Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].[H-].[Na+].[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>CN(C=O)C>[OH:26]/[C:20](=[CH:1]\[C:2](=[O:3])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)/[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(O)=C/C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.2 %

Procedure:
To a solution of 4-benzyloxyacetophenone 1.1 (20.0 g, 88.4 mmol) in DMF (100 ml) at rt, was added NaH (60% in oil, 4.26 g, 106 mmol). The mixture was stirred at rt for 45 min, cooled to 0° C., and diethyl oxalate (14.4 ml, 106 mmol) was added dropwise, and the suspension warmed to rt and stirred for 17 h. The reaction mixture was poured over a mixture of ice and 1N HCl and the suspension stirred for 30 min, filtered, and the solid rinsed with water and dried to afford 28.9 g of the butenoate 1.2. MS (ESI) 325.2 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22].C(O)(=O)C.C([BH3-])#N>CO>[CH3:23][C:20]([NH:19][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Si:2]([CH3:18])([CH3:17])[CH3:1])[CH:4]=2)[N:14]=1)([CH3:24])[CH2:21][OH:22]
Reactant: CC(C)(N)CO
Reactant: C[Si](C)(C)c1cccc(-c2cccc(C=O)n2)c1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(CO)NCc1cccc(-c2cccc([Si](C)(C)C)c2)n1
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of Example 226A (1.00 g, 3.92 mmol) in methanol (20 mL) at ambient temperature was added 2-amino-2-methyl-1-propanol (0.349 g, 3.92 mmol), acetic acid (0.90 mL, 15.7 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.5 g). After 2 hours, the mixture was filtered, concentrated and the residue partitioned between ether and 1N NaOH. The organic layer was extracted with 1N aquoues HCl (×2) and the organic phase discarded. The aqueous layer was neutralized with 1N NaOH and extracted with EtOAc. The EtOAc extract was dried and concentrated to provide 700 mg (54%) of the title compound. MS (DCI+) m/z 329 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.97-7.90 (m, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.64-7.54 (m, 2H), 7.48 (t, J=7.5 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 3.95 (s, 2H), 3.42 (s, 2H), 1.18 (s, 6H), 0.39-0.25 (m, 9H).
Reaction SMILES: [ClH:1].[CH3:2][NH:3][O:4][CH3:5].[NH2:6][C:7]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][C:8]=1[C:9](O)=[O:10].CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[ClH:1].[CH3:5][O:4][N:3]([CH3:2])[C:9](=[O:10])[C:8]1[CH:12]=[C:13]([Br:16])[CH:14]=[N:15][C:7]=1[NH2:6]
Reactant: CNOC
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
In a nitrogen flushed flask 3.00 g (30.76 mmol) of N,O-dimetylhydroxylamine hydrochloride and 3.53 g (16.27 mmol) of 2-amino-5-bromonicotinic acid are dissolved in a mixture of 350 ml of dichloromethane, and 30 ml of N-methylmorpholine. 12.70 g (24.40 mmol) of PyBOP (1-benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate) is added and the reaction mixture stirred at room temperature for 5 hours. The mixture is then washed with 150 ml of a 2 M solution of sodium hydroxide in water and then twice with 100 ml of a 10% aqueous citric acid solution and dried over sodium sulfate. The solvent is evaporated and the resulting oil is dissolved in 300 ml of ether. The precipitate formed is filtered off and discarded. The clear filtrate is concentrated to about half its volume and diluted with 30-60 ml of dichloromethane. The resulting solution is stirred vigorously and a 1 M solution of hydrogen chloride in anhydrous ether is added until formation of the resulting precipitate is complete. The precipitate is filtered off, washed with ether and dried by suction to afford 3.15 g (12.04 mmol, 74% yield) of N-methoxy-N-methyl-2-amino-5-bromonicotinamide hydrochloride as an off-white to beige-brown powder. 1H-NMR (d6-DMSO) δ: 8.24 [1H] d, 7.97 [1H] d, 3.56 [3H] s, 3.26 [3H] s. MS: m/z 260 [MH+]
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].Cl[CH2:12]Cl.[N+](=C)=[N-]>CCOCC>[CH3:12][O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10]
Reactant: C#CCN1CC[C@H](O)C1=O
Reactant: ClCCl
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: C#CCN1CC[C@H](OC)C1=O

