Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=O)[O:17][C:15](=[O:16])[C:14]2=[CH:20][C:21]=1[Cl:22]>C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]2[C:14](=[CH:20][C:21]=1[Cl:22])[C:15](=[O:16])[N:1]([C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8])[C:18]2=[O:17]
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: NC(=O)c1sccc1N
Solvent: CC(=O)O
Product: NC(=O)c1sccc1N1C(=O)c2cc(Cl)c(Cl)cc2C1=O

Procedure:
3-aminothiophene-2-carboxamide was added to an acetic acid solution of 4,5-dichlorophthalic anhydride and stirred all night heated to reflux to give 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide. 1M NaOH aq was added to THF-MeOH solution of the obtained 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide and stirred for 2.5 hours at 80° C. to give 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid. Sulfuric acid was added to a MeOH-1,4-dioxane solution of the obtained 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid and stirred for three days at 70° C. to give methyl 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoate.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=2)[C:24]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][O:48][Si](C(C)C)(C(C)C)C(C)C)[CH:20]=[CH2:21]>C1COCC1.CCOC(C)=O>[CH2:19]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=2)[C:24]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][OH:48])[CH:20]=[CH2:21]
Reactant: C=CCn1c(-c2ccccc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCn1c(-c2ccccc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Tetrabutylammonium fluoride (1.3 eq., 1M solution in THF) was added dropwise to an ice cooled solution of methyl 1-allyl-3-cyclohexyl-2-(2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate in THF (0.036M). The mixture was stirred at RT for 1 h then diluted with EtOAc, washed with saturated aq. NH4Cl, water and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 4:1). After evaporation of the solvent the product was obtained as colourless solid (95%). MS (ES+): 404.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[H-].[Na+].Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:3]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: N#Cc1ccc(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1OCC(=O)N1CCOCC1
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
To a solution of intermediate 129, 4-fluoro-2-hydroxybenzonitrile, (685 mg, 5 mmol) in dimethylformamide (8 mL, Sure Seal; Aldrich) was added NaH (200 mg, 5 mmol; 60% oil dispersion; Aldrich), and the mixture stirred for 5 min under an anhydrous nitrogen atmosphere. To this was added 4-(2-chloroacetyl)morpholine (900 mg, 5.5 mmol, 1.1 eq.; Avocado Organics), and stirring continued at room temperature for 21 hrs. The reaction was quenched by careful addition of water (30 mL). The resulting mixture was extracted with CH2Cl2 (25 mL×2). The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was triturated to obtain 1.10 g (4.17 mmol, Yield 83%) of the title compound as a white solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.63 (2H, t, J=4 Hz, NCH2), 3.67 (1H, m, OCH), 3.72 (1H, m, OCH), 4.86 (2H, s, OCH2), 6.80-6.86 (2H, m, Ar—Hs), 7.61 (1H, dd, J=8.5 Hz, 6.1 Hz, Ar—H); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 42.63, 46.04, 66.80, 68.33, 98.45, 98.47, 101.57, 101.79, 109.56, 109.74, 115.42, 135.48, 135.57, 161.26, 161.35, 114.79, 165.23, 167.28. HRMS calcd for C13H14N2O3F (M+H) 265.0988, found 265.0998.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.[N:20]([CH:23]([C:25]1[N:26]=[C:27]2[S:35][CH:34]=[C:33]([CH3:36])[N:28]2[C:29](=[O:32])[C:30]=1Br)[CH3:24])=[N+:21]=[N-:22]>O1CCOCC1.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>[N:20]([CH:23]([C:25]1[N:26]=[C:27]2[S:35][CH:34]=[C:33]([CH3:36])[N:28]2[C:29](=[O:32])[C:30]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:24])=[N+:21]=[N-:22]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccn3)c(=O)n12
Temperature: 65 °C
Yield: 13.1 %

