Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(OCC)(=O)C.O>CO>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCc1nc(C)n(-c2ccc(C(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(C(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[1-(4-acetylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) in methanol (10 mL) was added sodium tetrahydroboron (0.11 g), and the mixture was stirred at 0° C. for 2 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.02 g, 100%).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].Cl.[C:33]([O:37][C:38](=[O:42])[C@H:39]([CH3:41])[NH2:40])([CH3:36])([CH3:35])[CH3:34].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([NH:40][C@H:39]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:42])[CH3:41])=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)N[C@@H](C)C(=O)OC(C)(C)C)cc3)[nH]c2n(CCC)c1=O
Temperature: 25 °C

Procedure:
Mix (-)-2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid (4.28 g, 10 mmol), L-alanine t-butylester hydrochloride (965 mg, 5.3 mmol), hydroxybenztriazole (1.65 g, 11 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.1 g, 11 mmol). Add a solution of diisopropylethylamine (3.8 mL) in methylene chloride (20 mL) and stir at room temperature for several hours. Dilute with ethyl acetate (150 mL), wash with cold 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: O.CO.[C:4]1([C@H:10]2[N:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C@@H:13]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:12]([C:34]([O:36]C)=[O:35])[O:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:4]1([C@H:10]2[N:14]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[C@@H:13]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:12]([C:34]([OH:36])=[O:35])[O:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H]1O[C@@H](c2ccccc2)N(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1O[C@@H](c2ccccc2)N(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1c1ccccc1
Reaction time: 5 h

Procedure:
Water (8 ml), methanol (8 ml) and THF (8 ml) are added to (2S,4S,5R)-2,4-diphenyl-3-(4-nitrobenzenesulfonamido)-5-methoxycarbonyl-1,3-oxazolidine (III, EXAMPLE 12A, 1.50 g 3.19 mmol). Potassium carbonate (1.018 g, 7.71 mmol) is then added. The resulting mixture is stirred at 20-25° until complete by TLC. After 5 hr the reaction is complete and the reaction mixture is extracted with basic methylene chloride (2×). The aqueous phase is then acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is then washed with water, saline and dried over magnesiuim sulfate. Concentration of the organic phase (ethyl acetate) gives the title compound, mp=61-65°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:4]1[CH:3]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]2)[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cncnc2)CC1
Temperature: 120 °C
Yield: 42.2 %

Procedure:
5-Bromo pyrimidine (1.0 g, 6.29 mmol) and 1-Boc-piperazine (1.17 g, 6.28 mmol) were dissolved in toluene (20 mL) and the solution was purged with argon for 10 min. Sodium tert-butoxide (816 mg, 8.49 mmol) and catalytic Pd(PtBu3)2 (320 mg, 0.63 mmol) were added and the reaction mixture was heated to 120° C. for 10 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 80% EtOAc in petroleum ether) to get tert-butyl 4-(pyrimidin-5-yl)piperazine-1-carboxylate (700 mg, yield 42%). 1H NMR (300 MHz, MeOD) δ 8.57 (s, 1H), 8.48 (m, 2H), 3.61-3.58 (m, 4H), 3.30-3.27 (m, 4H), 1.47 (s, 9H). MS (ESI) m/z: Calculated for C13H20N4O2: 264.16. found: 265.0 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[N:37]1(C2C=CC(C(=O)C)=CC=2)[CH:41]=[CH:40][N:39]=[CH:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][C:3]([N:37]4[CH:41]=[CH:40][N:39]=[CH:38]4)=[CH:4][CH:5]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(-n5ccnc5)cc4)ccc3c1)n2C1CCCCC1
Yield: 59 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-imidazol-1-yl-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (75 mg, 59% yield). MS: 514.23 (M+H+); HPLC Procedure A, retention time=8.40 min.
Reaction SMILES: BrCCC[N:5]1[C:9](=O)[C:8]2=[CH:11]C=CC=C2C1=O.[P:16]([O:23]CC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[NH2:5][CH2:9][CH2:8][CH2:11][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCN)OCC
Temperature: 140 °C
Yield: 34 %

