Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS([O-])=O.[Na+].[CH3:6][O:7][N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1.[C-:16]#[N:17].[K+]>O>[OH:15][CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([O:7][CH3:6])[CH2:9][CH2:10]1)[C:16]#[N:17]
Reactant: [C-]#N
Reactant: CON1CCC(C=O)CC1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CON1CCC(C(O)C#N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaHSO3 (11.4 g, 110 mmol) was added to a solution of 1-methoxy-piperidine-4-carbaldehyde (7.5 g, 52.4 mmol) in water (200 mL). After the mixture was stirred at room temperature for 3 h, a solution of KCN (7.2 g, 110 mmol) in water (100 mL) was added to the mixture. The reaction mixture was stirred for 2 h. Then the mixture was extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel. Yield: 6.2 g of hydroxy-(1-methoxy-piperidin-4-yl)-acetonitrile as an oil.
Reaction SMILES: CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C.[O:20]1[CH2:24][CH2:23][O:22][CH:21]1[CH2:25][NH:26][CH2:27][C:28]1[N:29]=[C:30]2[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][N:31]2[CH:38]=1.[F:39][C:40]1[CH:55]=[C:54]([F:56])[CH:53]=[C:52]([F:57])[C:41]=1[C:42]([C:44]1[CH:45]=[C:46]([C:49](O)=[O:50])[NH:47][CH:48]=1)=[O:43].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>>[C:36]([C:34]1[CH:33]=[CH:32][N:31]2[CH:38]=[C:28]([CH2:27][N:26]([CH2:25][CH:21]3[O:20][CH2:24][CH2:23][O:22]3)[C:49]([C:46]3[NH:47][CH:48]=[C:44]([C:42](=[O:43])[C:41]4[C:40]([F:39])=[CH:55][C:54]([F:56])=[CH:53][C:52]=4[F:57])[CH:45]=3)=[O:50])[N:29]=[C:30]2[CH:35]=1)#[N:37]
Reactant: O=C(O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Reactant: N#Cc1ccn2cc(CNCC3OCCO3)nc2c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccn2cc(CN(CC3OCCO3)C(=O)c3cc(C(=O)c4c(F)cc(F)cc4F)c[nH]3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a DMF 3 mL solution of product obtained in step A (410 mg, 1.58 mmol) were added 4-(2,4,6-trifluoro-benzoyl)-1H-pyrrole-2-carboxylic acid (427 mg, 1.58 mmol), EDC (396 mg, 2.06 mmol), HOBt (316 mg, 2.06 mmol) and triethylamine (0.443 mL, 3.17 mmol). The reaction mixture was stirred overnight at room temperature. The resulting suspension was filtered and diluted with EtOAc, washed with sat. ammonium chloride aq., sat. sodium bicarbonate aq. and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as foam (430 mg). LC/MS: m/z 510(M+H).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH2:24][O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:27][C:20]1[CH:21]=[C:22]([CH2:24][O:25][CH3:26])[CH:23]=[C:18]([O:17][CH3:16])[C:19]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Reactant: COCc1cc(OC)c(OB(O)O)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCc1nn2c(-c3c(OC)cc(COC)cc3OC)cccc2c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (1.0 g) dissolved in a mixture of 1,2-dimethoxyethane (50 mL) and water (25 mL) was added 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (1.26 g), tetrakis(triphenylphosphine)palladium(0) (0.64 g) and barium hydroxide octahydrate (1.75 g), and the reaction mixture was heated and stirred for 2 hours at 80° C. To the resultant reaction mixture was added water and ethyl acetate, and remove insoluble residue was filtered out with celite. The filtrate was extracted with ethyl acetate, the organic extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and the title compound (0.77 g) was obtained as yellow crystals from the n-hexane:ethyl acetate (3:1) fraction.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[O:16][C:15]([CH3:17])=[N:14][C:13]=2[CH3:18])[C:9](=[O:19])[NH:8][C:7]1=[O:20].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([C@:29]23[CH2:34][C@H:33]2[CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CCO>[ClH:1].[CH3:17][C:15]1[O:16][C:12]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:32][C@H:33]4[C@:29]([C:26]5[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:36])[F:35])=[CH:28][CH:27]=5)([CH2:34]4)[CH2:30]3)[CH:11]=2)=[C:13]([CH3:18])[N:14]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: Cc1nc(C)c(-c2cn(CCCCCl)c(=O)[nH]c2=O)o1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)c(-c2cn(CCCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)o1
Reaction time: 3 h
Yield: 24 %

