Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[O-2].[Mg+2].O.[CH:13]([O:26][C:27](N=[N+]=[N-])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[CH:13]([O:26][C:27]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:28])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=NC(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)OC(c1ccccc1)c1ccccc1)C(=O)O

Procedure:
To a mixture consisting of 13.1 g. of L-leucine, 6 g. of magnesium oxide, and 150 ml. of water is added a solution of 25.3 g. of benzhydrylazidoformate in 150 ml. of dioxane, and the resulting mixture is stirred at room temperature for 2 days. It is then filtered, and the filtrate is concentrated to remove the dioxane. The aqueous concentrate is acidified with solid citric acid, and the acidified mixture is extracted with ethyl acetate. The extract is dried and evaporated to dryness to give an oily residue of N-benzhydryloxycarbonyl-L-leucine, which is suitable for use without further purification. To a mixture of 32 g. of this intermediate product, 25 g. of pentachlorophenol, and 300 ml. of ethyl acetate, at 5° C., is added 20 g. of dicyclohexylcarbodiimide, and the resulting mixture is kept at 5° C. for 5 hours and filtered. The filtrate is concentrated to small volume, and the concentrate is treated with petroleum ether to give a precipitate of N-benzhydryloxycarbonyl-L-leucine pentachlorophenyl ester, which is isolated and crystallized from ethanol-water; m.p. 84°-86° C.; [α]D25 -27.8° (2% in methanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[OH:19][CH2:18][C@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of the compound of Step A (1) ((R)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 6.3 g, 23 mmol) in THF (200 mL) was added triethylamine (36.5 mmol) followed by ethyl chloroformate (27.3 mmol). The mixture was stirred at rt for 2 h. NaBH4 (91.0 mmol) was then added and the mixture was stirred for 10 min. To the resulting mixture was added MeOH (40 ml) very slowly. When the addition was complete, the mixture was stirred for 3 h. The reaction was then concentrated in vacuo and the residue was partitioned between 1N NaOH and ethyl acetate (600 mL). The organic phase was washed with H2O, dried (Na2SO4), and concentrated in vacuo to give 5.5 g (91%) of the title compound: 1H NMR (CDCl3, 500 MHz) δ 1.49 (9H, s), 3.02 (1H, dd, J=5, 15 Hz), 3.50 (2H, brd s), 3.61 (1H, d, J=10 Hz), 4.30 (1H, d, J=15 Hz), 4.44-4.52 (1H, m), 4.67-4.76 (1H, m), 7.09-7.18 (4H, m). MS (ESI) (M+H)+ 264.19.
Reaction SMILES: [Si:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([N+:23]([O-])=O)[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[NH2:23][C:21]1[CH:22]=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:10]3=[O:26]
Reactant: CC(C)(C)[Si](C)(C)ON1C(=O)c2cccc3cc([N+](=O)[O-])cc(c23)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)ON1C(=O)c2cccc3cc(N)cc(c23)C1=O
Yield: 86.5 %

Procedure:
The hydrogenation of 2-tert-butyldimethylsilyoxy-5-nitro-benzo[de]isoquinoline-1,3-dione (1.0 g, 2.7 mmol, from Example A-1 or A-2) at 40 psi in the presence of 10% Pd/C catalyst (1.0 g) in ethyl acetate (20 mL) afforded 0.8 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.[O:10]1[CH:12]([CH2:13][CH3:14])[CH2:11]1>C(O)=O>[OH:10][CH:12]([CH2:13][CH3:14])[CH2:11][N:3]1[C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Reactant: CCC1CO1
Solvent: O=CO
Product: CCC(O)Cn1c([N+](=O)[O-])cnc1C
Temperature: 10 °C
Reaction time: 8 h

Procedure:
The reaction mixture of 2-methyl -5-nitroimidazole (127 g, 1.0 mol) and 88% formic acid will be cooled to 10° C. under stir, then 1,2-epoxybutane (360 g, 5.0 mol) will be added dropwise to above cold solution under the condition of 10° C. After the dropping, the reactants will be placed at room temperature overnight. The formic acid will be recovered under reduced pressure. To this residue, 100 ml of water will be added. The mixture will be filtered and the filter residue will be washed with water. The water phases will be combined, alkalified with 10 M sodium hydroxide aqueous solution up to pH 9. The solution will be placed in the cold room overnight for crystallization. The crystals will be collected, washed with water, and then dried. Crude product will be recrystallized from toluene to give 1-(2-hydroxybutyl)-2-methyl-5-nitro-1H-imidazole.
Reaction SMILES: C([O:3][C:4]([O:6][NH:7][C:8](=[NH:42])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:18]3=[N:17][C:16]=2[C:30]#[C:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[CH:11][N:10]=1)=O)C.N1CCCN2CCCCCC=12.Cl>CC1C=CC=CC=1C>[O:27]1[CH2:26][CH2:25][N:24]([C:23]2[C:18]3[N:19]([C:15]([C:12]4[CH:13]=[CH:14][C:9]([C:8]5[N:42]=[C:4]([OH:3])[O:6][N:7]=5)=[N:10][CH:11]=4)=[C:16]([C:30]#[C:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:17]=3)[N:20]=[CH:21][CH:22]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)ONC(=N)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1C
Product: Oc1nc(-c2ccc(-c3c(C#Cc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)no1
Temperature: 25 °C

