Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].Br[CH2:22][CH2:23][O:24][CH2:25]C>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:25][O:24][CH2:23][CH3:22])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOCCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCSc1ccc(N)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. of dimethylformamide is treated under nitrogen with 1.17 g. of sodium borohydride in 10 ml. of dimethylformamide at not greater than 30° C. The mixture is stirred at 15° to 20° C for 1 hour, then treated with 5 g. of 2-bromoethyl ethylether at 20°-25° C. The mixture is heated to 100° C for 2 hours, then cooled and diluted with water. The product is extracted with chloroform and after drying of the chloroform solution with sodium sulfate, 1-amino-2-nitro-4-(2-ethoxyethylthio) benzene is obtained by evaporation of the solution.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:17])[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:36]([N:44]1[C:48](=[O:49])[CH:47]=[CH:46][S:45]1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C)C=O.O1CCCC1.Cl>[CH2:36]([NH:44][C:48](=[O:49])/[CH:47]=[CH:46]\[S:45][CH:8]([C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: Cn1cccc1C(=O)CC(=O)c1ccccc1
Reactant: CCCCCCCCn1sccc1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)/C=C\SC(C(=O)c1ccccc1)C(=O)c1cccn1C
Yield: 18.7 %

Procedure:
To a stirred solution of 0.78 g (0.0034 mol) of 1-(1-methylpyrrol-2-yl)-3-phenyl-1,3-propanedione in 5 mL of N,N-dimethylformamide under nitrogen was added 3.4 mL (0.0034 mol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 10 min a solution of 0.73 g (0.0034 mol) of 2-n-octyl-4-isothiazolin-3-one in 5 mL of N,N-dimethylformamide was added. After 12 h another 3.4 mL of the 1M tetrabutylammonium fluoride solution was added. After 12 h the reaction mixture was diluted with 10% aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were washed several times with water, once with brine, and dried over magnesium sulfate. Removal of solvents and recrystallization of the crude product from ethyl acetate/hexane gave 0.28 g (19% yield) of N-n-Octyl-cis-3-{[1-phenyl-3-(1-methylpyrrol-2-yl)-1,3-propanedionyl]thio}acrylamide as a white solid, m.p. 131°-132° C. See Table 1.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1C1C=CC=CC=1.Cl[C:31]1[CH:36]=[N:35][CH:34]=[C:33]([Cl:37])[N:32]=1.IC1C=CC=CC=1>>[Cl:37][C:33]1[N:32]=[C:31]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:36]=[N:35][CH:34]=1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Reactant: Clc1cncc(Cl)n1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cncc(Cl)n3)c(=O)c2)cc1

