Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].C[O:7][C:8]([C:10]1[O:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=1)=O.Cl>C1COCC1>[C:3]([CH2:4][C:8]([C:10]1[O:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=1)=[O:7])#[N:5]
Reactant: COC(=O)c1ccc(C#N)o1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(C#N)o1
Yield: 43.4 %

Procedure:
To 1,67 g (41.7 mmol, 60% dispersion in mineral oil) sodium hydride in a 2-necked flask fitted with a reflux condenser was added dropwise 150 ml THF and the mixture was then heated to reflux. A solution of 1.0 ml (208 mmol) acetonitrile and 6.30 g (41.7 mmol) 5-cyano-furan-2-carboxylic acid methyl ester in 100 ml dry THF was added dropwise and the reaction mixture heated at reflux for 4 hours. The reaction mixture was then cannulated into a rapidly stirred solution of 1M hydrochloric acid at 0° C. The mixture was extracted three times with ethyl acetate and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/1) afforded 2.90 g (43%) 5-cyanoacetyl-furan-2-carbonitrile as an orange oil. EI-MS m/e (%): 160 (M+, 19), 120 ([M—CH2CN]+, 100).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:66]=[CH:65][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:42][CH2:41][C@H:40]([S:43][C:44]3[N:45]=[CH:46][N:47]4[CH:51]=[C:50]([Sn](CCCC)(CCCC)CCCC)[S:49][C:48]=34)[CH2:39]2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:50]3[S:49][C:48]4=[C:44]([S:43][C@H:40]5[CH2:41][CH2:42][N:38]([C:36]([O:35][CH2:34][C:33]6[CH:65]=[CH:66][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=6)=[O:37])[CH2:39]5)[N:45]=[CH:46][N:47]4[CH:51]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S[C@H]5CCN(C(=O)OCc6ccc([N+](=O)[O-])cc6)C5)c4s3)[C@H](C)[C@H]12
Yield: 46 %

Procedure:
The procedure of Example 1a) was repeated, except that 143 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 287 mg of 7-[(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 136 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:18])([CH3:17])[CH2:10][N:11]1[CH:15]=[C:14](I)[N:13]=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Br)C.[CH3:23][Sn:24](Cl)([CH3:26])[CH3:25]>C(Cl)Cl>[Si:1]([O:8][C:9]([CH3:18])([CH3:17])[CH2:10][N:11]1[CH:15]=[C:14]([Sn:24]([CH3:26])([CH3:25])[CH3:23])[N:13]=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(Cn1cnc(I)c1)O[Si](C)(C)C(C)(C)C
Reactant: C[Sn](C)(C)Cl
Agent: CC[Mg]Br
Solvent: ClCCl
Product: CC(C)(Cn1cnc([Sn](C)(C)C)c1)O[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Yield: 74 %

Procedure:
To a mixture of 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-1H-imidazole in DCM was added ethylmagnesium bromide at −78° C. The temperature of the mixture was allowed to warm up to about 10° C. slowly and cooled again. Trimethyltin chloride was added dropwise at −78° C. After the addition, the temperature was allowed to slowly warm up to room temperature. The reaction mixture was pouted into saturate NH4Cl solution, then extracted with DCM. The organic phase was washed with water twice, dried over anhydrous Na2SO4, and concentrated to give 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(trimethylstannyl)-1H-imidazole (Yield=74%). LC-MS: m/z=419 [M+H+] 1H NMR (CDCl3, 400 MHz): δ 7.63 (s, 1H), 7.00 (s, 1H), 3.79 (s, 2H), 1.22-1.19 (s, 6H), 0.86 (s, 9H), 0.27 (s, 6H), 0.02 (s, 6H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](/[N:8]=[CH:9]/[C:10]2[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[O:28][C:27](=[O:29])[NH:26][N:25]=2)[CH2:20][CH2:19]1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[O:28][C:27](=[O:29])[NH:26][N:25]=2)[CH2:22][CH2:23]1
Reactant: O=c1[nH]nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)o1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3F)CC2)o1
Yield: 80.8 %