Procedure:
A mixture of 2-(tributylstannyl)pyridine (Aldrich, 0.176 g, 0.382 mmol), 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (from example 8, step 3; 0.10 g, 0.318 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.0184 g, 0.0159 mmol) in 1,4-dioxane (0.5 mL) was heated at 65° C. overnight. After being cooled and quenched with saturated ammonium chloride, the resulting mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to provide the desired product (13 mg, 13%). LCMS calculated for C14H13N6OS (M+H)+: m/z=313.1. Found: 313.0.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.[OH-].[Na+].[BrH:18]>O.[Cu]Br>[Br:18][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: Nc1cccc2ncccc12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1cccc2ncccc12
Temperature: 75 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Sodium nitrite (2.5 g, 41.8 mmol) was dissolved in 15 mL water. Copper (I) bromide (6.0 g, 41.8 mmol) was dissolved in 38 mL of 48% HBr and heated to 75° C. The 5-aminoquinoline (5.0 g, 34.7 mmol) was suspended in 15 mL water and 18 mL 48% HBr and cooled to 0° C. The sodium nitrite solution was added to the 5-aminoquinoline solution at 0° C. The resulting diazonium solution was added slowly to the warmed CuBr solution. The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was basified with sodium hydroxide, then filtered through celite. The solid was washed with methylene chloride, and the aqueous material was extracted with methylene chloride. The organic layers were combined, dried with Na2SO4, and concentrated in vacuo. The crude product was chromatographed with 2:1 hexane/ethyl acetate to yield 5.7 g (80%) of 5-bromo-quinoline as a yellow oil. MS (APCI) m/z 208.0 (M+1).
Reaction SMILES: [NH3:1].Cl[C:3](=[N:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:4]([O:6][CH2:7][CH3:8])=O>C1COCC1>[Cl:17][C:13]1[CH:12]=[C:11]([NH:10][N:9]=[C:3]([NH2:1])[CH2:4][O:6][CH2:7][CH3:8])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(Cl)=NNc1cccc(Cl)c1
Reactant: N
Solvent: C1CCOC1
Product: CCOCC(N)=NNc1cccc(Cl)c1
Reaction time: 1 h

Procedure:
45.0 mL (60.2 mmol) aqueous ammonia solution (25%) was added over 20 minutes to a solution of 15.0 g (57.4 mmol) ethyl 2-chloro-2-(2-(3-chlorophenyl)hydrazono)acetate in 75 mL THF and stirred for 1 h. The resulting mixture was diluted and extracted with hexane and EtOAc (1:1 mixture). The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and used without further purification for the next synthesis step (yield: 12.0 g (92%)).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:17]([NH:19][C:20]3[CH:51]=[CH:50][C:23]([C:24]([N:26]([CH3:49])[C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)=[O:41])=[O:25])=[CH:22][C:21]=3[O:52][CH3:53])=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:54]([O:56][CH2:57][CH3:58])=[O:55])=O)(C)(C)C>FC(F)(F)C(O)=O>[CH2:57]([O:56][C:54]([C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[C:12]([C:17]([NH:19][C:20]1[CH:51]=[CH:50][C:23]([C:24]([N:26]([CH3:49])[C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=3[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])=[O:25])=[CH:22][C:21]=1[O:52][CH3:53])=[O:18])[CH:13]=[CH:14][CH:15]=2)=[O:55])[CH3:58]
Reactant: CCOC(=O)c1cc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.2 %

Procedure:
The mixture of 4-[(1-tert-butoxycarbonyl-2-ethoxycarbonylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (75 mg) in trifluoroacetic acid (2.0 ml) was stirred at ambient temperature for 5 minutes. Trifluoroacetic acid was removed in vacuo and the residue was diluted with aqueous saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate and the organic layer was washed with brine. Drying, filtering and removal of solvents afforded 4-[(2-ethoxycarbonylindol-4-yl)-carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (50 mg) as a yellow amorphous powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][N:20]4C(=O)C5=CC=CC=C5C4=O)[CH:16]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.[N:34]1[CH:35]=[C:36]2[N:45]3[C:40](=[CH:41][CH:42]=[CH:43][C:44]=13)[S:39][C:38]([C:46]([OH:48])=O)=[CH:37]2.CN.P(C#N)(OCC)(OCC)=O.C(=O)([O-])O.[Na+]>C(O)C.CN(C)C=O.C(N(CC)CC)C>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][NH:20][C:46]([C:38]4[S:39][C:40]5[N:45]6[C:36](=[CH:35][N:34]=[C:44]6[CH:43]=[CH:42][CH:41]=5)[CH:37]=4)=[O:48])[CH:16]=3)[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)CN(CCCc1ccccc1)C2
Agent: CCOP(=O)(C#N)OCC
Agent: CN
Agent: NN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc2c(c1)CN(CCCc1ccccc1)C2)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C