Procedure:
4-{3-[1-(6-chloro-pyrazin-2-yl)-2-oxo-1,2-dihydro-pyridin-4-ylmethyl]-3H-imidazol-4ylmethyl}-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2,6-dichloropyrazine for the iodobenzene in Step 3.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH2:15][O:16][CH2:17][C:18]#[CH:19])[CH2:6][NH:7]C(=O)OC(C)(C)C)[C:2]#[CH:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:4][CH:5]([CH2:15][O:16][CH2:17][C:18]#[CH:19])[CH2:6][NH2:7])[C:2]#[CH:3]
Reactant: C#CCOCC(CNC(=O)OC(C)(C)C)OCC#C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCOCC(CN)OCC#C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 2,3-bis(prop-2-ynyloxy)propylcarbamate (I-13a:1.583 g, 5.92 mmol) in CH2Cl2 (23.69 mL) at 0° C. was added TFA (4.56 mL, 59.2 mmol). The mixture was stirred at room temperature for 2 h. Concentrated, and put on pump for 16 h, giving 2,3-bis(prop-2-ynyloxy)propan-1-amine as a yellow oil used as is for next step. LC-MS (M+1) 168.1, t=0.44 minute.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[C:4]([CH3:14])[CH:3]=1.[CH2:15]([SH:18])[CH2:16][SH:17].B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]32[S:18][CH2:15][CH2:16][S:17]3)=[C:4]([CH3:14])[CH:3]=1
Reactant: SCCS
Reactant: Cc1cc(Br)c(C)c2c1CCCC2=O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(Br)c(C)c2c1CCCC21SCCS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 20.0 g of the title compound of Step A in 500 mL of methylene chloride was added 11.2 mL of 1,2-ethanedithiol (purchased from Aldrich Chemical Co.) and 17.0 mL of boron trifluoride diethyl etherate (purchased from Janssen Chimica). The mixture was stirred at room temperature for 3 h. To this reaction mixture was added 15% aqueous sodium hydroxide and the resulting mixture was extracted with methylene chloride. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 20.2 g of the title compound of Step B as a white solid melting at 164°-165° C. 1H NMR (CDCl3): δ 1.98 (m, 2H), 2.15 (s, 3H), 2.38 (m, 2H), 2.58 (t, 2H), 2.78 (s, 3H), 3.40-3.60 (m, 4H), 7.35 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]2[N+:10]([O-:18])=[CH:11][CH:12]=[C:13]([N+]([O-])=O)[CH:14]=2)=[CH:5][CH:4]=1.[OH:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][CH:28]([C:32]([OH:34])=[O:33])[CH2:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:21][C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][CH:28]([C:32]([OH:34])=[O:33])[CH2:29]4)=[CH:24][CH:23]=3)[CH:12]=[CH:11][N+:10]=2[O-:18])=[CH:5][CH:4]=1
Reactant: O=C(O)C1CCc2ccc(O)cc2C1
Reactant: COc1ccc(CNc2cc([N+](=O)[O-])cc[n+]2[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Oc3ccc4c(c3)CC(C(=O)O)CC4)cc[n+]2[O-])cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of N-(4-methoxybenzyl)-4-nitropyridin-2-amine 1-oxide (25.6 g, 0.0929 mol), 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (17 g, 0.088 mol) and cesium carbonate (92 g, 0.28 mol) in DMF (200 mL, 3 mol) was heated with stirring at 80° C. overnight. The reaction mixture was allowed to cool and then concentrated to small volume and 200 ml of water was added. The solution was acidified with conc. HCl to pH=4. The aqueous solution was removed and the remaining organic solution was washed with water (3×). The residue was treated with 1N NaOH (150 ml) and extracted with DCM (3×). The aqueous solution was acidified with conc. HCl. A precipitate formed and was filtered, washed with water (3×), and dried to give 7-({2-[(4-methoxybenzyl)amino]-1-oxidopyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (33 g, 89%) as a brown solid. 1H NMR (d6-DMSO, 400 MHz) δ: 12.40 (s, 1H); 8.03 (d, 1H); 7.80 (t, 1H); 7.20 (d, 2H); 7.12 (d, 1H); 6.82 (d, 2H); 6.76 (m, 2H); 6.20 (s, 1H); 6.10 (d, 1H); 4.30 (d, 1H); 3.70 (s, 3H); 2.80 (m, 4H); 2.65 (m, 1H); 2.08 (m, 1H); 1.74 (m, 1H) LCMS ES+ 421.1
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([C:11]([C:13]2[C:18]([CH:19]([CH3:21])[CH3:20])=[C:17]([O:22][CH3:23])[N:16]=[C:15]([O:24][CH3:25])[N:14]=2)=[O:12])[CH:7]=[C:8]([CH3:10])[CH:9]=1.Cl>C(Cl)(Cl)Cl.CO>[CH:19]([C:18]1[C:13]([C:11]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([CH3:10])[CH:7]=2)[CH:3]=[O:2])=[O:12])=[N:14][C:15]([O:24][CH3:25])=[N:16][C:17]=1[O:22][CH3:23])([CH3:21])[CH3:20]
Reactant: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C(OC)OC)c2)n1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C=O)c2)n1
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a stirred solution of (3-dimethoxymethyl-5-methyl-phenyl)-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-methanone (3.13 g, 8.36 mmol) in chloroform (30 ml) at room temperature, was added hydrogen chloride in methanol solution [prepared from methanol (30 ml) and acetyl chloride (4 ml)]. After stirring for 2 hr., the mixture was evaporated in vacuo. The residue was dissolved in ether, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, i) MC, ii) MC:EA (9:1)) to afford 2.3 g (84%) of a white solid. m.p. 111-113° C.; 1H NMR (300 MHz, CDCl3) δ 1.20 (6H, d, J=7.2 Hz), 2.50 (3H, s), 2.85 (1H, m), 3.93 (3H, s), 4.08 (3H, s), 7.94 (1H, s), 7.99 (1H, s), 8.08 (1H, s), 10.02 (1H, s).
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([Sn](C)(C)C)=[CH:12][N:13]=[C:8]2[NH:7][CH2:6][C:5]1=[O:18])([CH3:3])[CH3:2].Br[C:20]1[C:25]([CH3:26])=[CH:24][C:23]([C:27]2[N:31]=[CH:30][N:29]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:28]=2)=[C:22]([F:38])[CH:21]=1>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:38][C:22]1[C:23]([C:27]2[N:31]=[CH:30][N:29]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:28]=2)=[CH:24][C:25]([CH3:26])=[C:20]([C:11]2[N:10]=[C:9]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:18])[CH2:6][NH:7][C:8]3=[N:13][CH:12]=2)[CH:21]=1
Reactant: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1Br
Reactant: CC(C)N1C(=O)CNc2ncc([Sn](C)(C)C)nc21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 140 °C
Yield: 52.7 %

