Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[CH2:24]([O:23][C:21]([C:20](=[O:26])[NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a solution of naphthalen-2-amine (2 g, 14.0 mmol) in dichloromethane (30 ml) was added triethylamine (4.24 g, 41.9 mmol, 3 eq). Then, ethyl 2-chloro-2-oxoacetate (1.92 g, 14.1 mmol, 1 eq) was added dropwise to the solution kept at 0-5° C. using an ice-bath. The resulting solution was allowed to warm to room temperature while stirring. The reaction was then quenched by the addition of water (50 ml), the product was extracted with dichloromethane (2×50 ml), and the organic layers were combined. The organic solution was washed with saturated aqueous sodium chloride (50 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to afford ethyl[(naphthalen-2-yl)carbamoyl]formate as a black solid (3 g, 88%). (ES, m/z) [M+H]+ 244; 1H NMR (300 MHz, CDCl3): δ 9.06 (broad s, 1H), 8.32 (d, J=1.8 Hz, 1H), 7.72-7.88 (m, 3H), 7.59 (dd, J=2.1 Hz, 8.7 Hz, 1H), 7.53 (m, 2H), 4.44 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][C:23](Cl)=[O:24]>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:23](=[O:24])[CH2:22][C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Product: CCOC(=O)c1cc(C(=O)Cc2ccc3ccccc3c2)c(C)[nH]1

Procedure:
5-Methyl-4-(2-naphthalen-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethyl ester (135) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and naphthalen-2-yl-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane/−40° C.→RT. Purification: no purification. LC/MS: 80%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH3:13][N:14](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.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>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[N:3]=[C:2]([C:13]#[N:14])[CH:11]=[CH:10][C:9]1=2
Reactant: O=C1CCCc2nc(Cl)ccc21
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(n1)CCCC2=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Under nitrogen, 42.25 g (0.23 mol) of 2-chloro-7,8-dihydroquinolin-5(6H)-one, 54.64 g (0.47 mol) of zinc cyanide and 13.44 g (0.01 mol) of tetrakis(triphenylphosphine)palladium were suspended in 200 ml of anhydrous N,N-dimethylacetamide (water content <0.01%, degassed with nitrogen beforhand), heated to 100° C. and stirred at this temperature for 2 hours. After complete conversion (monitored by TLC, mobile phase petroleum ether/ethyl acetate 2:1), the reaction mixture (grey suspension) was cooled to room temperature and filtered through Celite, and the filter cake was washed with 500 ml of ethyl acetate. 200 ml of saturated aqueous sodium chloride solution were then added to the resulting organic solution. A white precipitate was formed, which was filtered off and discarded. The organic phase was separated off, washed three times with in each case 200 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness. The residue obtained was applied to 20 g of silica gel and purified by column chromatography on silica gel (80 g cartridge; flow rate: 60 ml/min; mobile phase: petroleum ether/ethyl acetate 95:5→60:40 over 40 min, then isocratic petroleum ether/ethyl acetate 60:40 for 30 min). This gave 26.35 g (0.15 mmol, 66% of theory) of the target compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][CH:20]([CH2:35]OS(C2C(C)=CC=CC=2)(=O)=O)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=2)=[O:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH2:19][CH:20]([CH2:35][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:29]=2)=[O:22])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CNS(=O)(=O)c2ccc(Cl)cc2)COS(=O)(=O)c2ccccc2C)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CNS(=O)(=O)c2ccc(Cl)cc2)Cn2ccnc2)cc1
Reaction time: 0.33 h
Yield: 70.7 %