Procedure:
A solution of 1-(4-chloro-butyl)-5-(2,4-dimethyl-oxazol-5-yl)-1H-pyrimidine-2,4-dione (Prep65, 100 mg, 0.34 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 68 mg, 0.3 mmol), and DIPEA (130 mg, 1 mmol) in absolute EtOH (3 ml) was placed in a microwave oven and irradiated at 130° C. for 3 hours. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic phase was evaporated, the crude dissolved in dichloromethane and treated with PS-isocyanate resin (400 mg) under stirring for 3 h. After filtration, the solvent was evaporated and the crude purified by preparative LC-MS. The residue was loaded over a SCX cartridge eluting with MeOH and the product obtained was treated with 4N HCl in dioxane (1 eq), to give the title compound as a white powder. (43 mg, 24% yield).
Reaction SMILES: [OH:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]1.[P:18](Cl)([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[S:19].C(N(CC)CC)C.O>C1COCC1>[CH2:21]([O:20][P:18]([O:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]1)([O:23][CH2:24][CH3:25])=[S:19])[CH3:22]
Reactant: CCOP(=S)(Cl)OCC
Reactant: Cc1ccccc1C(C#N)=C1C=CC(=NO)S1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=S)(OCC)ON=C1C=CC(=C(C#N)c2ccccc2C)S1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
8 g (33 mmol) of (5-Hydroxyimino-5H-thiophen-2-ylidene)-(2-methylphenyl)-acetonitrile, prepared as described in example 7.1, are dissolved in 90 ml of THF and cooled in an ice bath. After adding 6.9 g (36 mmol) of diethyl chlorothiophosphate to the solution, 5.0 g (50 mmol) of triethylamine are added dropwise, keeping the temperature below 50° C. The reaction mixture is stirred at 50° C. for 60 min, then is poured into 100 ml of water, and extracted with ethyl acetate. The organic phase is washed with 0.1N hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by a recrystallization from 2-PrOH. The product is obtained in the form of a brown solid, melting point 86-87° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 1.41 (t, 6H), 2.37 (s, 3H), 4.35-4.46 (m, 4H), 6.13 (d, 1H), 6.85 (d, 1H), 7.19-7.38 (m, 4H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([OH:10])=[CH:5][C:4]=1[NH:11][NH:12][CH:13]=[O:14].[OH-].[Na+].CO.[CH3:19][C:20]([CH3:22])=O>O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH2:22][C:20]#[CH:19])=[CH:5][C:4]=1[NH:11][NH:12][CH:13]=[O:14]
Reactant: CC(C)=O
Reactant: O=CNNc1cc(O)c(Cl)cc1Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCOc1cc(NNC=O)c(Cl)cc1Cl
Temperature: 40 °C