Procedure:
5-[1-(2-Fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9e, 0.40 g, 1 mmol) on reduction with sodiumcyano borohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 5-[1-(2-fluoro-4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (10e, 326 mg, 81%).
Reaction SMILES: [OH:1][C:2]1[C:16]([CH3:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=O.C1(C)C=CC=CC=1.Cl>O.[Zn]>[OH:1][C:2]1[C:16]([CH3:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: Cc1cc(C)c(C(=O)CCCCC(=O)O)c(O)c1C
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(CCCCCC(=O)O)c(O)c1C

Procedure:
To 5-(2'-hydroxy-3', 4', 6'-trimethylbenzoyl)pentanoic acid (formula II-1 wherein R=H3C, X=H, Y=OH, n=4 , in the free form) (0.262 part) were added water (16 volume parts), toluene (20 volume parts), concentrated hydrochloric acid (4 volume parts) and zinc amalgam prepared from 2 parts of zinc. The mixture was refluxed for 16 hours, during which time concentrated hydrochloric acid (6 volume parts) was added in three portions. After cooling, the reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with water and dried. The solvents were distilled off under reduced pressure to obtain 6-(2'-hydroxy-3', 4', 6'-trimethylphenyl)hexanoic acid (formula II-2 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.251 part) as colorless needles melting at 96°-108° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[Cl:1][C:2]1[C:7]([NH:8][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(N)c(Cl)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(C)nc1Cl)C(=O)OCC
Temperature: 140 °C
Yield: 95 %

Procedure:
A mixture of 2-chloro-6-methyl-3-pyridinylamine (8.5 g) and diethyl ethoxymethylenemalonate (22.0 mL) is heated at 140° C. for 18 hours. The mixture is cooled to room temperature and the resulting solids are recrystallized from a mixture of heptane (400 mL) and CH2Cl2 (2 mL) to obtain 17.9 g (95%) of the title compound as a pale red solid. Physical characteristics: MS (ESI+) m/z 313 (M+H).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>ClCCl.C(OCC)C>[ClH:35].[C:1]1([CH:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(Nc1cc(N2CCNCC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of t-butyl 4-(3-(1-phenylethylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate (50 mg, 0.1 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (20 mL). The reaction mixture was stirred for 2 hours. The solvent was removed by rotary evaporation to afford the title compound (31 mg, 72% yield). 1H NMR (400 MHz, CD3OD): δ 7.63 (d, 1H), 7.36 (m, 5H), 6.36 (d, 1H), 5.86 (s, 1H), 4.75 (m, 1H), 3.52 (m, 2H), 3.45 (m, 2H), 3.17 (m, 4H), 1.60 (d, 3H); MS (ESI) m/z: Calculated for C20H23F3N3O: 378.18; Observed: 378.5 (M++1) [corresponding to the free base].
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH2:16]1[CH2:20]OC[CH2:17]1.C(Cl)(=O)C(Cl)=O.CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[CH2:20]([O:14][C:13]([C:11]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)=[O:15])[CH:16]=[CH2:17]
Reactant: O=C(O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nitroterephthalic acid (6.33 g) in methylene chloride 475 ml) and THF (15 ml) was converted to the mono acid chloride using oxalyl chloride (2.63 ml), DMF (2.55 ml) and N-methylmorpholine (7.95 ml) at −10° C. After 1 hour the solvents were removed and, without further purification, the product was dissolved in allyl alcohol (20 ml) and THF (10 ml) and stirred overnight at ambient temperature. The solvents were removed and the residue partitioned between EtOAc and aqueous NaHCO3. Acidification of the NaHCO3 solution and extraction with EtOAc gave the product, 4-allyloxycarbonyl-2-nitrobenzoic acid (6.8 g). Nmr (CDCl3): δ 4.89 (d, 2H); 5.31-5.49 (m, 2H); 5.95-6.15 (m. 1H); 7.94 (d, 1H); 8.36 (dd, 1H); 8.54 (d, 1H). Without purification, this acid was converted by the method above to the acid chloride which was dissolved in THF (100 ml) at 0° C. Ammonia gas was bubbled into the solution until the reaction was completed. The solution was partitioned between EtOAc and water, and the product from the organic fraction purified on silica, eluting with methylene chloride followed by EtOAc. The product (4 g), containing a small impurity, was reduced with SnCl2 by a similar method to that in example 12 giving 4-allyloxycarbonyl-2-aminobenzamide. Nmr (DMSO-d6): δ 4.79 (d, 2H); 5.22-5.46 (m, 2H); 5.91-6.13 (m, 1H); 7.02 (dd. 1H); 7.37 (d, 1H); 7.61 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C:10]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)([CH2:15][N+:16]([O-])=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C([O-])=O.[NH4+].C(OCC)(=O)C.O>O1CCCC1.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:9][C:10]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:11]([F:13])([F:12])[F:14])[CH2:15][N:16]=2)[CH:5]=[CH:4][C:3]=1[CH2:28][N:29]1[C:30](=[O:39])[C:31]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:32]2[C:33]1=[O:34]
Reactant: O=C(CC(C[N+](=O)[O-])(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(CN2C(=O)c3ccccc3C2=O)c(Br)c1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C