Procedure:
To a solution of 0.401 g (1.011 mM) of N-[2-(3-phenylpropan-1-yl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-phthalimide in 20 ml of ethanol was added 0.05 ml (1.11 mM) of hydrazine monohydrate and the mixture was refluxed for 2 hours. After cooling to room temperature, the precipitate that had formed was filtered off and washed with ethanol. From the pooled filtrate, the solvent was distilled off. The resulting crude N-[2-(3-phenylpropan-1-yl)-2,3-dihydro-1H-isoindol-5-yl]methylamine was not purified but used as it was in the next reaction. To a solution of 0.22 g (1.21 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid, the above crude N-t2-(3-phenylpropan-1-yl)-2,3-dihydro-1H-isoindol-5-yl]methylamine, and 0.17 ml (1.21 mM) of triethylamine in 20 ml of N,N-dimethylformamide was added 0.18 ml (1.21 mM) of diethyl cyanophosphate dropwise at room temperature with constant stirring and the mixture was stirred at the prevailing temperature for 3 days. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=9/1) to provide the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:4]([O:3][C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([O:14][CH3:17])=[O:13])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 96.6 %

Procedure:
To a solution of BOC-isonipecotic acid (45.0 g, 0.20 mol) dissolved in a 3:1 solution of dichloromethane/methanol (1200 mL) at 0° C. was added a solution of trimethylsilyldiazomethane (147 mL, 0.29 mol, 2.0M in hexane) over 30 min via an addition funnel. The reaction mixture was then concentrated to afford the title compound (47 g) as a light yellow oil. This was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9]2)[CH:4]([OH:15])[CH2:3][CH2:2]1.Cl.[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21]Cl>>[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][O:15][CH:4]1[CH:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9][CH:10]2[CH2:1][CH2:2][CH2:3]1
Reactant: OC1CCCC2Oc3ccccc3OC12
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCOC1CCCC2Oc3ccccc3OC12
Yield: 55.6 %

Procedure:
In an analogous manner as described in Example 5, but starting with 10 g (0.048 mole) of the alcohol of Example 1 and 6.6 g (0.042 mole) of 3-dimethylamino-1-chloropropane hydrochloride, there were obtained 6.8 g of the title-compound of boiling point 165° C. at a pressure of 1.33 Pa, having the elementary analysis:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:21]3[N:20]4[C:16](=[CH:17][CH:18]=[CH:19]4)[C:15](=[O:22])[C:14]=3[S:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[C:21]3[N:20]4[C:16](=[CH:17][CH:18]=[CH:19]4)[C:15](=[O:22])[C:14]=3[S:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2csc3c2-n2cccc2C3=O)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2csc3c2-n2cccc2C3=O)cc1O
Reaction time: 0.5 h

Procedure:
A solution of 0.6 mmol of the compound of Example 3 and an excess of aluminium chloride in chloroform is stirred at 50° C. for 30 minutes. After concentration under reduced pressure, the residue is stirred in water for 30 minutes to yield red crystals. After filtration, chromatography on silica gel (chloroform) allows the expected product to be isolated.
Reaction SMILES: [NH2:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][C:2]2([CH2:15][O:16][C:17](=[O:18])[NH:1]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1(CO)CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: O=C1NC2(CCN(Cc3ccccc3)CC2)CO1
Yield: 89.5 %

Procedure:
1.04 g (4.72 mmol) of 4-amino-1-benzyl-4-hydroxymethylpiperidine (for preparation see: Eur. J. Med. Chim. Ther. (1974) 9, 424-433) are suspended in 16 ml of dichloromethane and 842 mg (5.2 mmol) of carbonyldiimidazole are added. As the reaction progresses, a solution forms, which following complete reaction is diluted with dichloromethane and washed first with water, then with a 5 percent sodium bicarbonate solution and once again with water. The organic phase is dried over sodium sulfate and freed from the solvent on a rotary evaporator. 1.04 g of the title compound are obtained as a crude product, which is reacted further as it is.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:38])[C:9]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[O:10])[CH2:4]1)[CH3:2].C(CC1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)(=O)=O)(O)=O.Cl.Cl.C(N1CC[C@@H](NC)C1)C>>[CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([N:8]([CH3:38])[C:9]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[O:10])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@H](N(C)C(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Agent: CCN1CC[C@@H](NC)C1
Agent: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CC(=O)O)ccc2c1OCC1CC21
Agent: Cl
Product: CCN1CC[C@@H](N(C)C(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 126, starting from methyl (1aRS,7bSR)-5-(2-carboxymethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 83) and N—((R)-1-ethylpyrrolidin-3-yl)-N-methylamine dihydrochloride (Intermediate 132) as a light brown foam.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[C:11](=[O:28])[C:10]=1[CH:29]=[CH2:30])C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[CH2:29]([C:10]1[C:11](=[O:28])[N:12]([CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[CH:13]=[CH:14][C:9]=1[OH:8])[CH3:30]
Reactant: [H][H]
Reactant: C=Cc1c(OCc2ccccc2)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Agent: [Pd]
Solvent: CCO
Product: CCc1c(O)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Yield: 96.4 %

