Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C@@H:38]2[CH2:40][O:39]2)=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C@@H:38]([OH:39])[CH2:40][N:19]2[CH2:20][CH2:21][C:16]3([O:15][C:14]4[C:24]5[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=4[S:23][CH2:22]3)=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:25]=5)[CH2:17][CH2:18]2)=[CH:34][CH:33]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3cc(-c4ccccc4)ccc3C(=O)C2=O)cc1

Procedure:
Compound 212 was synthesized using 9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=151-152° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.98 (m, 2H), 7.86 (d, J=7.6 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.53 (m, 3H), 7.28 (m, 2H), 6.85 (m, 2H), 4.85 (brs, 1H), 3.98 (brm, 3H), 3.10 (s, 2H), 2.82 (m, 2H), 2.44 (m, 4H), 2.0 (m, 2H), 1.80 (m, 2H), 1.20 (s, 9H); LCMS: 584 [M+H].
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])([OH:10])=[O:9].[C:12]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19](O)[CH2:18][CH2:17]1)(=[O:14])[CH3:13].C(=O)([O-])O.[Na+]>C(#N)C>[C:12]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([O:9][N+:8]([O-:11])=[O:10])[CH2:18][CH2:17]1)(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
28.3 ml (0.3 mol) acetic acid anhydride are mixed with 375 ml acetonitrile, cooled in an ice-bath to 0°-5° C. and 12.6 ml (0.3 mol) 100% nitric acid added dropwise. After 30 minutes, 15.7 g (0.1 mol) solid trans-N-acetyl-4-hydroxycyclohexylamine are added thereto with stirring and cooling at 0°-5° C. The reaction mixture is further stirred for 3 h at 0°-5° C. and subsequently allowed to flow carefully into a solution of 150 g (18 mol) sodium hydrogen carbonate in 500 ml ice water. After extraction with ethyl acetate, drying of the organic phase with sodium sulphate and distilling off in a vacuum, there remain 17.8 g of crude product. After recrystallisation from ethyl acetate, there are obtained 10.3 g of the title compound of the m.p. 146°-148° C., i.e. 50% of theory.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:22][CH:23]1[CH2:27][CH2:26][O:25][CH2:24]1>>[O:25]1[CH2:26][CH2:27][CH:23]([NH:22][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:24]1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Reactant: NC1CCOC1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC2CCOC2)[nH]n1
Yield: 48 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (492 mg, 1.7 mmol) was converted, using rac-3-aminotetrahydrofuran instead of 4-aminotetrahydropyran, to the title compound (280 mg, 48%) which was obtained as a colorless oil. MS: m/e=349.2 [M+H]+.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5](Br)[CH:4]=1.Cl.[CH3:17]C1C=C(C)C=CC=1NN>>[ClH:1].[CH3:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5]([CH3:17])[CH:4]=1
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Reactant: Cc1ccc(NN)c(C)c1
Agent: Cl
Product: Cc1cc(C)c2[nH]cc(CCN)c2c1

Procedure:
5,7-Dimethyltryptamine hydrochloride was prepared (2.86 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2,4-dimethylphenylhydrazine hydrochloride (15.0 g) as starting material. ##STR51##
Reaction SMILES: Br[CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[CH3:15][NH:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][N:16]([CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:17]
Reactant: N#Cc1cccc([N+](=O)[O-])c1CBr
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1c(C#N)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a stirred mixture of 2-(bromomethyl)-3-nitrobenzonitrile (1.10 g, 4.56 mmol) (prepared according to the method described in Tetrahedron 40: 1863-1868 (1984)) and dimethylamine hydrochloride (0.74 g, 9.13 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.85 g, 18.25 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 h and evaporated to dryness under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (3×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 2-((dimethylamino)methyl)-3-nitrobenzonitrile (0.75 g, 80%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.93 (br d, 1H, J=8.0 Hz), 7.85 (dd, 1H, J=8.0, 1.4 Hz), 7.55 (t, 1H, J=8.0 Hz), 3.94 (s, 2H), 2.24 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[F:10][C:11]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.[OH-].[Na+]>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:13]([C:12]3[CH:16]=[CH:17][C:18]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:19][C:11]=3[F:10])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)ccc3[nH]2)c(F)c1
Temperature: 195 °C
Yield: 43.3 %