Procedure:
A solution of imidazole (6.9 mg) in DMF (0.5 ml) was added to a 60% NaH (4.0 mg) suspension in anhydrous DMF (0.5 ml) prepared at 0° C., under argon. After stirring for 20 minutes, a DMF solution of (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-toluenesulfonyloxypropanamide (12 mg) was added. The whole was stirred at 0° C. to room temperature overnight. The reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na2SO4. The solvent was evaporated, and the residue was purified by column chromatography (6% water-containing silica gel, chloroform/methanol=5/1) to obtain the desired (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (7 mg).
Reaction SMILES: [C:1]([S:4][CH2:5][C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([Cl:19])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SC[C@@H](Cc1ccccc1)C(=O)O
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Cl

Procedure:
(S)-2-Acetylthiomethyl-3-phenylpropanoic acid (Ia S) (Example 2, stage e) is treated with thionyl chloride according to the same procedure as that described in Example 3, stage f.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.C(O)(=[O:20])C.S(=O)(=O)(O)N.[Cl-].[Na+]>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[C:9]([OH:20])=[O:10])[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Agent: NS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
40 g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde 160 mL of glacial acetic acid and 32.0 g of sulphamic acid (2.0 eq) were loaded in a reactor. The mixture was cooled at 5-10° C. and the temperature was not allowed to exceed 20° C., adding slowly a previously prepared solution of 44.77 g of sodium chloride and 61 mL of deionised water. After the addition, the reaction was kept for 1 hour at 15-20° C. 450 mL of deionised water was loaded and then it was cooled at 0-5° C. and kept for 1 h at this temperature. The solid was filtered and washed four times with 200 mL of deionised water. The product was dried for 15 h at 40° C., obtaining 36 g (yield 85%) of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (II) as solid.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[C:18]1([CH2:24][CH2:25][NH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=NCCc1ccccc1)NC#N
Yield: 40.9 %

Procedure:
A solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.69 g) and 2-phenylethylamine (7.2 g) in acetonitrile (50 ml) was heated under reflux for 24 hours. Following concentration and ether extraction to remove excess 2-phenylethylamine the crude product was chromatographed on a column of silica gel and eluted with ethyl acetate-isopropyl alcohol (4:1). Recrystallisation from ethanol-ether afforded the title compound (1.4 g) m.p. 135°-136°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].CC(C)([O-])C.[K+].Br[C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=1>CC(N(C)C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=1
Reactant: Nc1cc(O)ccc1F
Reactant: N#Cc1ccc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(F)c(N)c2)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
A solution of 3-amino-4-fluoro-phenol (5.6 g, 44 mmol) in dimethylacetamide (60 mL) was degassed in vacuo and was treated with potassium tert-butoxide (5.3 g, 47 mmol). The resulting solution was stirred for 30 min. 5-Bromo-pyridine-2-carbonitrile (6.6 g, 36 mmol) was added in one-portion and the mixture was heated at 80° C. overnight. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to provide 5-(3-amino-4-fluorophenoxy)picolinonitrile (3.5 g, 44% yield). 1H-NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=3.0 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.44 (dd, J=8.8, 2.7 Hz, 1H), 7.06 (t, J=9.2 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.28 (m, 1H), 5.44 (br s, 2H); MS (ESI) m/z: 230.0 (M+H+).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH:13]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[NH:17]1)([CH3:15])[CH3:14]>>[CH:13]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC(C)[C@H]1COC(=O)N1
Product: CC(C)[C@H]1COC(=O)N1c1ccc(C(=O)O)cc1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 18 and using ethyl 4-iodobenzoate (2.9 mL) and (S)-4-isopropyloxazolidin-2-one (2.5 g), the title compound (4.5 g) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15](OCC)=[O:16])=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.CCOCC>[CH2:1]([C:5]1[NH:6][C:7]([CH2:15][OH:16])=[C:8]([N:10]2[CH:11]=[CH:12][CH:13]=[CH:14]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-n2cccc2)c(C(=O)OCC)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1nc(-n2cccc2)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 2-butyl-4-(1H-pyrrol-1-yl)imidazol-5-carboxylate (Example 21, 0.5 g) in tetrahydrofuran (15 mL) was treated with a 1M solution of LiAlH4 in ether (2.1 mL). The reaction was stirred overnight at room temperature then quenched by addition of saturated aqueous (NH4)2SO4. The resulting suspension was extracted three times with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate and evaporated to afford the title compound as an off-white solid MS (DEI) 205 (m)
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Br.[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:3][CH:2]([F:5])[F:1])=[CH:9][CH:8]=1
Reactant: FC(F)CBr
Reactant: NCc1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: FC(F)CNCc1ccc(Cl)nc1
Temperature: 100 °C
Yield: 83.1 %

