Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:35])[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[N:3]=1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>>[ClH:1].[ClH:1].[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:35])[C:21]3[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=3)[N:3]=2)[CH2:39][CH2:38]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
368 mg of the product obtained in Stage 1 above and 402 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to 140° C. for 6 hours. After evaporating the solvent, chromatography on silica is carried out (eluent methylene chloride/methanol/ammonium hydroxide 85/15/1.5) followed by taking up in an ethanolic solution of hydrochloric acid, leaving to crystallize, separating, drying under reduced pressure and 210 mg of expected product is recovered.
Reaction SMILES: [CH2:1]([CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[BH4-].[Na+].Cl>O1CCCC1.CO.CCOCC>[CH2:1]([CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCCC(C=O)CCCCCCCC/C=C\CCCCCCCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCCCC(CO)CCCCCCCC/C=C\CCCCCCCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Crude 2,3-di(9-(Z)-octadecenyl) propanal of formula (10) from Preparation 7 (10.0 g, 16.9 mmol) was dissolved in tetrahydrofuran/methanol (1:1, 200 ml) and cooled to 0° C. Sodium borohydride (3.13 g, 85.0 mmol) was added and the mixture was stirred overnight. The solution was acidified with 1N HCl to pH<2, diluted with ether, washed with water, concentrated and column chromatographed (chloroform) to give the title compound as an oil.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[NH:4][C:3]1=[O:14].[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>ClCCl.O>[CH3:13][O:12][C:10]([CH2:9][CH2:8][CH2:7][O:6][C@@H:5]1[NH:4][C:3](=[O:14])[C@H:2]1[NH:1][C:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:11]
Reactant: COC(=O)CCCO[C@@H]1NC(=O)[C@H]1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCCO[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 10.6 %

Procedure:
(3S,4S)-3-Amino-4-[3-(methoxycarbonyl)propoxy]azetidin-2-one (30 mg, 0.148 mmol) was dissolved in dry dichloromethane (2 mL) and treated with triphenylmethyl chloride (41 mg, 0.148 mmol) followed by diisopropylethylamine (19 mg, 0.148 mmol). The solution was stirred at RT under argon for 5 h, diluted with water and extracted with dichloromethane. The organic phases were combined, washed with water and brine, dried (magnesium sulfate), filtered, and concentrated. The residue was purified by preparative thin layer chromatography (Whatman, silica gel 60A, 20×20 cm, 1000 um, 40% ethyl acetate:hexane) to give the title compound (7 mg). MS(ES) m/e 445.2 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21]Cl.O>CN(C)C=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21][N:9]1[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: ClCc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(Cc2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
To a mixture comprising 1.94 g 1-ethoxycarbonylpiperazine and 3.45 g anhydrous potassium carbonate, in 20 mL of N,N-dimethylformamide, stirred at room temperature, under a nitrogen atmosphere, there was added 2.01 g of 2,5-dichlorobenzyl chloride. Then after 24 hr stirring at room temperature, this reaction mixture was poured into 200 mL of water, followed by extraction with ethyl acetate (3×100 mL). The obtained organic phase was dried over anhydrous sodium sulphate, followed by evaporation under vacuum. The obtained residue was then purified by flash chromatography (petroleum ether—ethyl acetate 85:15). The solvents were then evaporated off completely to give 2 g of Compound 14A (yield 63%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.Br>C(#N)C>[Br-:10].[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[CH:4]1)([OH:17])=[O:16]
Reactant: O=C(O)CCCCBr
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1cccc2ccccc12
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CCCCn1c[n+](Cc2cccc3ccccc23)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 5-bromopentanoic acid (1.33 g, 7.36 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 1-(bromomethyl)naphthalene (1.63 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting product will be collected and analyzed.
Reaction SMILES: CON=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:17]=[C:16]([CH2:18][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[O:15][C:14]=3[C:25]3[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.Cl.CC(C)=[O:36].C(OCC)(=O)C>O1CCOCC1>[CH3:32][S:31][C:27]1[N:26]=[C:25]([C:14]2[O:15][C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:17][C:13]=2[C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[C:4](=[O:36])[CH2:5][CH2:6]3)[CH:30]=[CH:29][N:28]=1
Reactant: CC(C)=O
Reactant: CON=C1CCc2cc(-c3cc(CN4CCCCC4)oc3-c3ccnc(SC)n3)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1nccc(-c2oc(CN3CCCCC3)cc2-c2ccc3c(c2)CCC3=O)n1
Temperature: 100 °C