Procedure:
A stirred suspension of formic acid N'-(2,4-dichloro-5-hydroxyphenyl)-hydrazide sodium salt (1.1 g, 5 mmol) in a mixture of 25 ml acetone and 25 ml water is reacted at room temperature with benzene sulfonic acid-(2-propargyl)ester (1.01 g, 5 mmol). Sodium hydroxide solution (0,2 g, 5 mmol in 5 ml water) is added dropwise within 30 minutes so that the pH value lies between 9.5 and 10. The result is reacted with 10 ml methanol to produce a clear solution. This is heated to 40° C. for 30 minutes during which a precipitate forms. The result is stirred over night, the product is filtered off and washed with water. Yield: 0.8 g (61%) pale brown crystals Melting point: 184° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[N:7]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C@H:22]([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=1)=[O:5])C.O.[OH-].[Li+].O>O1CCCC1.Cl>[CH3:32][N:31]([CH2:30][C@@H:22]([NH:21][CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:7]1[CH:6]([C:4]([OH:5])=[O:3])[CH2:10][CH2:9][S:8]1(=[O:12])=[O:11])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH3:33]
Reactant: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(CN[C@@H](Cc2ccccc2)CN(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C[C@H](Cc1ccccc1)NCc1cccc(CN2C(C(=O)O)CCS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (360 mg, approx. 0.67 mmol) in tetrahydrofuran (4 mL) was added lithium hydroxide hydrate (57.4 mg, 1.37 mmol) followed by water (1 mL). It was stirred at room temperature for 2 h. To the stirred solution was added ˜15 drops 1N hydrochloric acid to bring the pH to 4.5. The sample was concentrated to dryness and dried over phosphorus pentoxide overnight. The crude 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (350 mg, ca 80% pure) (LiCl present) was used in the next step.
Reaction SMILES: OO.[CH3:3][S:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([Br:14])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16].[OH2:18].C(O)(=[O:21])C>>[CH3:3][S:4]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:12])[CH3:13])[C:8]([Br:14])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:21])=[O:18]
Reactant: CC(=O)O
Reactant: CSc1cc(C(C)C)c(Br)cc1C(C)C
Reactant: O
Agent: OO
Product: CC(C)c1cc(S(C)(=O)=O)c(C(C)C)cc1Br
Temperature: 90 °C

Procedure:
4-Bromo-2,5-diisopropylphenyl methyl sulfone was prepared as follows. A 55-g portion of 30% hydrogen peroxide was added to a solution of 28.7 g of 4-bromo-2,5-diisopropylphenyl methyl sulfide (prepared in Example 1C) in 100 ml of acetic acid over a period of 25 min. while maintaining the temperature at 50°-60°C. The reaction mixture was then refluxed at 90°C for 4 hrs., after which time it was poured into cold water. The product was filtered and washed with water to give 23.1 g of 4-bromo-2,5-diisopropylphenyl methyl sulfone. After recrystallization from 75% ethanol water the 4-bromo-2,5-diisopropylphenyl methyl sulfone melted at 107°-112°C.
Reaction SMILES: [CH3:1][C:2]1[C:6](Br)=[C:5]([NH2:8])[S:4][N:3]=1.[C:9]([S-:11])#[N:10].[K+]>CO>[CH3:1][C:2]1[C:6]([S:11][C:9]#[N:10])=[C:5]([NH2:8])[S:4][N:3]=1
Reactant: Cc1nsc(N)c1Br
Reactant: N#C[S-]
Agent: [K+]
Solvent: CO
Product: Cc1nsc(N)c1SC#N

Procedure:
386 g of 3-methyl-4-bromo-5-aminoisothiazole and 200 g of KSCN in methanol are refluxed for 6 hours. The product crystallizes out on cooling. 800 ml of water are added and the product is filtered off under suction and washed with water.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([CH2:8]O)[CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34])([O-:26])=[O:25]>C(Cl)Cl>[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:1]1[C@H:2]2[C@H:7]([CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]2)[CH2:8]1)(=[O:35])=[O:34])([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](N)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])[C@@H]2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.6 %

Procedure:
The product of Example 61D (39.8 mmol) in CH2Cl2 (200 mL) at 0° C. was treated with triethylamine (16.7 mL, 0.120 mol) followed by 2-nitrobenzenesulfonyl chloride (19.5 g, 88.0 mmol). The ice-bath was removed and the solution stirred at ambient temperature for 20 hours. The mixture was concentrated under reduced pressure and the residue dissolved in a mixture of ethanol and 5% aqueous NaOH (2:1, 200 mL). The mixture was stirred for 30 minutes, concentrated under reduced pressure, diluted with ethyl acetate (200 mL) and the layers were separated. The organic layer was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified via chromatography (SiO2, 50% ethyl acetate/hexanes) to provide the title compound (11.0 g, 27.7 mmol, 70% yield for two steps). MS (DCI/NH3) m/z 415 (M+NH4)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C@@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:5][C:6]([OH:8])=[O:7].[CH2:33](O)[CH3:34].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:33]([O:7][C:6](=[O:8])[CH2:5][C@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:3][CH:2]([CH3:32])[CH3:1])[CH3:34]
Reactant: CCO
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 8 h
Yield: 55 %