Procedure:
19.9 g (0.135 mol) of 2,2-difluoro-1-bromoethane, 10 g (0.067 mol) of 1-(6-chloropyridin-3-yl)methanamine and 8.2 g of triethylamine are initially charged with 31 g of N-methylpyrrolidone. The mixture is heated to 100° C. for 2 hours and then cooled again to 80° C. The N-methylpyrrolidone is distilled off at 80° C. under reduced pressure and the reaction mixture is poured onto 50 ml of water. 2 ml of 45% sodium hydroxide solution are used to adjust the pH to 12, and the mixture is then extracted twice with 30 ml of toluene. The product is subsequently finely distilled under reduced pressure. This gives 11.5 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (corresponds to 83.1% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:27]=O.C[O-].[Na+].[BH4-].[Na+].[OH-].[Na+]>CO>[CH3:27][NH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4cccc(N)c4)cc3)sc2c1
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1cccc(C(=O)Nc2ccc(-c3nc4ccc(C)cc4s3)cc2)c1
Temperature: 25 °C
Yield: 18.5 %

Procedure:
To a stirred mixture of 3-amino-N-[4-(6-methylbenzothiazol-2-yl)-phenyl]-benzamide (0.50 g, 1.39 mmol) and paraformaldehyde (0.059 g, 1.95 mmol) in MeOH (15 ml) at 0° C. was added dropwise a solution of sodium methoxide in MeOH (0.5 M, 3.9 ml, 1.95 mmol). The reaction mixture was then heated under reflux for 1 h. The reaction mixture was cooled to room temperature, sodium borohydride (0.081 g, 2.09 mmol) was added and heating was continued under reflux for 1 h. The reaction mixture was cooled to 0° C. amd 1 M NaOH solution (10 ml) was added, followed by extraction with DCM (3×70 ml). The combined organic extracts were dried (Na2SO4) and the solvent removed under reduced pressure to give an almost colourless solid. This was purified by flash chromatography (1:1 Hexane/EtOAc) to give the title compound (0.096 g, 18%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](O)(=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[C:23](=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: CC(=O)CCC(=O)O
Solvent: CCCCO
Product: CC1=NN(c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)C(=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
To a suspension of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (2 g) in n-Butanol (40 mL) was added of 0.744 g of levulinic acid. The mixture was heated at reflux. After 3 h, the mixture was cooled at 0° C. and the 4-({4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-hydrazono)-4-methyl-butyric acid (1.92 g, 73%) was recovered by filtration. Mp 218–220° C., 1H NMR DMSO-d6) 12.1 (1H, OHacid), 9.93 (1H, s, NH), 9.48 (1H, s, NH), 8.64 (1H, d, 5 Hz), 8.24 (1H, d, 5 Hz), 8.0 (1H, s), 7.76 (2H, m), 7.46 (1H, d, 5 Hz), 7.38 (1H, dd, 2 Hz, 5 Hz), 7.30 (1H, t, 8 Hz), 6.98 (1H, dd, 1 Hz, 8 Hz), 2.51 (4H, s), 1.92 (3H, s), 13C NMR (DMSO-d6 176.2, 164.6, 161.6, 161.2, 150.5, 150.1, 147.5, 144.0, 134.9, 132.1, 122.97, 120.13, 119.2, 113.7, 111.1, 105.9, 35.33 (CH2), 32.56(CH2), 18.09 (CH3), MS (ES−) 409 (M−1, 100), 819 (2M−1, 30). The 4-({4-[2-(3-Chloro-phenylamino)-pyrimnidin-4-yl]-pyridin-2-yl}-hydrazono)-4-methyl-butyric acid (1.5 g) was dissolved in acetic acid (40 mL). The solution was stirred at 110° C. for 3 h then the solution was poured in a mixture of water and ice (250 mL) and neutralised with a solution saturated of sodium hydrogenocarbonate until pH 7. The mixture was extracted with ethyl acetate (3×100 mL). The organic phase were combined, dried over MgSO4, and concentrated. Flash silica chromatography, eluting with ethyl acetate-tetrahydrofuran (3-1), afforded the title compound as a solid (0.7263 g, 51%). Mp 189–192° C., 1H NMR (DMSO-d6) 10.07(1H, NH), 8.73 (1H, d, 5 Hz), 8.69 (1H, d, 5 Hz), 8.16 (1H, s), 8.06 (2H, m), 7.73 (1H, dd, 3 Hz, 10 Hz), 7.60(1H, d, 5 Hz), 7.31 (1H, t, 8 Hz), 7.03(1H, dd, 3 Hz, 8 Hz), 2.63 (4H, m), 2.07 (3H, s). 13C NMR (DMSO-d6) 165.3, 160.3, 159.6, 159.3, 154.9, 153.9, 149.0, 141.1, 132.5, 129.7, 120.7, 119.2, 117.8, 117.6, 116.7, 108.66, 26.4, 25.3, 22.0. MS (ES+) 393 (MH+, 100), 785 (2 MH+, 60).
Reaction SMILES: [CH2:1]1[CH2:8][O:7][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2]1.[CH3:9][CH:10]([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O[K])(C)(C)C>C(O)(C)(C)C>[CH2:14]([O:13][C:11]([C:10]([CH3:9])([C:16](=[O:17])[CH3:18])[CH2:8][CH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:12])[CH3:15]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: O=S1(=O)CCCCO1
Agent: CC(C)(C)O[K]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(C)(CCCCS(=O)(=O)O)C(C)=O
Yield: 75 %