Procedure:
4-bromobenzene-1,2-diamine (1.75 g, 9.39 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.39 mmol) were dissolved in polyphosphoric acid (70 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H2O) followed by removal of EtOAc afforded the crude. Crude was purified on combiflash with a gradient mixture of EtOAc and Petether (33:67) to obtain the titled compound (1.5 g) as an off-white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[NH:14][CH:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=2)=[N:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1>CN(C=O)C>[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH:46][C:15]([C:12]2[CH:11]=[C:10]([C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][N:2]=3)[NH:14][CH:13]=2)=[O:17])=[CH:43][CH:42]=1
Reactant: O=C(O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1c[nH]c(-c2n[nH]c3ncccc23)c1

Procedure:
A mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (50 mg, 0.22 mmol), HOBt (74 mg, 2.5 eq.). EDAC•HCl (105 mg, 2.5 eq.), 4-chlorobenzylamine (4 eq.) and TEA (0.5 mL) in DMF (1 mL) was heated at 40° C. overnight. The reaction was concentrated and the residue was purified on a silica gel column to give the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:18]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[N:8]([CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CCCC(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCCC(=O)N2C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (prepared according to: Hassner, A.; Amit, B.; Marks, V.; Gottlieb, Hugo E., J. Org. Chem. 2003, 68(18), 6853-6858.) (300 mg, 1.57 mmol) in 15 mL of DMF was cooled to 0° C. in an ice bath, and to the solution was added NaH (60% in mineral oil) (70 mg, 1.73 mmol). After 10 minutes of stirring at 0° C., Iodomethane (270 mg, 1.88 mmol) was added to the solution. The reaction was allowed to warm to room temperature and upon completion (after 30 minutes) was quenched with ice and water. The aqueous solution was extracted 3× with diethyl ether, and the organic layers were washed with water and brine, dried with MgSO4, and concentrated to give 6-Methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a yellow oil (quantitative yield). 1H-NMR (CDCl3) δ 7.22 (t, J=8.2 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.33 (s, 3H), 2.52-3.09 (br pk, 2H), 2.29 (t, J=7.1 Hz, 2H), 2.12 (br s, 2H); LC/MS (ESI-pos) m/z 205.98 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[NH2:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2N)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The 4-(3-nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (633 mg) was then diluted with MeOH/EtOAc (1:1, 10 mL) and to the resulting solution was added Pd on carbon (5% Pd). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for about 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to provide 4-(3-amino-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a solid form. HPLC-MS RT=1.10 min, mass calculated for formula C14H22N4O2 278.17, observed LCMS m/z 279.28 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[N:24][C:23]([NH2:26])=[N:22]1>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[N:24][C:23]([NH:26][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:22]1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ncn(Cc2cccc(Cl)c2)n1
Product: Cc1cn(-c2ccc(Nc3ncn(Cc4cccc(Cl)c4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(3-chloro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a yellowish solid (Yield=64%). MS ISP (m/e): 390.1 (100) [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N+:19]([O-])=[CH:18][CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:30].O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18](=[O:30])[CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2cc[n+]([O-])c4ccccc24)CCC3)n1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nn3c(c2-c2cc(=O)[nH]c4ccccc24)CCC3)n1
Reaction time: 40 h

Procedure:
To a solution of 4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline-1-oxide (103 mg, 0.30 mmol) in N,N-dimethylformamide (3 mL) is added trifluoroacetic anhydride (425 μL, 3.0 mmol). The mixture is stirred for 40 h, poured into water, and the pH adjusted to 8 with saturated aqueous sodium bicarbonate solution. The mixture is extracted three times with ethyl acetate, the combined organic extracts washed three times with water and once with brine, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is triturated with 10% acetone/90% dichloromethane and filtered. The solid is dried under vacuum to yield the title compound, 11.6 mg (10%), as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(O[CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:20]1([CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88.6 %