Procedure:
To a solution of 0.70 g of N-[2-bromo-4-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-(nitromethyl) butanoyl]phenylmethyl]phthalimide and 1.03 g of ammonium formate in 20 mL of tetrahydrofuran, 1.07 g of zinc powder was added and the resultant reaction mixture was stirred while heating the mixture to reflux for 1 hour. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature, and 100 mL of ethyl acetate and 50 mL of water were added to the reaction mixture, followed by filtering the reaction mixture with Celite. Subsequently, the organic phase was separated off and was dehydrated and dried over a saturated brine and anhydrous magnesium sulfate in this order, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with chloroform to obtain 0.18 g of the objective substance as a white crystal.
Reaction SMILES: C([SiH](CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([C:17]2([C:20]([NH2:22])=[O:21])[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1)([O-])=O>CO.[Pd]>[NH2:8][C:11]1[CH:12]=[C:13]([C:17]2([C:20]([NH2:22])=[O:21])[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: NC(=O)C1(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: NC(=O)C1(c2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
Triethylsilane (7.75 ml, 48.5 mmol) was added dropwise to a suspension of 1-(3-nitrophenyl)cyclopropanecarboxamide (1 g, 4.85 mmol) and Pd/C (10%, 250 mg) in MeOH (20 ml). Resulting suspension was stirred at RT for 20 min. and filtered through celite. The filtrate was evaporated and triturated in hexane to obtain the crystals which were collected by filtration to afford the title compound (0.68 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=O)=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].O.[OH-].[Na+].Cl>CO>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:4]=[C:5]2[C:9]=1[C:8]1[C:7]([CH2:13][CH2:14][CH3:15])([CH2:6]2)[CH2:16][CH2:17][C:18](=[O:20])[CH:19]=1
Reactant: CCCC1(CCC(C)=O)Cc2cc(CCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC12CCC(=O)C=C1c1c(cc(CCC(=O)O)c(Cl)c1Cl)C2

Procedure:
3-[6,7-Dichloro-2,3-dihydro-1-oxo-2-(3-oxobutyl)-2-propyl-inden-5-yl]propionic acid (3.1 g, 0.00805 mole) was stirred at 25° C. in a mixture of methanol (2 ml), water (6 ml) and 1N sodium hydroxide (25 ml) for 96 hours. After dilution with water, the mixture was acidified with hydrochloric acid and extracted with a mixture of diethyl ether and tetrahydrofuran. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from acetic acid-acetonitrile (1:1) to obtain the product mp 201°-3° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[OH:10][C:9]1[CH:8]=[C:7]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]=[CH:5][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCCCCCCCBr
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C(C)=O)c(O)c1
Temperature: 55 °C
Reaction time: 168 h