Procedure:
1-Isopropyl-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (300 mg, 0.84 mmol), 3-(4-bromo-2-fluoro-5-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (428 mg, 1.26 mmol) and bis(triphenylphosphine)palladium(II)dichloride (56 mg, 0.08 mmol) were combined in N,N-dimethylformamide (5 mL). The mixture was degassed and heated at 140° C. under nitrogen for 3 h. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative TLC (15% methanol in dichloromethane) to give the title compound (200 mg, yield 52%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]1)[CH2:5][NH2:6].[N:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[C:23]([CH3:30])[N:24]=[CH:25]2)=[C:18]=[O:19].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]1)[CH2:5][NH:6][C:18]([NH:17][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[C:23]([CH3:30])[N:24]=[CH:25]2)=[O:19]
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: CC1CCN(c2ccc(CN)cc2F)CC1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCC(C)CC4)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 3-fluoro-4-(4-methyl-1-piperidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.52 (s, 1H), 8.66 (s, 1H), 8.59 (d, 1H, J=8.4 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.83 (t, 1H, J=8.4 Hz), 7.62 (t, 1H, J=6 Hz), 7.10 (m, 3H), 4.32 (d, 2H, J=6 Hz), 3.31 (m, 2H), 2.79 (s, 3H), 2.69 (m, 2H), 1.71 (m, 2H), 1.49 (m, 1H), 1.32 (m, 2H), 0.95 (d, 3H, J=6 Hz). MS (ESI) 407 (M+H)+; Anal. Calcd for C24H27FN4O.2.3HCl: C, 58.79; H, 6.02; N, 11.43. Found: C, 58.73; H, 6.18; N, 11.19.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:4]([C:8](=[N:10][OH:11])N)=[N:5][O:6][N:7]=1.N([O-])=O.[Na+]>O>[NH2:2][C:3]1[C:4]([C:8]([Cl:1])=[N:10][OH:11])=[N:5][O:6][N:7]=1
Reactant: Cl
Reactant: NC(=NO)c1nonc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nonc1C(Cl)=NO
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
A solution of 3 M of hydrogen chloride in water (190 mL) was treated with 4-amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide [J. Heterocycl. Chem. (1965), 2, 253] (7.3 g, 0.051 mol) at 0° C. The reaction mixture was treated with enough 12 M hydrogen chloride (˜19 mL) to dissolve the solid and then treated with a solution of sodium nitrite (4.4 g, 0.063 mol) in water (24 mL) dropwise while maintaining an internal temperature at 0-5° C. with an ice/brine bath. The reaction mixture was stirred at 0° C. for 1.5 h and filtered to yield a beige solid. Purification of the crude mixture by preparative HPLC gave the desired product (1.7 g, 21%) as an off-white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]([NH2:9])[CH3:8].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[CH3:43][C:31]1[N:30]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:24][CH:25]=2)[C:38]2[C:33]([C:32]=1[CH3:42])=[CH:34][C:35]([C:39](=[O:40])[NH:9][C@H:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:8])=[CH:36][CH:37]=2
Reactant: C[C@H](N)c1ccccn1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccccn3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(pyridin-2-yl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 504 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH3:21][C:22]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([N+:29]([O-:31])=[O:30])[C:22]=2[CH3:21])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: C=CCOc1cc(C)cc(Oc2ccc(C=O)cc2)c1
Product: C=CCOc1cc(C)cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 89B and 2-methyl-3-nitroaniline were processed as in Example 6A to provide the title compound. MS (ESI−) m/z 403 (M−H)−.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2]1.[H-].[Na+].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.O>COCCOC>[O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:13])[CH:7]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:25][CH:24]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccoc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of ethyl 3-(3-furanyl)-3-oxopropionate (20 g, 110 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 4.4 g, 110 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (26.2 g, 110 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 3 hrs. The reaction solution was poured into water (300 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give ethyl 3-(3-furanyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (28.8 g, 77%).
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH3:1][CH:2]1[O:9][C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[O:8][CH:6]([CH3:7])[CH2:5][N:4]2[CH2:3]1
Reactant: CC(O)CNCC(C)O
Reactant: CC(C)CCCCCC(=O)O
Product: CC(C)CCCCCC12OC(C)CN1CC(C)O2
Temperature: 180 °C
Reaction time: 3.5 h

Procedure:
To a 1 liter stirred reactor, equipped with a distillation column, condenser, and graduated receiver, the following constituents were added: 331.2 g of diisopropanol amine (DIPA) and 390.5 g (98%) of isononanoic acid. The contents were heated to 180° C. under a nitrogen blanket. After 3.5 hours, 43.4 g of water was collected overhead. The pressure was then slowly lowered to strip out unreacted DIPA. At a batch temperature of 183° C. and a pressure of 60 Pa, a cut consisting of 188 g of DIPA was removed. The batch temperature was then raised to 200° C. and the pressure dropped 333 Pa. During this period, a cut of 220 g of the amide acetal was recovered. The water of reaction passed through the condenser and was not captured with the amide acetal. This represents a 35% conversion of the isononanoic acid to amide acetal.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([NH:13][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)(=[O:16])=[O:15])=[CH:22][CH:21]=2)=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Reaction time: 18 h