Procedure:
Boron trifluoride-ether complex (0.65 ml, 5.29 mmol) was added to a solution of ethyl indole-2-carboxylate (10.0 g, 52.9 mmol) in 100 ml of methylene chloride, and a solution of benzhydryl acetate (11.4 g, 50.2 mmol) in 50 ml of methylene chloride was dropwise added thereto, followed by stirring at room temperature for 40 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution for neutralization followed by extraction with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product. The obtained crude product was washed with diisopropyl ether to give 15.8 g (yield: 84%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][NH:8][C:9]1[S:10][C:11]([CH:14]=[O:15])=[CH:12][N:13]=1)[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[C:21](=O)([O:37]N1C(=O)CCC1=O)[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2>C1COCC1.O>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([NH:1][C@@H:2]([CH2:6][CH2:7][NH:8][C:9]3[S:10][C:11]([CH:14]=[O:15])=[CH:12][N:13]=3)[C:3]([OH:5])=[O:4])=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: N[C@@H](CCNc1ncc(C=O)s1)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cnc(NCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)s1
Reaction time: 1.5 h
Yield: 23.1 %

Procedure:
To a solution of the crude material from Example 50 (6.76 g, 9.86 mmol) in a mixture of THF (74.0 ml) and water (24.7 ml) is added sequentially sodium bicarbonate (4.97 g, 59.2 mmol), and (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (3.33 g, 9.86 mmol) and the reaction is stirred at room temp. for 1.5 h. The solvent is removed in vacuo and the residue is partitioned between water (25 mL) and EtOAc (25 mL). The organic layer is discarded, and the aqueous layer treated with 1N HCl until pH 3 is achieved. The aqueous layer is extracted with CH2Cl2 (3×25 mL), the organic layers are combined, washed with brine, dried over MgSO4, filtered and evaporated to dryness to give 1.03 g (20.8%) of the title compound as a pale orange solid. LC/MS (Condition A): ret. T=3.59 min, (M+H)+ 452.14. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.75 (1 H, br. s.), 9.65 (1 H, s), 8.98 (1 H, br. s.), 8.06 (1 H, s), 7.91 (2 H, d, J=7.53 Hz), 7.68-7.83 (3 H, m), 7.39-7.47 (3 H, m), 7.30-7.39 (3 H, m), 4.19-4.39 (3 H, m), 3.97-4.10 (1 H, m), 3.41 (2 H, d, J=4.52 Hz), 2.10 (1 H, dd, J=13.55, 4.77 Hz), 1.90 (1 H, dd, J=13.55, 9.79 Hz).
Reaction SMILES: O.NN.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH2:26][N:27]2C(=O)C3C(=CC=CC=3)C2=O)([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO>[NH2:27][CH2:26][C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:10])[CH2:16][CH2:15]1)([C:18]([O:20][CH3:21])=[O:19])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)(C(=O)OC)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)C(CN)(C(=O)OC)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -5 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
A solution of 2.9 ml (64 mmol) of hydrazine hydrate in 8 ml of methanol is added to a solution of 27.5 g (58 mmol) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)malonate in 300 ml of methanol cooled beforehand to −5° C. The reaction medium is stirred at from −5° C. to ambient temperature over the course of 3 h. After evaporation and addition of 300 ml of water, the reaction medium is extracted with ethyl acetate. The organic phases are washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on silica gel, elution being carried out with an 8/2 heptane/ethyl acetate mixture and then an increase in polarity up to a 90/10 ethyl acetate/methanol mixture. 10 g (50%) of dimethyl 2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate are thus obtained in the form of a light oil.
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][CH:19]=[N:18][CH:17]=3)[C@H:14]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:37])[CH3:36])[C:27]([O:29]C(C)(C)C)=[O:28])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][CH:19]=[N:18][CH:17]=3)[C@H:14]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:36])[CH3:37])[C:27]([OH:29])=[O:28])=[O:10])=[CH:38][CH:39]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@@]1(C(=O)OC(C)(C)C)C[C@@H](c2ccncn2)[C@H](c2cncs2)N1C(=O)c1ccc(C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@]1(C(=O)O)C[C@@H](c2ccncn2)[C@H](c2cncs2)N1C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1. Purification was achieved by reverse phase HPLC on a Supelco ABZ plus column using a gradient of 45-50% acetonitrile/water as the eluent and analysis of the fractions by electrospray mass spectroscopy. The second eluting component was collected and confirmed by nOe studies to be the title compound, isolated as a solid. The first eluted component was the 4-α epimer (Example 56).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.[H-].[Na+]>CN(C=O)C>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:6]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[C:2]1[CH3:1]
Reactant: BrCCCCCBr
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
(Scheme 2 (E)) To a solution of 2-Methyl-4,5-diphenyl-1H-imidazole (2.0 g, 8.5 mmol) and 1,5-dibromopentane (3.01 g, 12.7 mmol) in DMF (100 mL) was added NaH (60% in mineral oil, 0.50 g, 12.7 mmol). The resulting mixture was stirred at rt for 1 hour, quenched by addition of water, extracted by CH2Cl2, washed by water, and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a pale yellow oil (2.2 g, 5.7 mmol, 67% yield): 1H NMR (DMSO): δ1.20 (m, 2H), 1.47 (m, 2H), 1.64 (m, 2H), 2.41 (s, 3H), 3.45 (t, 2H), 3.72 (t, 2H), 7.16 (m, 3H), 7.31 (m, 4H), 7.55 (t, 3H). Mass Spec: 384.57 (MH+).
Reaction SMILES: [O:1]1[CH:15]2[CH:2]1[C:3](=[O:25])[C@@H:4]([C@H:14]2/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>O>[C:32]([O:24][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])/[CH:17]=[CH:16]/[C@@H:14]1[C@@H:4]([CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:3](=[O:25])[CH:2]2[O:1][CH:15]12)(=[O:34])[CH3:33]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C2OC2C(=O)[C@@H]1C/C=C\CCCC(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCC[C@@H](/C=C/[C@H]1C2OC2C(=O)[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O
Reaction time: 18 h