Procedure:
A solution of compound 42b (0.10 g, 0.18 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.10 g, 0.66 mmol) in o-xylene (2 mL) was stirred at 130° C. in an oil bath for 2 h. The reaction mixture was allowed to cool to rt, and the solution was adjusted to pH 7 with 0.5 N HCl. The solids formed were collected by filtration and washed with CH2Cl2/MeOH (1:10) (3×10 mL) to obtain the title compound 26 as a brown solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 13.25 (s, 1H), 9.48 (s, 1H), 8.79-8.75 (m, 1H), 8.47 (d, J=8.4 Hz, 1H), 8.33 (d, J=5.7 Hz, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.06-8.01 (m, 2H), 7.87-7.66 (m, 3H), 7.56 (d, J=6.0 Hz, 1H), 4.10-3.98 (m, 4H), 3.91-3.78 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H20N8O3: 517.2 (M+H). Found: 517.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[F:18].C(=O)(O)[O-].[Na+].O>CS(C)=O>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:3]1[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]1[CH3:1]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1c[nH]c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)c(C)n1
Temperature: 80 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
Step T (1): A mixture of 2,4-dimethyl-1H-imidazole (5.00 g, 52.0 mmol), 1,2-difluoro-4-nitrobenzene (8.27 g, 52.0 mmol), and sodium bicarbonate (4.37 g, 52.0 mmol) in DMSO (100 mL) was heated at 80° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The dark residue was dissolved in ethyl acetate (200 mL). Hexane (50 mL) was added to the solution. The resulting mixture was allowed to age for 72 h at rt. The resulting solid was collected by vacuum filtration. The solid was dried under high vacuum to afford 1-(2-fluoro-4-nitrophenyl)-2,4-dimethyl-1H-imidazole (6.68 g, 27.8 mmol, 54% yield) as a yellow crystalline solid. LC-MS (M+H)+=236.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.13-8.22 (m, 2 H), 7.51 (dd, J=8.9, 7.3 Hz, 1 H), 6.72 (s, 1 H), 2.28-2.36 (m, 3 H), 2.22-2.28 (m, 3 H).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17]([OH:19])=O)[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>ClCCl>[F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17]([Cl:23])=[O:19])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCCc2c1c1ccccc1n2CCF
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCCc2c1c1ccccc1n2CCF
Yield: 102 %

Procedure:
9-(2-Fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid (31) (0.5 g, 1.91 mmol) in dry dichloromethane (6 mL) was stirred under an atmosphere of nitrogen at room temperature with oxalyl chloride (490 mg, 3.8 mmol, 0.34 mL) and a drop of DMF. The reaction was concentrated in vacuo to afford 545 mg (quantitative) of 9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carbonyl chloride (32) which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 20.2, 21.6, 26.7, 43.1, 43.4, 50.6, 80.9, 83.1, 105.3, 108.8, 118.3, 120.0, 121.6, 126.5, 136.2, 137.5, 176.1.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[O:16][CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][S:2]([O:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[O:16][CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(OS(C)(=O)=O)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(OCCc2cccc(OCc3ccccc3C(=O)O)c2)cc1
Yield: 16 %

Procedure:
Methyl 2-{[3-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoate (0.109 g, 0.24 mmol) was dissolved in a mixture of THF/water (7/1, 2.5 ml). Lithium hydroxide (23 mg, 0.96 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The mixture was acidified (HCl, 1 ml, 1 M) and the water phase was extracted with two portions of EtOAc (2×5 ml). The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation and gave 17 mg of 2-{[3-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoic acid (yield 16%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Cn1nc2c(-c3ccc(F)cc3)c(-c3ccc(F)cc3)ccn2c1=O
Temperature: 200 °C
Yield: 66.9 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-fluorophenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 mg, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (33 mg, 0.087) as a pale yellow solid. MS: [M+H]+=380.
Reaction SMILES: FC1C=CC(N[C:9]([C:11]2(C(NC3C=CC(OC4C5C(=CC(OC)=C(OC)C=5)N=C(C)N=4)=CC=3)=O)CC2)=[O:10])=CC=1.[CH3:39][O:40][C:41](=[O:53])[C:42]1[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[CH:44][C:43]=1[NH2:52].C(OC(=O)C)(=O)C>CCCCCCC>[CH3:39][O:40][C:41](=[O:53])[C:42]1[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[CH:44][C:43]=1[NH:52][C:9](=[O:10])[CH3:11]
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Reactant: COc1cc2nc(C)nc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(OC)c(OC)cc1NC(C)=O