Procedure:
A mixture of 2.0 g of (S)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 70 g of silica gel and 200 ml of dichloromethane was cooled in an ice bath. A 300 ml solution of diazomethane in ether was added portionwise. The reaction was filtered, washed with methanol and concentrated in vacuo. The residue was purified by chromatography (silica gel), giving 700 mg of (S)-3-methoxy-1-(2-propynyl)-2-pyrrolidinone, [α]D26 =-71° (dichloromethane).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=3[O:27][CH3:28])(=[O:18])=[O:17])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:34]([O:33][C:31](=[O:32])[CH2:30][N:15]([S:16]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[O:27][CH3:28])(=[O:18])=[O:17])[C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(OC)c(S(=O)(=O)Nc2nc(-c3ccc(C(C)C)cc3)cs2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(S(=O)(=O)N(CC(=O)OC(C)(C)C)c2nc(-c3ccc(C(C)C)cc3)cs2)c1

Procedure:
{(2,5-Dimethoxy-benzenesulfonyl)-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-acetic acid tert-butyl ester was prepared following general procedure F using N-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-2,5-dimethoxy-benzenesulfonamide (126 mg, 0.3 mmol), tert-butyl bromoacetate (90.4 μL, 98%, 0.6 mmol), potassium carbonate (124 mg, 0.9 mmol) and DMF (1 mL). Purification (silica gel, ethyl acetate/hexanes 1:4) gave the product compound (111 mg, 0.208 mmol). LCMS m/z: 533 (M+1)+.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23]>>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Reactant: CC(C)(O)CCCCCl
Product: C=CCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2CC

Procedure:
This compound was prepared as described in Example 1 starting with 7-Allyl-3-ethyl-xanthine and 1-chloro-5-hydroxy-5-methylhexane and recrystallizing the final product from diisopropyl ether with addition of some ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]/[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]/[CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: COc1ccc2c(c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A solution of tert-butyl (E)-4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)vinyl]piperidine-1-carboxylate (0.0692 g, 0.185 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0270 g, 0.185 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((E)-2-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}vinyl)piperidine-1-carboxylate (0.0712 g, 77%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:34])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH2:29][O:30][CH3:31])=[C:22]([O:32][CH3:33])[CH:21]=1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C)C=O>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([O:15][CH3:16])[C:3]([C:17](=[O:34])[CH2:18][CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH2:29][O:30][CH3:31])=[C:22]([O:32][CH3:33])[CH:21]=2)=[C:2]([O:1][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COCOc1c(OC)cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1OC
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1c(OC)cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)OC)cc1OC
Reaction time: 0.75 h

Procedure:
Then, 10 ml of dimethylformamide was dropped into a mixture of 2.3 g of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1-propanone and 0.2 g of sodium hydride at 0° C., and the mixture was stirred for 45 minutes. Then, 0.5 ml of methyl α-bromoacetate was added to the mixture at 0° C., and the mixture was stirred for 20 minutes. After the reaction, the solvent was removed from the reaction liquid mixture by distillation and the residue was dried under a reduced pressure to obtain substantially quantitatively 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1-propanone in the form of a colorless transparent oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[C:16]([CH3:22])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:23].[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][C:16]([CH3:22])=[C:17]([CH3:21])[CH:18]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(N2CCNCC2)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,3,5,6-tetrachloropyridine (10 g), t-Boc-piperazine (8.6 g) and potassium carbonate (13 g) was added 2-butanone (140 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g). To a mixture of the obtained 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g), palladium(II) acetate (516 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.9 g), potassium fluoride (24 g) and methylboronic acid (12 g) was added tetrahydrofuran (140 ml), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g). The obtained 4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g) was dissolved in chloroform (28 mL), 4N hydrogen chloride/ethyl acetate (25 ml) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (100 mL), and the precipitate was collected by filtration to give the title compound (11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.CC[O-].[Na+].Cl.[NH2:18][CH:19]([CH2:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:33])[C:20]([OH:22])=[O:21]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][CH:19]([CH2:23][CH:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][C:25]2=[O:33])[C:20]([OH:22])=[O:21])=[O:8])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1
Reactant: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Yield: 9.8 %