Procedure:
to a solution of 1 part of (5Z,13E,15S)-10ξ,11ξ-epoxy-15-hydroxy-9-oxoprosta-5,13-dien-1-oic acid in 30 parts of pyridine at 5° is added 10 parts of acetic anhydride. The resultant mixture is allowed to stand at 5° for 18 hours, whereupon it is poured into 10 volumes of water. The mixture thus obtained is allowed to stand for 1 hour, then extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual red oil is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 20% ethyl acetate in benzene, on evaporation of solvent, (5Z,13E,15S)-15-acetoxy-10ξ,11ξ-epoxy-9-oxoprosta-5,13-dien-1-oic acid is obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:13]=1[N+:26]([O-:28])=[O:27].Cl.[CH:30]1([CH:33]([NH2:36])[CH2:34][CH3:35])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:36][CH:33]([CH:30]2[CH2:32][CH2:31]2)[CH2:34][CH3:35])[C:13]=1[N+:26]([O-:28])=[O:27]
Reactant: CCC(N)C1CC1
Reactant: CN(C)c1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Agent: Cl
Product: CCC(Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 43.4 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester (548 mg, 1.76 mmol) and 1-cyclopropyl-propylamine HCl (479 mg, 3.5 mmol) were treated substantially as described in Part C of Example 19a to produce 300 mg (43%) of crude [4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (EI) m/z 393.22 [(M+H)+, 100].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH2:19][CH2:20][C:21]([OH:23])=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11]3[C:10]=1[CH2:19][CH2:20][C:21](=[O:23])[C:12]=3[CH:13]=[CH:14][CH:15]=2
Reactant: COc1ccc2ccccc2c1CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2cccc3c2c1CCC3=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 250 ml three-necked flask, oxalyl chloride (1.95 ml, 2.19.10−2 mol, 1 eq.) is added dropwise, under argon, to a solution of the acid obtained in Step D (5 g, 2.17.10−2 mol) in anhydrous dichloromethane (225 ml) at 0° C. A few drops of anhydrous dimethylformamide are then added. After 1 hour at 0° C., slight evolution of gas is still observed and the three-necked flask is left at ambient temperature for 40 minutes. After return to 0° C., aluminium chloride (7.5 g, 5.62.10−2 mol, 2.6 eq.) is added using a spatula. The initially yellow solution becomes red, orange and then khaki-green. After 15 minutes' stirring at 0° C., the mixture is poured into an ice/1N HCl mixture. After separation of the phases and washings of the acidic aqueous phase with dichloromethane, the combined organic phases are washed with water, then treated with a saturated NaHCO3 solution and finally washed with a saturated NaCl solution. After drying over MgSO4 and evaporation under reduced pressure, the yellow oil obtained crystallises in a freezer.