Procedure:
′N-(4-fluorophenyl)-N′-(4-{[2-methyl-6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide. Commercially available 2-amino-4,5-dimethoxy-benzoic acid methyl ester (3 g, 0.014 mol) and acetic anhydride (4.03 mL, 0.0426 mol) were heated in heptane at 100° C. for 3 hours. After removal of heptane in vaccuo, the crude product of 2-acetylamino-4,5-dimethoxy-benzoic acid methyl ester was obtained and used without further purification. LC/MS: m/z 254 (M+H).
Reaction SMILES: [CH2:1]([N:26]1[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([C:41](F)(F)F)[CH:35]=2)[C:27]1=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21](F)(F)F)[CH:15]=2)[C:7]1=[O:25].C(N1C(C)(C)C(=O)N(C2C=CC([N+]([O-])=O)=C(C)C=2)C1=O)CCCCN1C(C)(C)C(=O)N(C2C=CC([N+]([O-])=O)=C(C)C=2)C1=O.C(N1C(C)(C)C(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O)CCCCN1C(C)(C)C(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O>>[CH2:5]([N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:21])[CH:15]=2)[C:7]1=[O:25])[CH2:4][CH2:3][CH2:2][CH2:1][N:26]1[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([CH3:41])[CH:35]=2)[C:27]1=[O:45]
Reactant: CC1(C)C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)N1CCCCCN1C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)C1(C)C
Agent: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Agent: Cc1cc(N2C(=O)N(CCCCCN3C(=O)N(c4ccc([N+](=O)[O-])c(C)c4)C(=O)C3(C)C)C(C)(C)C2=O)ccc1[N+](=O)[O-]
Product: Cc1cc(N2C(=O)N(CCCCCN3C(=O)N(c4ccc(N)c(C)c4)C(=O)C3(C)C)C(C)(C)C2=O)ccc1N
Yield: 69 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 8 starting from the compound of Example 10, which replaces the compound of Example 2. The expected compound is obtained in the form of a white foam with a yield of 69%.
Reaction SMILES: [CH:1]1([C:10](O)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[C:16]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:17][C:18]2[O:22][CH2:21][CH2:20][C:19]=2[CH:23]=1.C([O-])(=O)/C=C/C([O-])=O>>[CH3:13][O:14][C:15]1[C:16]([N:24]2[CH2:25][CH2:26][N:27]([CH2:10][CH:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[CH2:28][CH2:29]2)=[CH:17][C:18]2[O:22][CH2:21][CH2:20][C:19]=2[CH:23]=1
Reactant: O=C(O)C1CCc2ccccc21
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: COc1cc2c(cc1N1CCN(CC3CCc4ccccc43)CC1)OCC2

Procedure:
Prepared as described in Example 9, starting from indan-1-ylcarboxylic acid and 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of the title compound melts at 195°-197° C. (ethanol).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([OH:29])[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[O:29][CH2:2][C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Reactant: C[Si](C)(C)CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOC(=O)COc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
A mixture of 2-trimethylsilylethyl bromoacetate (J. Org. Chem. 51, 1537 (1986) (13.72 g, 56.0 mmol), 3-benzyloxy-4-nitrophenol (EP application 095121) (13.38 g, 55.9 mmol), and potassium carbonate (15.46 g, 112 mmol) in DMF (40 mL) is stirred at RT for 18 h. The mixture is poured into EtOAc and extracted once with water and five times with brine. The organic layer is dried, filtered, and concentrated to afford the title compound as a pale brown liquid: 1H NMR (CDCl3)δ 7.93 (d, J=9.1 Hz, 1H), 7.42 (d, J=7.1 Hz, 2H), 7.34 (t, J=7.1 Hz, 2H), 7.28 (t, J=7.1 Hz, 1H), 6.60 (d, J=2.5 Hz, 1H), 6.41 (dd, J=9.1, 2.5 Hz, 1H), 5.15 (s, 2H), 4.57 (s, 2H), 4.25 (m, 2H), 0.97 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14](OCC)(OCC)(OCC)[CH2:15][CH3:16]>>[Cl:1][C:2]1[C:11]2[N:10]([C:14]([CH2:15][CH3:16])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: NNc1nc2ccccc2nc1Cl
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2c(Cl)nc3ccccc3n12
Temperature: 25 °C
Yield: 85 %