Procedure:
70 ml of triethyl phosphite was added to 40 g of N-(3-bromopropyl)phthalimide (7). The mixture was heated to a temperature of 140° C. The by-produced ethyl bromide was distilled off. The system was then heated over 4 hours. Excess triethyl phosphite was distilled off under reduced pressure by an aspirator. 9 ml of ethanol and hydrazine hydrate were added to the concentrated solution. The system was heated under reflux over 20 minutes. The resulting crystals were filtered off. A mixture of 10 g of oxalic acid and 50 ml of acetone were added to the filtrate. The resulting crystals were filtered off. The filtrate was concentrated. A small amount of water and acetone were added to the residue. The resulting crystals were filtered off. The filtrate was cooled to deposit crystals of oxalic acid salt of diethyl 3-aminopropylphosphonate (8). The crystals were filtered and dried under reduced pressure by a vacuum pump to obtain 12 g of diethyl 3-aminopropylphosphonate (8) in the form of oxalate. (Yield: 34 %; m.p. 54° C.)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[NH2:26][C@@H:27]([C@H:32]([OH:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl.CN(C=O)C>[OH:34][C@H:32]([CH3:33])[C@H:27]([NH:26][C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:18])[C:28]([O:30][CH3:31])=[O:29]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Compound 8 (5.0 g, 20.08 mmol) was dissolved in CH2Cl2 (50 mL), NMM (2.43 mL, 22.08 mmol) and IBCF (2.74 mL, 23.09 mmol) were added and stirred at −15° C. for 30 minutes under inert atmosphere. A mixture of (2S,3R)-methyl 2-amino-3-hydroxybutanoate (2.93 g, 22.08 mmol) and NMM (2.43 mL, 22.08 mmol) in DMF (15 mL) were added drop wise at −15° C. The resultant reaction mixture was stirred at RT for 3 h. It was diluted with DCM (200 mL) and the organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude was purified by silica gel column chromatography eluting with 30% EtOAc/Hexane to afford compound 9 (3.1 g, 42%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]#[N:12].[CH:13](N)(C)C.[F-].[K+].C[N:20]1[CH2:24][CH2:23][CH2:22]C1=O>O>[C:11]([C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[NH:20][CH2:24][CH:23]([CH3:13])[CH3:22])#[N:12]
Reactant: CN1CCCC1=O
Reactant: N#Cc1ccc(C(=O)O)nc1Cl
Reactant: CC(C)N
Agent: [F-]
Agent: [K+]
Solvent: O
Product: CC(C)CNc1nc(C(=O)O)ccc1C#N
Temperature: 95 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 6-chloro-5-cyanopicolinic acid (30 mg, 0.16 mmol), isopropylamine (20 ul, 0.23 mmol), and KF (28 mg, 0.48 mmol) in N-methylpyrrolidinone (1 ml) was heated for 18 hrs at 95° C. The mixture was diluted with water (4 ml) and stranded overnight. The resulting precipitate was collected by filtration and dried under vacuum to afford 25 mg (75%) of the desired product 70. 1H NMR (600 MHz, DMSO-d6) δ 13.2 (s, 1H), 8.03 (d, 1H, J=7.8 Hz), 7.25-7.21 (m, 1H), 7.17 (d, 1H, J=7.8 Hz), 3.26-3.24 (m, 2H), 1.99-1.95 (m, 1H), 0.89 (d, 6H, 6.6 Hz). MS: m/z Calcd 219.2 Found MH+ 220.1
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]([O:13][CH2:14]C)=[O:12])[C:6]([O:8][CH2:9]C)=[O:7])=[O:2].C(C=C)=O.CO>C(O)C>[CH:1]([CH:3]1[CH2:5][C:4]1([C:6]([O:8][CH3:9])=[O:7])[C:11]([O:13][CH3:14])=[O:12])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1C=O
Agent: C=CC=O
Solvent: CCO
Solvent: CO
Product: COC(=O)C1(C(=O)OC)CC1C=O

Procedure:
By following the procedure of D. T. Warner, cited above, used for preparing diethyl 2-formylcyclopropane-1,1-dicarboxylate from acrolein but using equivalent amounts of dimethylbromoalonate and methanol instead of diethylbromomalonate and ethanol, respectively, the title compound, nmr (CDCl3) δ 1.98 (m, 2H), 2.80 (m, 1H), 3.79 (s, 6H), 8.82 (d, J = 4 cps, 1H), is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:33]/[C:34](/[CH3:40])=[CH:35]\[C:36]([O:38][CH3:39])=[O:37]>C(O)(C)C>[CH3:40][C:34]1[NH:33][C:14]([CH3:16])=[C:13]([C:12]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH2:23][CH2:22]2)=[O:17])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:35]=1[C:36]([O:38][CH3:39])=[O:37]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN1CCN(c2ccccn2)CC1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(c3ccccn3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 54.5 %