Procedure:
In 100 ml of ethanol, 1.66 g of ethyl p-chlorobenzoate, 0.5 g of sodium ethylate and 1.98 g of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride prepared in Reference example 1 were added, then the mixture was placed in an autoclave, and reacted under 110 atmospheric pressure at 140°-150° C. for 6 hours. After cooling, the reaction mixture was concentrated under a reduced pressure, the residue was dissolved in 200 ml of chloroform, then the chloroform solution was washed with 1% potassium carbonate aqueous solution, diluted hydrochloric acid and water in this order, the chloroform solution was dried with anhydrous sodium sulfate. The solvent was removed by evaporation, the residue was recrystallized from methanol-water to obtain 270 mg of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate in the form of colorless powdery substance. Melting point: 133-135° C. [α]D25 -50.3° (C=1, methanol)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=O.CC(O)=O.[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+]>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]1)[CH3:18]
Reactant: CCOC(=O)C=O
Reactant: CN1CCN(CCCN)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
A solution of 4-(3-aminopropyl)-1-methylpiperazine (3.1 mL, 20 mmol) in MeOH (50 mL) was cooled in an ice bath and treated with ethyl glyoxylate (50% solution in toluene, 5.6 mL, 27 mmol) and AcOH (3 mL). After stirring for 15 min, NaBH3CN (1.37 g, 21.8 mmol) was added and the mixture was allowed to stir for 7 h while slowly warming to room temperature. The mixture was diluted with saturated aqueous NaHCO3 (150 mL) and then extracted with EtOAc (3×100 mL) followed by CH2Cl2 (3×100 mL). The combined CH2Cl2 layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (1.81 g, 38%) as a colorless oil: MS (ESI) m/e 244 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=O)[CH2:6][C:5](=[O:10])[CH2:4]1)[CH3:2].C([O-])(=O)C.[NH4+:15]>>[NH2:15][C:7]1[CH2:8][CH:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:10])[CH:6]=1
Reactant: CCC1CC(=O)CC(=O)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CCC1CC(=O)C=C(N)C1

Procedure:
In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-ethylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:31][O:32][C:33](=[O:49])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Cl)=[CH:36][C:35]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]>CN(C=O)C.C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:49])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][O:13][CH2:12][C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[CH:36][C:35]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]
Reactant: OCc1ccc(-c2ccccc2)o1
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCc2ccc(-c3ccccc3)o2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
The 5-phenyl-2-hydroxymethylfuran prepared in Example 327B (345 mg, 1.98 mmol) was dissolved in 5 mL of dry DMF and NaH (50 mg, 1.98 mmol) was added followed by 15-crown-5 (436 mg, 1.98 mmol) and the reaction stirred for 5 minutes at ambient temperature. To the reaction was then added 4-chloromethyl-2-(2-methylphenyl)benzoic acid methyl ester (659 mg, 2.40 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was taken up in ethyl acetate and washed with water (3×) and brine (3×), dried over Na2SO4, filtered, evaporated and purified by flash chromatography (15% ethyl acetate-hexanes) to give the desired compound (670 mg, 82%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:20])[C:4]([C:13]([CH3:19])([CH3:18])[CH2:14][C:15]([OH:17])=[O:16])=[C:5]([CH3:12])[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9][CH3:10].[Cl:21][CH2:22][CH2:23][N:24]([CH2:32][CH2:33][Cl:34])[C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:3](=[O:20])[C:4]([C:13]([CH3:19])([CH3:18])[CH2:14][C:15]([O:17][C:28]2[CH:27]=[CH:26][C:25]([N:24]([CH2:23][CH2:22][Cl:21])[CH2:32][CH2:33][Cl:34])=[CH:30][CH:29]=2)=[O:16])=[C:5]([CH3:12])[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCC1=C(C)C(=O)C(C(C)(C)CC(=O)O)=C(C)C1=O
Reactant: Oc1ccc(N(CCCl)CCCl)cc1
Product: CCCC1=C(C)C(=O)C(C(C)(C)CC(=O)Oc2ccc(N(CCCl)CCCl)cc2)=C(C)C1=O
Yield: 32 %

Procedure:
Using an analogous procedure to that described in Example 5, 3-(2,5-dimethyl-3-propyl-1,4-benzoquinonyl)-3-methylbutyric acid was reacted with 4-[bis(2-chloroethyl)amino]phenol to give 4-[bis(2-chloroethyl)amino]phenyl 3-(2,5-dimethyl-3-propyl-1,4-benzoquinonyl)-3-methylbutyrate in 32% yield; NMR Spectrum: (CDCl3) 0.91 (t, 3H), 1.39 (m, 2H), 1.52 (s, 6H), 1.95 (s, 3H), 2.18 (s, 3H), 2.35 (t, 2H), 3.2 (s, 2H), 3.55-3.73 (m, 8H), 6.6 (d, 2H), 6.84 (d, 2H); Mass Spectrum: (M+H+) 498, 496, 494.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]2[N:16]=[C:15]3[N:18]([C:22]4[C:23]([CH3:31])=[N:24][C:25]([N:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=4)[CH2:19][CH2:20][CH2:21][N:14]3[C:13]=2[C:12]([CH:32]([OH:35])[CH2:33][CH3:34])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:1]([O:35][CH:32]([C:12]1[C:13]2[N:14]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[C:23]([CH3:31])=[N:24][C:25]([N:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=4)[C:15]3=[N:16][C:17]=2[C:9]([Cl:8])=[CH:10][CH:11]=1)[CH2:33][CH3:34])(=[O:3])[CH3:2]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.4 %