Procedure:
A slurry of 2,4-dihydroxy actophenone (3.8 g; 25 mmol) and KHCO3 (2.75 g; 27.5 mmol) in DMF (50 mL) was stirred at 50° C. for 1 hour and then added 1-bromooctane (4.75 mL; 27.5 mmol). The reaction mixture was stirred at 50-60° C. for 7 days, poured onto H2O (100 mL) and the aqueous phase extracted with diethyl ether (3×). The combined organic fractions was dried (MgSO4), filtered, evaporated to dryness and purified by column chromatography (SiO2; EtOAc/PE80-100° C.=1:10) to yield 4.39 g (66%) as yellow oil. MS (direct; Cl): 265 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[CH:3]=1.C(O)=O>C(N(CC)CC)C.[Pd]>[OH:11][CH2:10][CH2:9][NH:8][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1c(NCCO)cc(Cl)cc1NCCO
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(NCCO)cccc1NCCO
Temperature: 70 °C

Procedure:
354 mg of palladium at a concentration of 10% on charcoal is added to 0.084 mole (23.1 g) of 4-chloro-2-(β-hydroxyethyl)amino-6-(β-hydroxyethyl)aminonitrobenzene in 23.7 g of triethylamine. 7 ml of formic acid are then run in dropwise. A high exothermicity is noted. The reaction mixture is heated to 70° C. for 1 hour 30. After dilution of the reaction mixture with ethanol, the catalyst is removed by hot filtration. The filtrate, evaporated to dryness under reduced pressure, enables a dry extract to be obtained. After dilution of the dry extract with water, the expected product precipitates. After being filtered off, washed with water and then dried under vacuum in the presence of phosphorus pentoxide, it is recrystallized twice from isopropanol. It melts at 103°-104° C., resolidifies and then melts at 112°-113° C.
Reaction SMILES: [N+:1]([CH2:4][C:5](=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([O-:3])=[O:2].[F-].[K+]>C(O)(C)(C)C>[C:5]([C:4]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:18][N:1]=1)(=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCC(=O)C[N+](=O)[O-]
Agent: [F-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCC(=O)c1noc(CCCCCCCCCCCC)c1[N+](=O)[O-]
Yield: 36.8 %