Procedure:
A mixture of m-nitrobenzaldehyde, 2-[4-(2-pyridyl)-1-piperazinyl)ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give methyl 2-[4-(2-pyridyl)-1-piperazinyl]ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 53°-56° C. (sintering). Yield 54.5%. IR(Nujol)cm-1 : 3280. NMR(CDCl3) δ: 2.35(3H,s, ##STR34## 2.37(3H,s, ##STR35## 3.64(3H,s,COOCH3), 4.21(2H,t,J=6,COOCH2CH2 --), 5.13(1H,s, C(4) --H), 5.77(1H,s,NH).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH:13][C@@H:14]([CH2:29][C:30]3[N:31]=[CH:32][S:33][CH:34]=3)[C:15]([N:17]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)=[O:16])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:38].O>CN(C=O)C>[CH2:25]([N:17]([CH2:18][C:19]1[N:20]=[C:21]([CH3:24])[S:22][CH:23]=1)[C:15](=[O:16])[C@@H:14]([N:13]([CH3:38])[S:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)(=[O:11])=[O:12])[CH2:29][C:30]1[N:31]=[CH:32][S:33][CH:34]=1)[CH:26]([CH3:27])[CH3:28]
Reactant: Cc1nc(CN(CC(C)C)C(=O)[C@H](Cc2cscn2)NS(=O)(=O)c2ccc3occc3c2)cs1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CN(CC(C)C)C(=O)[C@H](Cc2cscn2)N(C)S(=O)(=O)c2ccc3occc3c2)cs1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of compound 58 (76 mg, 0.15 mmol) in DMF (1 ml) were added sodium hydride (12 mg, 0.30 mmol) and iodomethane (14 μl, 0.23 mmol). After 1 hr, water (7 ml) was added to quench the reaction. The aqueous phase was extracted with EtOAc (10 ml) and the organic layer was washed with brine (5 ml), dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by preparative TLC (EtOAc) to provide compound 80 (49 mg, 61%) as an oil. [M+H]+ 533.0, HPLC purity: >99%.
Reaction SMILES: [CH2:1]([C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:39]([NH2:41])[CH3:40].Cl[CH2:43][CH2:44]Cl>>[CH2:1]([C:8]1[N:16]([CH2:40][CH2:39][NH:41][CH2:43][CH3:44])[C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCn1c(=O)c2c(nc(Cc3ccccc3)n2CCNCC)n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 3, 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine, is reacted with sodium carbonate, 1,2-dichloroethane and ethylamine to yield 8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By the method of Example 4, 8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-propylxanthine free base. The corresponding dihydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [CH3:1][O:2][CH2:3]/[C:4](/OS(C(F)(F)F)(=O)=O)=[CH:5]/[C:6]([O:8][CH3:9])=[O:7].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].O1CCOC[CH2:38]1>>[C:26]([C:28]1[CH:29]=[C:30](/[C:4](/[CH2:3][O:2][CH2:1][CH3:38])=[CH:5]\[C:6]([O:8][CH3:9])=[O:7])[CH:31]=[CH:32][CH:33]=1)#[N:27]
Reactant: C1COCCO1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COC/C(=C/C(=O)OC)OS(=O)(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOC/C(=C/C(=O)OC)c1cccc(C#N)c1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of methyl (Z)-4-methoxy-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-butenoate (246 mg, 1.0 mmol) in 5 ml anhydrous dioxane was added potassium phosphate (318 mg, 1.5 mmol), 3-cyanophenyl boronic acid (162 mg, 1.0 mmol), and tetrakis (triphenylphosphine)palladium(0) (29 mg, 0.0251 mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 20 ml ethyl acetate. Organic was washed with 2×20 ml water, 2×20 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give methyl (E)-3-(3-cyanophenyl)-4-ethoxy-2-butenoate (220 mg, 75%) as a clear brown oil which was sufficiently pure to be used without further purification. ES-MS (M+H+): 232.1
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1.[OH-:27].[Na+]>C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=O)C=1>[CH:1]1([S:7]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[O:11])(=[O:24])=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccccc1SC1CCCCC1
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccccc1S(=O)(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 2-(cyclohexylthio)benzaldehyde (3.22 g, 14.6 mmol) in DCM (100 mL) at 0° C. was added mCPBA (70-77% wt in water, 7.17 g, 30.7 mmol) portionwise over 30 minutes, then stirred for 1 hour at 0° C. Additional mCPBA (150 mg, 0.6 mmol) was added and stirred for a further 30 minutes, before aqueous 1N NaOH was added to the reaction mixture and stirred vigorously for 5 minutes. The product was extracted with DCM, and the combined organic phase washed successively with 1N NaOH, then saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 2-(cyclohexylsulfonyl)benzaldehyde (3.34 g, 13.2 mmol, 91%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].I[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].[OH-].[K+]>[Cu].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: COc1ccccc1S
Reactant: O=C(O)c1ccccc1I
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Sc1ccccc1C(=O)O