Procedure:
416.5 mg (1.85 mmol) of tin(II) chloride dihydrate are added to a solution of 136 mg (0.37 mmol) of N-benzyl-4′-nitrobiphenyl-4-sulfonamide (Example 9A) in 2.0 ml, of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated in vacuo and dried under high vacuum. 117 mg (84.3% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][NH2:37])=[CH:31][CH:30]=1)([O-:28])=[O:27].Cl>C1COCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:37][CH2:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:34][CH:33]=1)=[O:9]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A solution of 8.8 g (47.2 mmol) of 5-chloro-2-methoxybenzoic acid and 8.5 g (51.9 mmol) of carbonylbisimidazole in 180 ml of absolute THF was stirred at room temperature for 2 h. 10 g (49.7 mmol) of 2-(4-nitrophenyl)ethylamine hydrochloride and 9.4 ml of triethylamine were added and the resulting solution was then stirred overnight at room temperature. The reaction solution was then slowly poured onto 1.2 l of 1N hydrochloric acid, and the deposited precipitate was filtered off and washed with water. Drying of the precipitate in a high vacuum yielded 13.8 g of the title compound as a white solid. M.p.: 159-160° C. Rf (silica gel, EA/heptane 4:1)=0.46. MS (ESI): m/z=334 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)(=O)[CH3:2].Cl.[NH2:14][OH:15].C([O-])(=O)C.[K+]>C(O)C>[C:1](=[N:14][OH:15])([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(=NO)c1ccc2c(c1)CCC2
Yield: 91.5 %

Procedure:
Anhydrous aluminum trichloride (25 g) is added dropwise to a stirred mixture of acetylchloride (11.8 g), indane (24 g) and dry benzene (100 ml) stirred at 5-8° C. The stirring is continued for 6 hours at this temperature until the evolution of hydrogen chloride is over; then, the mixture is partitioned with ice (200 g) and 6N hydrochloric acid (100 ml), the organic phase is separated, the aqueous phase is extracted with benzene. The organic benzene layers are collected, washed until neutral, dried on MgSO4 and the excess solvent is evaporated under vacuum. The residue (28.5 g) is distilled in high vacuum (1 mmHg) and the fractions with b.p. 80°-85° C. are collected affording 16 g of 5-acetylindane. I.R.=1680 cm-1. H-NMR (CDCl3 /TMS): 7.1-7.8 (m, 3H, Ar); 2.9 (t, 4H); 2.55 (s, 3H, CH3); 1.9-2.4 (m, 2H). A solution of 5-acetylindane (15 g) in ethanol (50 ml) is treated with a solution of hydroxylamine hydrochloride (15 g) and potassium acetate (21.5 g) in ethanol (50 ml) for 20 minutes at the reflux temperature. The excess of the solvent is evaporated in vacuum and the mixture is diluted with water. The precipitate is collected by filtration affording 15.01 g of 5-acetylindane oxime m.p. 104° C. I.R.=3200 cm-1. H-NMR (CDCl3 /TMS): 8.15 (s, 1H, N--OH); 2.3 (s, 3H, CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[CH:7]=[C:8]([C:29]([CH3:31])=O)[C:9]([O:11][CH:12]1[CH2:15][N:14]([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13]1)=[O:10])([O-:3])=[O:2].Cl.[C:36]([CH2:39][C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])(=[NH:38])[NH2:37].C[O-].[Na+]>C(O)(C)C>[NH2:38][C:36]1[NH:37][C:29]([CH3:31])=[C:8]([C:9]([O:11][CH:12]2[CH2:15][N:14]([CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:13]2)=[O:10])[CH:7]([C:6]2[CH:32]=[CH:33][CH:34]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:39]=1[C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41]
Reactant: CC(C)OC(=O)CC(=N)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC1=C(C(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(N)N1
Yield: 56.4 %

Procedure:
1.6 g (0.0035 mole) of 1-benzhydryl-3-azetidinyl 2-(3-nitrobenzylidene)acetoacetate (prepared as described in Preparation 15) and 0.63 g (0.0035 mole) of isopropyl amidinoacetate hydrochloride were dissolved in 40 ml of isopropanol. 0.19 g (0.0035 mole) of sodium methoxide was then added to the mixture, and the mixture was heated under reflux for 4 hours. At the end of this time, the mixture was cooled, and the insoluble material was filtered off. The solvent was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, using a 4:1 by volume mixture of toluene and ethyl acetate as eluent, to give 1.15 g (yield 56%) of the title compound as pale yellow crystals, melting at 104°-107° C.