Procedure:
Acetic anhydride (0.30 mL, 3.15 mmol) was added to a stirred solution of 1-{9-chloro-1-[6-(dimethylamino)-2-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}propan-1-ol (103 mg, 0.258 mmol) in pyridine (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 6 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-90% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate to give the title compound as a colorless crystal (86.9 mg, 0.197 mmol, 76%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]2[C:7]([O:9][C:10](=[O:11])[C:3]=2[CH:2]=1)=O.[F:12][C:13]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=1)([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15]>C1COCC1>[F:12][C:13]([C:22]1[CH:28]=[CH:27][C:25]([N:26]2[C:7](=[O:9])[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][C:3]=3[C:10]2=[O:11])=[C:24]([CH3:29])[CH:23]=1)([C:18]([F:19])([F:20])[F:21])[C:14]([F:17])([F:16])[F:15]
Reactant: O=C1OC(=O)c2cnccc21
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N1C(=O)c2ccncc2C1=O
Reaction time: 3 h

Procedure:
In 10 ml of THF were dissolved 1.50 g of pyridine-3,4-dicarboxylic acid anhydride and 2.75 g of 4-(heptafluoro-2-propyl)-2-methylaniline, and the reaction was carried out at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and 20 ml of trifluoroacetic anhydride was added to the resulting residue, and the reaction was carried out with refluxing for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain crude N-[4-(heptafluoro-2-propyl)-2-methylphenyl]pyridine-3,4-dicarboximide quantitatively.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:21]=2[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:12][CH2:11]1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:21]=2[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:12][CH2:11]1
Reactant: Cc1ccc(NCCCN2CCN(c3ccccc3[N+](=O)[O-])CC2)c(C(=O)N(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NCCCN2CCN(c3ccccc3N)CC2)c(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-{3-[4-(2-nitrophenyl)piperazin-1-yl]propylamino}-N,N,5-trimethylbenzamide (580 mg, 1.36 mmol), prepared as in Example 26, and 10% palladium on carbon (70 mg) in 15 mL of ethanol was added and stirred under hydrogen at room temperature for approximately 12 hours. The mixture was filtered and concentrated to give 2-{3-[4-(2-aminophenyl)piperazin-1-yl]propyl-amino}-N,N,5-trimethylbenzamide.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12](Cl)[CH:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22].C(N(CC)CC)C>CN(C=O)C.O>[CH3:17][O:18][C:19](=[O:23])[CH2:20][CH2:21][NH:22][C:12]1[CH:11]=[C:10]([Cl:15])[N:9]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1
Reactant: Clc1cc(Cl)nc(Cc2ccccc2)n1
Reactant: COC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCNc1cc(Cl)nc(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
0.503 g (2.1 mmole) of 2-benzyl-4,6-dichloro-pyrimidine was dissolved in 10 mls of DMF. To this solution was added 0.340 g of 3-amino-propionic acid methyl ester HCl. Next 0.6 mls of triethyl amine 94.3 mmoles) was added dropwise and the reaction stirred at room temperature for 12 hours. The reaction was diluted with 10 mls of H2O and extracted with two portions of EtOAc. The combined organic layers were washed with two portions of saturated NaCl solution, dried over MgSO4, filter and evaporated under reduced pressure to yield a crude oil. This material was chromatographed on silica gel with 10% Ethyl Acetate-90% Heptane as the eluent. 3-(2-benzyl-6-chloro-pyrimidin-4-ylamino)-propionic acid methyl ester (0.531 g, 79%) was isolated a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1.[H][H]>[Ni].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH2:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Sc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Cl)ccc1Sc1ccccc1
Yield: 88.2 %

Procedure:
A solution of 4-chloro-2-nitro-1-(phenylthio)benzene (11.0 g) and Raney nickel in ethanol (3A; 9.3 mL) was reacted in a Parr Hydrogenator under hydrogen atmosphere at 5 psi and room temperature. When the theoretical amount of hydrogen uptake was reached, the reaction was filtered to remove the catalyst and evaporated in vacuo to yield 8.61 g (88%) of a light orange solid. mp: 59°-61° C.