=[C:54]([NH2:59])[C:52]=3[N:53]=2)[CH:31]=1.[NH2:66][C:20]([NH2:22])=[O:21]
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](C)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1nc(N)c2nc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Solvent: CN(C)C=O
Product: NC(N)=O

Procedure:
Conjugation Via Leu-Ala-Leu-Ala Spacer: The N-hydroxysuccinimide ester of aminopterin was prepared as above. To 10.2 ml of a 23 mM solution of the aminopterin derivative (0.236 mmol) in dimethylformamide were added 104 mg (0.236 mmol) of solid L-Leu-L-Ala-L-Leu-L-Ala (LALA). The mixture was stirred overnight at 50° C. during which time the solid LALA dissolved. To the reaction mixture was added 48.7 mg (0.236 mmol) of dicyclohexylcarbodiimide in 0.58 ml of dimethylformamide. Copious quantities of urea formed within 2 hours at room temperature and were removed by filtration. The filtrate containing the N-hydroxy succinimide ester of the LALA derivative of aminopterin was retained.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[C:22]([NH:29][C@@H:30]([C:38](O)=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O.O.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:25]([O:24][C:22]([NH:29][C@H:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:38]([NH:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21])=[O:39])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CN1C(=O)C(N)N=C(C2CCCCCC2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(C2CCCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3(R,S)-amino-5-cycloheptyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (4.08 g) in anhydrous dimethyl formamide (30 ml), under an atmosphere of nitrogen, was added in succession Boc-D-phenylalanine (3.98 g), 1-hydroxybenzotriazole trihydrate (2.03 g) and 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide hydrochloride (2.88 g). Triethylamine (2.09 ml) was then added and the resulting suspension stirred at ambient temperature for 1 h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (100 ml) and 10% citric acid solution (100 ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with 10% sodium hydroxide solution (100 ml), water (50 ml) and brine (50 ml). The organic layer was separated, dried (Na2SO4) and evaporated in vacuo to afford crude 3(R,S)-[2(R)-(tert-butyloxycarbonyl)amino-3-phenylpropionylamino]-5-cycloheptyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([NH2:22])[CH:9]=2)=[N:6][NH:5][C:4](=[O:23])[CH2:3]1.N.[C:25](O)(=O)[CH3:26]>>[CH2:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:2]([CH3:1])[CH2:3][C:4](=[O:23])[NH:5][N:6]=3)=[CH:9][C:10]=2[N:22]=[C:25]1[CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)O
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(N)c1
Agent: N
Product: Cc1nc2cc(C3=NNC(=O)CC3C)ccc2n1Cc1ccccc1

Procedure:
The product obtained according to (a) was taken up in 100 ml of glacial acetic acid and refluxed for 2.5 hours. The mixture was mixed with ice and made alkaline with ammonia, and the precipitated product was purified by chromatography on silicagel (eluting agent: at first pure methylene chloride, then increasing amounts of acetone up to a mixture ratio methylene chloride/acetone=10:3). After evaporation, the product was obtained in crystalline form by trituration with ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7])(C)([CH3:3])[CH3:2]>Cl.O1CCOCC1>[CH:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reaction time: 3 h
Yield: 14 %

Procedure:
2-(tert-Butoxycarbonyl)amino-5-trifluoromethylbenzoic acid (6.0 g) was dissolved in 4M HCl (4 mL) in dioxane. After 3 h, the solution was concentrated to a white solid. A portion of this material (900 mg) was dissolved in THF (10 mL), water (2 mL), and Et3N (1.8 mL) prior to the addition of 1M i-propyl chloroformate (4.5 mL) in toluene. The reaction was stirred for 4 h before EtOAc was added. The EtOAc layer was washed with 1N HCl and brine before it was dried, filtered, and concentrated to a crude material. This material was crystallized with CH2Cl2 to give the title compound (800 mg). MS found: (2M−1)−=581.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])=[CH:41][CH:42]=1)[CH3:2]
Reactant: CCc1ccccc1N
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCc1ccccc1NC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-ethylaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-ethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (49%) as a colorless solid: mp 203-204° C.; 1H NMR (300 MHz, CDCl3) δ7.96-7.83 (m, 3H), 7.69 (s, 1H), 7.52-7.44 (m, 2H), 7.31-7.13 (m, 5H), 7.10-7.02 (m, 1H), 6.82-6.74 (m, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.03 (ABq, 2H), 4.86 (ABq, 2H), 4.60-4.51 (m, 2H), 3.11-2.92 (m, 2H), 2.67 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 165.2, 161.9, 161.3, 141.8, 139.8, 135.1, 134.9, 134.6, 132.7, 128.8, 128.6, 127.8, 127.7, 126.8, 125.8, 124.1, 123.7, 120.0, 119.9, 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 29.0, 24.4, 14.0; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[O:20][CH2:21][C:22]([O:24]CC)=[O:23].O[Li].O.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[O:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)COc1cccc(NCc2cc(-c3cccc(F)c3)ccc2F)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(NCc2cc(-c3cccc(F)c3)ccc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 2-[3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (317.0 mg, 0.83 mmol, 1.0 eq) in a mixture of THF (6 mL) and H2O (6 mL) was added LiOH.H2O (134 mg, 3.19 mmol, 4.0 eq). The reaction was stirred at room temperature for 1 h, then diluted with water (30 mL) and the solution neutralized by addition of 1M HCl. The mixture was extracted with EtOAc, the combined organic extracts were washed with brine, dried (Na2CO3), filtered and evaporated in vacuo. The residue obtained was triturated with petroleum ether and EtOAc (2:1) and the solid that formed collected by filtration, washed with petroleum ether:EtOAc (2:1) and dried to give the title compound I(a) as an off-white solid (200 mg, 68%).