Procedure:
10% palladium carbon (containing 55% water, 0.767 g) was added to an ethanol (30 mL) solution of tert-butyl 4-(4-(benzyloxy)-2-oxo-3-vinylpyridin-1(2H)-yl)piperidine-1-carboxylate (1.48 g), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, and then, the solvent in the filtrate was distilled off under reduced pressure. The obtained residue was passed through a silica gel, and then, the solvent was distilled off under reduced pressure to obtain the title compound (1.12 g).
Reaction SMILES: Cl.[CH:2]1([C:8](=[NH:10])[NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.N[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C>CN(C=O)C.O>[CH:2]1([C:8](=[NH:9])[NH:10][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N=C(N)C1CCCCC1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=N)C1CCCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 28.4 %

Procedure:
To a solution of cyclohexanecarboximidamide hydrochloride (2.00 g) and tert-butyl glycinate hydrochloride (2.06 g) in DMF (16 ml) was added triethylamine (4.30 ml) at room temperature, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (0.84 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]=O)=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:17]([NH2:18])[CH:16]=[N:15][N:14]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:10]=[N:18][N:17]3[CH:16]=[N:15][N:14]=[C:13]3[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=CC(=O)c1ccc(F)cc1
Reactant: Nc1nncn1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccc(-c2cnn3cnnc3n2)cc1

Procedure:
A solution of 11.9 g. of p-fluorophenylglyoxal, 9.5 g. of 3,4-diamino-4H-1,2,4-triazole and 5.74 g. of sodium acetate in 120 ml. of 67% acetic acid is heated on a steam bath and then filtered through celite. The filtrate is heated for an additional hour and the resulting solid is collected by filtration giving the desired product as cream-colored plates, m.p. >300° C.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:22])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][S:43]([C:46]1[CH:51]=[CH:50][C:49](Br)=[CH:48][C:47]=1[N+:53]([O-:55])=[O:54])(=[O:45])=[O:44].[Cl-].[NH4+]>O1CCCC1.[Zn].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]>[CH3:10][O:11][C:12](=[O:22])/[C:13](/[C:49]1[CH:50]=[CH:51][C:46]([S:43]([CH3:42])(=[O:45])=[O:44])=[C:47]([N+:53]([O-:55])=[O:54])[CH:48]=1)=[CH:14]/[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CS(=O)(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: COC(=O)/C(I)=C\C1CCCCC1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane (187 mg, 1.5 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (110 mg, 1 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (prepared in Example 4, 1.2 g, 4.2 mmol) in dry tetrahydrofuran (2 mL) over 5 min. The reaction mixture was then stirred at 40-45° C. For 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (4 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) and triphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (4 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromo-2-nitrophenyl methyl sulfone (0.94 g, 3.35 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. For 15 h. The reaction mixture was then cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (70 mL), and the organic compound was extracted into ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 9/1 to 3/1 hexanes/ethyl acetate) afforded (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-nitro-phenyl)-acrylic acid methyl ester (1 g, 82%) as an amorphous white solid: EI-HRMS m/e calcd for C17H21NO6S (M+) 367.1090, found 367.1091.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[CH:16]=2)[CH2:11][CH2:10]1)(=[O:7])[CH3:6]>CO.[Pd]>[C:5]([O:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[CH:16]=2)[CH2:13][CH2:14]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC1CCN(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)OC1CCN(c2ccc(N)c(OC(C)C)c2)CC1
Temperature: 80 °C
Yield: 39.5 %

Procedure:
622 mg of ammonium formate and 525 mg of Pd/C (10%) are added to a solution of 530 mg of 1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-4-yl acetate in 13 ml of methanol. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel, and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure. The residue is taken up with 20 ml of ethyl acetate, 2 ml of water and 8 ml of a saturated aqueous sodium chloride solution. The two phases are separated and the aqueous phase is washed with 3 times 10 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. The residue is purified on silica, elution being carried out with dichloromethane/MeOH (95/5), so as to give 190 mg of 1-[4-amino-3-(propan-2-yloxy)phenyl]piperidin-4-yl acetate in the form of a brown oil.