Procedure:
A solution of 1-nitro-2-tetradecanone (13.0 grams, 50 mmoles) in tertiary butanol (75 milliliters, 0.95 mole) containing anhydrous potassium fluoride (0.2 gram, 3.44 mmoles) was refluxed for 3 hours with the slow removal of 25 milliliters of tertiary butanol. The residual solvent was stripped from the reaction mixture by evaporation at 30°-35° C. under a reduced pressure of 30 millimeters. The evaporation residue was recrystallized from petroleum ether to afford 4.4 grams of 3-tridecanoyl-4-nitro-5-dodecylisoxazole having a melting point of 60°-62° C.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH:12]3[CH2:16][CH2:15][CH2:14][N:13]3[CH2:17][CH2:18][NH2:19])[CH:9]=[C:8]([CH3:20])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH:31]=O)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][NH:19][CH2:18][CH2:17][N:13]3[CH2:14][CH2:15][CH2:16][CH:12]3[C:10]3[CH:9]=[C:8]([CH3:20])[N:7]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:11]=3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: Cc1cc(C2CCCN2CCN)nc(-n2ccnc2)n1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C2CCCN2CCNCc2ccc3c(c2)OCCO3)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A solution of 2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethylamine (77 mg, 286 μmol), 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (47 mg, 286 μmol) and p-toluenesulfonic acid monohydrate (5 mg, 26 μmol) in dioxane (3 mL) was heated at 60° C. for 16 h. Sodium triacetoxyborohydride (180 mg, 860 μmol) was then added. The reaction mixture was stirred at r.t. for 1 h. EtOAc (25 mL) and 1N NaOH (25 mL) were then added. The organic layer was isolated, dried (MgSO4), filtered, and concentrated. Silica gel chromatography (0% to 10% MeOH/DCM) afforded 69 mg (57%) of (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-amine. [M+H]+ 421.23; 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.89 (s, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 6.68-6.79 (m, 3H), 4.21 (s, 4H), 3.54 (t, 1H), 3.22 (m, 1H), 2.70-2.82 (m, 2H), 2.20-2.60 (m, 9H), 1.84 (m, 2H), 1.70 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[Br:20][C:21]1[N:22]([CH3:29])[CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:20][C:21]1[N:22]([CH3:29])[CH:23]=[C:24]([C:26]([N:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[C:4]([O:3][C:2]([F:18])([F:1])[F:19])[CH:5]=2)=[O:27])[N:25]=1
Reactant: Cn1cc(C(=O)O)nc1Br
Reactant: FC(F)(F)Oc1cccc(CNC2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1cc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A mixture of N-[3-(trifluoromethoxy)benzyl]tetrahydro-2H-pyran-4-amine (190 mg), 2-bromo-1-methyl-1H-imidazole-4-carboxylic acid (100 mg), HATU, diisopropylethylamine (190 mg) and acetonitrile (3 mL) was stirred overnight at room temperature. Acetonitrile was distilled off under reduced pressure and the residue was purified by column chromatography (NH silica gel cartridge; hexane/ethyl acetate=3:1 to 1:2) to give the titled compound (130 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12]>>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2ccc(N)cc2)CC1

Procedure:
4-(4-Ethyl-piperazin-1-yl)-phenylamine is prepared in 2 steps from 1-bromo-4-nitro-benzene and 1-ethyl-piperazine as described in Example 1, Step A and B.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].[C:20]([O:25][CH2:26][CH:27]1[O:29][CH2:28]1)(=[O:24])[C:21]([CH3:23])=[CH2:22]>O1CCCC1>[C:20]([O:25][CH2:26][CH:27]([OH:29])[CH2:28][C:7]1[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:16][C:17]=2[CH:18]=[CH:19][C:6]=1[C:3](=[O:5])[CH3:4])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: CC(=O)c1ccc2c(c1)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCC(O)Cc1c(C(C)=O)ccc2c1Nc1ccccc1S2
Reaction time: 48 h
Yield: 72.3 %

Procedure:
0.20 g (0.0086 mol) of sodium hydride was added carefully to a solution of 2-acetylphenothiazine (2 g, 0.0083 mol) in 150 ml tetrahydrofuran under agitation below 5° C. A solution of glycidyl methacrylate (1.88 g, 0.013 mol) in 10 ml tetrahydrofuran was added dropwise to above solution. The reaction was kept at room temperature for 48 hours. After the solvent was removed, the residue was washed with dilute HCl and water. Dried. 2.3 g of product was obtained by recrystallization with ethyl acetate.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28]I)=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C>[CH2:2]([N:4]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)[CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:22](=[O:23])[C:21]1[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:19]([O:18][CH3:17])[CH:20]=1)[CH3:3]
Reactant: CCNC1CCc2cc(OC)ccc2C1
Reactant: COc1cc(C(=O)OCCCCI)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN(CCCCOC(=O)c1cc(OC)c(OC)c(OC)c1)C1CCc2cc(OC)ccc2C1

Procedure:
Using 2.0 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride, 3.3 g of 4-iodobutyl 3,4,5-trimethoxybenzoate, 0.9 g of anhydrous sodium carbonate and 40 ml of methyl ethyl ketone, the free base, N-ethyl-N-[4-(3,4,5-trimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, was obtained using the procedures described in Example 2 (ii). The free base was treated with methanesulfonic acid to obtain 1.5 g of N-ethyl-N-[4-(3,4,5-trimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine methanesulfonate as a pale-yellow oil.