Procedure:
A mixture of the product from Step 3 (0.310 g, 0.692 mmol) and 5M HCl (3 ml) in dioxane (3 ml)/acetone (1 ml) was heated at 100° C. for 1 hour. The mixture was then cooled to room temperature and poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The ethyl acetate was then dried and the solvent evaporated in vacuo and the residue chromatographed on silica gel eluting with a mixture of 0.880 ammonia/methanol/dichloromethane (0.5:4.5:95) to furnish the title compound (0.145 g, 0.345 mmol); MS(ES+) m/e 420 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C@@:9]([CH3:15])([CH2:13][OH:14])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][C:18](Cl)=[O:19]>>[CH2:1]([N:8]1[C:18](=[O:19])[CH2:17][O:14][CH2:13][C@@:9]1([CH3:15])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: C[C@@](CO)(NCc1ccccc1)C(=O)O
Product: C[C@@]1(C(=O)O)COCC(=O)N1Cc1ccccc1
Yield: 65 %

Procedure:
(S)-2-(benzylamino)-3-hydroxy-2-methylpropanoic acid (2.09 g, 10 mmol) was reacted with chloroacetyl chloride (1.74 g, 15.4 mmol) according to the procedure as described in Example 46, Step B to give the title compound as a gray solid (1.62 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C([N-:14]C(C)C)(C)C.[Li+].O.O.O.C([O-])(=O)C.[Na+].N[O:28][S:29]([OH:32])(=O)=O>O1CCCC1>[S:29]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=2[CH:8]=1)(=[O:32])(=[O:28])[NH2:14]
Reactant: Clc1nccc2occc12
Reactant: CC(C)[N-]C(C)C
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc2c(Cl)nccc2o1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-chloro-furo[3,2-c]pyridine (6.17 g, 40.2 mmol) in tetrahydrofuran (80 ml), under a nitrogen atmosphere at -70° C., was added dropwise a solution of 0.7M lithium diisopropylamide in THF (64 ml, 44.8 mmol). After stirring for 1/2 hour, sulfur dioxide gas was bubbled over the surface of the reaction and the temperature was allowed to gradually rise to room temperature. Dilution with diethyl ether (150 ml) caused the lithium sulfinate intermediate to precipitate. This precipitate (15 g) was collected by filtration and dissolved in water (80 ml). After addition of sodium acetate trihydrate (21.6 g, 0.26 mol) and hydroxylamine-O-sulfonic acid (10.4 g, 0.088 mol), mixture was stirred for 18 hours as the product slowly precipitated. The precipitated crude product was collected by filtration, dissolved in ethyl acetate/methanol. This solution was dried over anhydrous sodium sulfate, filtered through a pad of charcoal and evaporated to give pure crystalline product (5.25 g, 56% yield). Recrystallization of this material from ethyl acetate gave product with m.p. 192°-194° C.
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[C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=O.O1CCCC1.[CH:28]1([Na])[CH:32]=[CH:31][CH:30]=[CH:29]1.O1CCCC1.Cl>C(OCC)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[C:31]1[CH:30]=[CH:29][CH:28]=[CH:32]1
Reactant: O=C(c1ccc2ccccc2c1)c1ccc2ccccc2c1
Reactant: [Na]C1C=CC=C1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1=CC(=C(c2ccc3ccccc3c2)c2ccc3ccccc3c2)C=C1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A 200-ml two-necked flask equipped with a magnetic stirrer and a three-way cock was thoroughly purged with nitrogen, and sequentially charged with 1.55 g (5.48 mmol) of di-2-naphthyl ketone produced by the method described in Heterocycles, vol. 40, No. 1, 79-83 (1995) and 40 ml of tetrahydrofuran. Then, 5.50 ml (11.0 mmol) of a 2.0 mol/l cyclopentadienyl sodium/tetrahydrofuran solution was gradually added while cooling the mixture in an ice water bath, and then the mixture was stirred at room temperature for 65 hours under a nitrogen atmosphere. Subsequently, 100 ml of 3 N hydrochloric acid and 100 ml of diethyl ether were gradually added. The two-layered solution thus obtained was transferred to a 300-ml separatory funnel and the funnel was shaken several times. The aqueous layer was then removed. This aqueous layer was subjected to extraction with 30 ml of diethyl ether once, and the extract was combined with the organic layer obtained previously. Subsequently, the organic layer obtained was washed 3 times with 100 ml of water and once with 100 ml of saturated brine, and dried over anhydrous magnesium sulfate for 2 hours. The solids were separated by filtration, and the solvent was distilled off to obtain solids. The solids were purified by separation using silica gel chromatography to obtain a target product (yield 1.21 g (67%)). The target product was identified by 1H-NMR spectroscopy.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[N:18]=[C:17]([NH2:19])[CH:16]=[C:15]([NH2:20])[C:12]=1[C:13]#[N:14]>O1CCOCC1>[NH2:20][C:15]1[C:12]([C:13]#[N:14])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:18]=[C:17]([NH2:19])[CH:16]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1c(N)cc(N)nc1Oc1ccccc1
Temperature: 190 °C
Reaction time: 0.25 h