Procedure:
0.35 ml (3.47 mmol) of 1,4-butane sultone were added to a mixture of 0.49 ml (3.47 mmol) ethyl 2-methylacetoacetate and 513 mg (4.2 mmol) of tert-BuOK in 12 ml tert-butanol and refluxed for 15 hours. The formed precipitate was filtered and washed with hexane to yield 730 mg of 5-ethyloxycarbonyl-5-methyl-6-oxo-1-heptanesulfonic acid. δH (200 MHz, DMSO-d6): 4.12 (2H, q, 7.1, 14.2 Hz, OCH2), 3.97 (2H, t, 5.8 Hz, CH2SO3H), 2.10 (3H, s, COCH3), 1.78-1.41 (4H, m, CH2), 1.24-1.01 (2H, m, CH2), 1.22 (3H, s, CCH3), 1.17 (3H, t, 7.3 Hz, CH2CH3).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:12]([NH:19]C(=O)[C@@H]1CCCN1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N.CCOC(C)=O>[C:32]([C@@H:31]1[CH2:30][CH2:29][CH2:28][N:19]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])#[N:27]
Reactant: CC(C)(C)OC(=O)NC(=O)[C@@H]1CCCN1
Reactant: c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C#N
Reaction time: 0.25 h
Yield: 14.9 %