Procedure:
2-Chloro-3-hydrazinoquinoxaline (4.5 g., 0.023 mole), the product of Example 1, was stirred with triethyl orthopropionate (50 ml.) at 100° C. for one hour. The mixture was cooled to room temperature and the white precipitate was collected by filtration and washed with cyclohexane to give 4.5 g. (85% yield) of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 158°-160° C. Mass spectrum: m/e, 232 (P).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[CH:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:38])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[N:30]=[N:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=3)=[N:27]2)=[CH:21][CH:20]=1)([CH3:14])([CH3:13])[CH3:12].[Na]>>[C:11]([O:15][C:16](=[O:38])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[N:30]=[N:29][C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[C:35]([C:10]#[C:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH:36]=3)=[N:27]2)=[CH:21][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cn2nnc(-c3cccc(Br)c3)n2)cc1
Reactant: C#CCc1ccc(F)cc1
Agent: [Na]
Product: CC(C)(C)OC(=O)COc1ccc(Cn2nnc(-c3cccc(C#CCc4ccc(F)cc4)c3)n2)cc1
Yield: 68.9 %

Procedure:
This reaction was carried out as described in Example D1, Step (c) using 1-fluoro-4-prop-2-ynyl-benzene (0.23 g, 1.7 mmol) and {4-[5-(3-bromophenyl) tetrazol-2-ylmethyl]phenoxy}acetic acid tert-butyl ester (0.30 g, 0.67 mmol) in place of 4-[5-(3-bromophenyl)tetrazol-2-ylmethyl]-benzenesulfonic acid, sodium salt. This afforded 0.23 g of the product (68.5% yield).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:18]([NH:25][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a suspension of P-HOBT 6 (1.01 g, 0.49 mmol) in CH2Cl2 (5 mL) was added p-toluenesulfonyl chloride (0.280 g, 1.47 mmol, 3.00 equiv.) and pyridine (0.155 g, 0.160 mL, 1.98 mmol, 4.04 equiv.). The suspension was subsequently rocked for 60 minutes at 25° C. The polymer was then filtered and washed with CH2Cl2 (3×5 mL), MeCN (3×5 mL), and MeOH (3×5 mL). The polymer was re-suspended in CH2Cl2 (5 mL), followed by the addition of benzylamine (0.026 g, 0.027 mL, 0.24 mmol, 0.49 equiv. based on P-HOBT 6). The suspension was rocked at 25° C. for 2 h. The polymer was then filtered and washed with CH2Cl2 (2×5 mL). The filtrate and washings were combined and concentrated to yield 0.050 g (77%) of N-benzyl-p-toluenesulfonarnide as a light yellow crystalline solid.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[NH:17][N:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[CH3:9][N:8]([CH3:10])[C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([N:17]2[C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=3[C:15]([C:14]([F:13])([F:25])[F:24])=[N:16]2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CN(C)C(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
A mixture of 4-iodo-N,N-dimethylbenzamide (100 mg, 0.36 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (83 mg, 0.44 mmol), copper (I) iodide (1 mol %, 0.7 mg, 0.0036 mmol), trans-1,2-diaminocyclohexane (10 mol %, 4 mg, 0.036 mmol) and potassium carbonate (105 mg, 0.76 mmol) in 1,4-dioxane (0.5 ml) was stirred at 180° C. in a microwave reactor for 15 minutes, then fresh copper (I) iodide (1 mol %, 0.7 mg, 0.0036 mmol) and trans-1,2-diaminocyclohexane (10 mol %, 4 mg, 0.036 mmol) were added and the reaction stirred at 180° C. in a microwave reactor for 20 minutes. Then fresh copper (I) iodide (1 mol %, 0.7 mg, 0.0036 mmol) and trans-1,2-diaminocyclohexane (10 mol %, 4 mg, 0.036 mmol) were added and the reaction stirred at 180° C. in a microwave reactor for 30 minutes. The reaction mix was cooled and added to a 5 g pre-packed silica column which was then eluted from ethyl acetate, the product was further purified by mass directed auto-prep to give a crop of the title compound as a brown oil (53 mg, 43%).
Reaction SMILES: O[C:2]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])([CH3:4])[CH3:3].S(Cl)(Cl)=O.N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:4][C:2]([C@H:5]1[N:8]([CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:30])=[CH2:3]
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@H]2C(C)(C)O)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1

Procedure:
A solution of (3S,4S)-4-(1-hydroxy-1-methylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2azetidinone (30 g) in dry toluene (350 ml) was treated with thionyl chloride (9.0 g) at 20°-30° C. for 5 hours in the presence of pyridine (10 ml). Water (100 ml) was added to quench the reaction at 10°-25° C. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was crystallized from a mixture of cyclohexane and ethyl acetate to yield (3S,4S)-4-(1-methylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 117°-118° C.