Procedure:
A heavy walled, sealable tube suitable for microwave heating was charged with 60 mg (1.5 mmol) of NaH (60% dispersion in mineral oil) and 3 mL of dioxane. To the suspension was added 150 mg (1.59 mmol) of phenol, then the mixture was stirred for 15 min. Next, 212 mg (1.00 mmol) of 2-bromo-4,6-diaminonicotinonitrile was added. The tube was sealed, and the mixture was heated with a microwave apparatus at 190° C. for 25 minutes then cooled and concentrated under reduced pressure. The residue was diluted with 10 mL of toluene and concentrated again under reduced pressure. The remaining material was taken up in 20 mL of ethyl acetate and extracted with 2M NaOH(aq.) (3×5 mL), and brine (1×5 mL), draining some red precipitate with the aqueous layers. The organic layer was dried over MgSO4, filtered, and concentrated to 178 mg (79%) of an orange solid. The product could be further purified via silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes to provide a white solid. 1H NMR (300 MHz, d6-DMSO) δ 7.38 (m, 2H), 7.17 (m, 1H), 7.10 (m, 2H), 6.37 (s, 2H), 6.25 (s, 2H), 5.41 (s, 1H); MS (ESI) m/e=227 (M+H)+, 225 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[F:1][C:2]1[C:3]2[O:10][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cccc(F)c2o1
Temperature: 100 °C
Yield: 51.9 %

Procedure:
A mixture of 3-fluoro-2-hydroxybenzaldehyde (5.00 g, 35.7 mmol), potassium carbonate (9.85 g, 71.4 mmol), and ethyl bromoacetate (4.30 ml, 39.3 mmol) in N,N-dimethylformamide (70 mL) was heated at 100° C. for 16 h. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3×150 mL). The combined organic solution was washed with brine (150 mL), dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate, 49/1→9/1) to afford ethyl 7-fluorobenzofuran-2-carboxylate (3.86 g, 52%) as a yellowish oil: 1H NMR (300 MHz, CDCl3) δ7.56-7.54 (m, 1H), 7.47-7.42 (m, 1H), 7.28-7.14 (m, 2H), 4.46 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H).
Reaction SMILES: CS[C:3]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1)=[N:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:25][C:26]1[CH:43]=[CH:42][C:29]([CH2:30][N:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH2:32][CH2:33][CH2:34][NH2:35])=[CH:28][CH:27]=1>N1C=CC=CC=1>[Br:25][C:26]1[CH:43]=[CH:42][C:29]([CH2:30][N:31]([CH2:32][CH2:33][CH2:34][NH:35][C:3]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[N:4][C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:28][CH:27]=1
Reactant: NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Reactant: CSC(=NC(=O)c1ccccc1)N1CCN(c2ccccn2)CC1
Solvent: c1ccncc1
Product: O=C(N=C(NCCCN(Cc1ccc(Br)cc1)c1ccccn1)N1CCN(c2ccccn2)CC1)c1ccccc1
Yield: 56.5 %

Procedure:
To a mixture of N-[methylsulfanyl-(4-(pyridin-2-yl)piperazin-1-yl)methylene]-benzamide (2.9 g, 8.52 mmol) in pyridine (50 ml) was added N1-(4-bromobenzyl)-N1-(pyridin-2-yl)-propane-1,3-diamine (3 g, 9.37 mmol) and the reaction mixture was heated at reflux for 18 h. The volatiles were evaporated in vacuo and the residue dissolved in dichloromethane (100 ml) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (600 ml) using first a mixture of ethyl acetate/triethylamine 95:5 (1 l) followed by a mixture of 20 ethyl acetate/methanol/triethylamine 90:5:5 as eluents affording 2.95 g of N-[[3-[N-(4-bromo-benzyl)-N-(pyridin-2-yl)amino]propylamino]-(4-pyridin-2-yl-piperazin-1-yl) methylene]benzamide as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.[CH3:17][O:18][CH2:19][C:20](=O)[CH2:21][C:22]([O:24][CH3:25])=[O:23]>>[CH3:17][O:18][CH2:19][C:20]1[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]2[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: Nc1cc[nH]n1
Reactant: COc1ccccc1C=O
Reactant: COCC(=O)CC(=O)OC
Product: COCC1=C(C(=O)OC)C(c2ccccc2OC)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and methyl 4-methoxyacetoacetate in the same manner as in Example 1.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:12][C:11]([OH:13])=[N:10][C:8]2=[O:9])=[CH:5][CH:6]=1.C=O.[C:22]([O-])([O-])=[O:23].[K+].[K+]>O>[C:14]1([C:7]2([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[NH:12][C:11](=[O:13])[N:10]([CH2:22][OH:23])[C:8]2=[O:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1N=C(O)NC1(c1ccccc1)c1ccccc1
Agent: C=O
Agent: [K+]
Solvent: O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Reaction time: 24 h
Yield: 91 %