Procedure:
Stir under reflux for 3 hours a mixture of 70 gm (0.5 mole) of o-methoxythiophenol, 120.5 gm (0.486 mole) of o-iodobenzoic acid, 81.7 gm (1.46 mole) of potassium hydroxide, 85 gm (1.34 mole) of copper powder and 800 cc of water. Filter the reaction mixture hot and again filter the filtrate through celite. Acidify the filtrate with concentrated hydrochloric acid. Separate the precipitate, wash well with water and dry in vacuo at 70° C. to obtain the title product. (m.p. 198°-200° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[Br:1][C:2]1[C:3]([CH2:9][N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:36]([NH:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(CNCc2nc(F)ccc2Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(Cc2nc(F)ccc2Br)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of (3-bromo-6-fluoro-pyridin-2-ylmethyl)-(4-methoxy-benzyl)-amine (637 mg, 2.0 mmol, 1.0 equiv) and N,N-diisopropylethylamine (700 μL, 4.0 mmol, 2.0 equiv) in dichloromethane (10 mL) was added phenyl isocyanate (260 μL, 2.4 mmol, 1.2 equiv) and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-60%) to afford (1-(3-bromo-6-fluoro-pyridin-2-ylmethyl)-1-(4-methoxy-benzyl)-3-phenyl-urea (760 mg). MS: [M+H]+=445.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:4][C:3]=1[OH:16].[CH2:17]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O1CCOCC1.N1C=CC=CC=1>O>[CH2:17]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:1][C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:4][C:3]=2[OH:16])=[O:33])=[CH:35][CH:36]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCc1ccc(O)c(N)c1
Reactant: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCCCCCCCCCOc1ccc(C(=O)Nc2cc(CCCCCCCC)ccc2O)cc1
Yield: 97.4 %

Procedure:
In a 50 ml-three-necked flask, 0.50 g (2.43 mM) of 2-amino-4-octylphenol, 0.82 g (2.54 mM) of 4-decyloxybenzoyl chloride and 20 ml of dioxane were placed and heated. To the mixture, 0.88 ml of pyridine was gradually added dropwise at around 90° C. under stirring, followed by further stirring for 35 minutes at around 90° C. After the reaction, the reaction mixture was poured into water to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from hydrous acetone to obtain 1.06 g of 2-(4-decyloxybenzoylamino)-4-octylphenol (yield: 90.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:6](=NNC(OC)=O)[CH3:7])[CH3:2].O.C(OCC)(=[O:28])C>CC(C)=O.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:6](=[O:28])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(C)=NNC(=O)OC
Reactant: CCOC(C)=O
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Titanium trichloride (10% solution in 20-30% HCl) was added to a solution of 3-(methoxycarbonylhydrazono)-2-(3-nitrophenylamino)butyric acid ethyl ester (compound 1c-51a) (5.0 g, 14.78 mmol) in acetone (50 mL), and the mixture was stirred at room temperature for 1 hour. Water was then added to the reaction mixture, extraction was performed with ethyl acetate, and the organic extract was washed with water and saturated saline. After drying over magnesium sulfate, it was concentrated under reduced pressure to yield a crude product, which was then purified by column chromatography to yield the title compound (3.75 g, 95%) as a yellow oil.