Procedure:
A solution of oxalyl chloride (11.0 ml, 0.126 mol) and DMF (11.4 ml, 0.138 mol) in MeCN (170 ml) was treated dropwise with a solution of N-Boc-L-proline amide (12.3 g, 0.57 mol) and pyridine (20.4 ml, 0.253 mol) in MeCN (30 ml) at 0° C. and stirred at this temperature for 15 minutes. The reaction mixture was diluted with EtOAc and washed with H2O (×3). The organic extract was dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was purified on a silica column eluting with a solvent gradient of pentane:EtOAc (80:20) gradually changing to (60:40) to afford the title compound (7.40 g, 66%).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(C(O)=O)[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:28][CH:29]([CH2:31][CH2:32][CH2:33][C@H:34]([C@@H:36]1[C@:53]2([CH3:54])[C@H:39]([C@H:40]3[C@H:50]([CH2:51][CH2:52]2)[C@:48]2([CH3:49])[C:43]([CH2:44][C@@H:45]([OH:55])[CH2:46][CH2:47]2)=[CH:42][CH2:41]3)[CH2:38][CH2:37]1)[CH3:35])[CH3:30]>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:10]([O:55][CH:45]2[CH2:46][CH2:47][C@@:48]3([CH3:49])[C:43](=[CH:42][CH2:41][C@@H:40]4[C@@H:50]3[CH2:51][CH2:52][C@@:53]3([CH3:54])[C@H:39]4[CH2:38][CH2:37][C@@H:36]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][CH:29]([CH3:28])[CH3:30])[CH2:44]2)=[O:11])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(OC(=O)C(Cc5ccc([N+](=O)[O-])cc5)Cc5ccc([N+](=O)[O-])cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 82.8 %

Procedure:
2.00 g (5.34 mmol) of 2,2-bis(4-nitrobenzyl)malonic acid and 2.07 g (5.35 mmol) 5-cholesten-3β-ol and 65 mg (0.53 mmol) 4-dimethylaminopyridine in 40 ml of dichloromethane were cooled to 0° C. and 1.16 g (5.62 mmol) N,N′-dicyclohexylcarbodiimde were added. The mixture was subsequently allowed to react for 2 hours at 0° C. and 19 hours at 25° C., filtered and concentrated by rotary evaporation. Chromatography of the residue on 50 g silica gel using toluene as eluant and recrystallisation form ethyl acetate yielded 3.09 g (83%) Cholest-5-en-3-yl 2-(4-nitrobenzyl)-3-(4-nitrophenyl)propanoate as a white powder.
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18]C2NC3C=CC=CC=3N=2)[CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3].[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[S:41])=[C:35]([N+:42]([O-:44])=[O:43])[CH:34]=1.[OH-].[Na+]>C(Cl)Cl>[CH2:28]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:40]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][C:35]=2[N+:42]([O-:44])=[O:43])=[S:41])[CH2:13][CH2:14]1)[CH:29]([CH3:31])[CH3:30]
Reactant: Cc1ccc(N=C=S)c([N+](=O)[O-])c1
Reactant: CC(C)CN(CCCN1CCN(CCCNc2nc3ccccc3[nH]2)CC1)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(NC(=S)NCCCN2CCN(CCCN(CC(C)C)CC(C)C)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of N4-(3-{4-[3-(diisobutylamino)propyl]piperizano}propyl)-amine (intermediate of example 16) (103 mg, 0.33 mmol) and 4-methyl-2-nitrophenyl isothiocyanate (128 mg, 0.66 mmol) in CH2Cl2 (10 mL) has been stirred for 4 h at room temperature. NaOH 1M is added until alkaline pH. Organic layer was washed with NaOH 0.5M and dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH: 90/10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COCCC=CC[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COCCCCC[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Reaction time: 7 h

Procedure:
5.4 g of 1-chloro-4-[trans-4-(5-methoxy-2-pentenyl)cyclohexyl]benzene are dissolved in 80 ml of ethyl acetate in an autoclave, treated with 1 g of Raney nickel and hydrogenated for 7 hours at 60° C. and 5 kg/cm2. The suspension is filtered and evaporated. The residue (5.2 g) is crystallized twice from 30 ml of ethanol each time and gives 3.4 g of 1-chloro-4-[trans-4-(5-methoxypentyl)cyclohexyl]benzene; m.p. (C--I) 52.8° C.