Procedure:
Phenytoin (5 g, 0.02 mol) was suspended in 180 mL of water; 20 mL of formaldehyde (37% solution) and 0.25 g K2CO3 were added and the mixture was stirred at 25°-30° C. for 24 hours. The white solid which formed was removed by filtration and washed repeatedly with a 3% solution of formaldehyde, then air-dried for 3 to 4 hours and over P2O5 in a vacuum desiccator. Yield 91-93%, m.p. 185°-189° C. Anal. calc. for C16H14N2O3 : C, 68.07; H, 5.00; N, 9.93. Found: C, 67.97; H, 5.05., N, 9.93. The product had the formula: ##STR70##
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][N:7]=1)=[O:5])C.[CH2:36]([NH2:38])[CH3:37]>CO>[CH2:36]([NH:38][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]([CH3:18])[CH3:19])[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][N:7]=1)=[O:5])[CH3:37]
Reactant: CCN
Reactant: CCOC(=O)c1cc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CO
Product: CCNC(=O)c1cc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 120 °C

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester was dissolved in excess 2M ethylamine in methanol and heated in the Smith Synthesiser microwave at 120° C. for 600 seconds. The solution was concentrated in vacuo to give a solid which was purified by hexane trituration, to give 5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethylamide.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]([O:28][C:29]1[N:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[N:30]=1)[C:23]([O:25][CH2:26]C)=[O:24].O>C(#N)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH:22]([O:28][C:29]1[N:30]=[C:31]([CH3:36])[CH:32]=[C:33]([CH3:35])[N:34]=1)[C:23]([O:25][CH3:26])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)C(Cl)Oc1nc(C)cc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(Oc1cccc(Oc2ccccc2)c1)Oc1nc(C)cc(C)n1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
3-Phenoxyphenol (1.0 g, 5.4 mmol) was placed in a flask with potassium carbonate (0.90 g, 6.5 mmol) and 20 mL of acetonitrile and to this was added dropwise with stirring at ambient temperature, a solution of ethyl 2-chloro-2-(4,6-dimethyl-2-pyrimidinyloxy)acetate (1.40 g, 5.7 mmol) in 5 mL of acetonitrile. The mixture was allowed to stir overnight and was then added to water and the resulting mixture was extracted 3 times with ether. The ethereal solution was extracted 2 times with 1N aqueous sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain about 1 g of the title compound as a crude yellow oil. This oil, which solidified on standing, was chromatographed on silica eluting with an 85:15 mixture of hexane and ethyl acetate to obtain 0.60 g (28 percent of theory) of the title compound as a white solid melting at 111°-112° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl.CO>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@@H:19]([O:22][C:3](=[O:4])[NH2:5])[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OC(N)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A solution of 4.52 g of trichloroacetyl isocyanate in 8 ml of methylene chloride was added to an ice-cooled solution of 3.75 g of (3R)-1-(t-butoxycarbonyl)-3-hydroxypyrrolidine in 40 ml of methylene chloride, and the mixture was stirred for 30 minutes with ice-cooling. After completion of the reaction, the solvent was stripped off from the reaction mixture and the residue was dissolved in 100 ml of methanol. The solution was stirred with 35 g of silica gel for 5 hours at 30° C., and then filtered. The filtrate was concentrated, giving 3.05 g of (3R)-1-(t-butoxycarbonyl)-3-carbamoyloxypyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[CH3:9][S-:10].[Na+].O>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([S:10][CH3:9])[CH:7]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cnnc(Cl)c1
Yield: 76 %

Procedure:
3,5-Dichloropyridazine, which is known in the art, (2.0 g, 0.0135 moles) and sodium thiomethoxide (1.14 g, 0.0162 moles) were stirred in THF (50 mL) at RT under N2 for 2 h. The mixture was then poured into water and extracted 2×100 mL with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated in-vacuo to give a crude solid which was recrystallized from cyclohexane/ethyl acetate to give 3-chloro-5(methylthio)pyridazine (1.64 g, 76% yield) as a brown solid, mp=98° C.-100° C.