Procedure:
(3R,10S)-5-Methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]-nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid (183 mg) was taken up in 40 mL of dry CH2Cl2 and at 0° C. ethanol (0.5 mL, 5 eq) was added followed by N,N-dimethylaminopyridine (0.1 eq, 5 mg) and finally EDCI (209 mg, 5 eq). The resulting solution was stirred from 0° C. to room temperature overnight. Additional CH2Cl2 (100 mL) was added and the mixture was washed with 0.5N HCl (2×50 mL), saturated NaHCO3 (2×50 mL) and finally with brine (1×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Recrystallization from ethyl acetate and petroleum ether gave (3R,10S)-5-Methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid ethyl ester as a white solid (Yield: 108 mg, 55%), MS: 470 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:4]([CH:25]=[O:26])[CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:27])=[O:14])=[C:4]([CH:25]=[O:26])[CH:3]=1
Reactant: COc1ccc(CN(CCCCC(=O)O)c2ccc(Br)cc2C=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCCCN(Cc1ccc(OC)cc1)c1ccc(Br)cc1C=O
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of 5-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)pentanoic acid (77.2 g) and potassium carbonate (30.5 g) in DMF (500 ml) was added dropwise a solution of iodomethane (36.5 g) in DMF (100 ml) at 0° C. under nitrogen atmosphere. After stirring for 2 hours, water was added and the mixture was extracted with ethyl acetate. After washing the organic layer with water three times and with saturated brine once, the resultant was dried with magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→hexane:ethyl acetate=4:1) to give methyl 5-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)-pentanoate (45.7 g) as a brown oily material.
Reaction SMILES: [CH3:1][C:2]1([CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:21][NH2:22]>O1CCCC1.[Cl-].[Na+].O>[CH3:21][NH:22][C:16](=[O:20])[CH:15]([CH2:19][CH2:18][OH:17])[C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(CCO)C1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A solution of 4,5-dihydro-3-(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-yl)-2(3H)-furanone (described in Example 1, 20 g, 0.074 mole) in tetrahydrofuran (200 ml) and 40% aqueous methylamine (200 ml) is refluxed for 24 hr. The reaction mixture is diluted with brine and extracted with diethyl ether. The organic extracts are washed with brine, dried over magnesium sulfate and evaporated. The residue is subjected to chromatography on silica gel using acetone-benzene (1:2). The eluates are evaporated and crystallized from diethyl ether-hexane to obtain isomer A (6.9 g) of the title compound, mp 169°-171° C. The eluant for the column is changed to acetone-benzene (1:1) and the eluates are evaporated followed by trituration of the residue to obtain isomer B (7.5 g) of the title compound, mp 194°-196° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CS(C)=O>CN(C)C=O>[O:31]1[CH2:32][CH2:33][N:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=4)[S:11][CH:12]=3)=[CH:4][C:3]=2[N+:25]([O-:27])=[O:26])[CH2:29][CH2:30]1
Reactant: C1COCCN1
Reactant: CCOc1ccc(-c2nc(-c3ccc(Cl)c([N+](=O)[O-])c3)cs2)cc1OCC
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCOc1ccc(-c2nc(-c3ccc(N4CCOCC4)c([N+](=O)[O-])c3)cs2)cc1OCC
Yield: 91.5 %

Procedure:
A solution of 1 g of 4-(4-chloro-3-nitrophenyl)-2-(3,4-diethoxyphenyl)thiazole and 636 mg of morpholine dissolved in 20 ml of dimethylformamide and 20 ml of dimethyl sulfoxide was refluxed at 150° C. for 2-3.5 hours with heating. The reaction mixture was subjected to vacuum distillation. The residue was added to ice water, and an aqueous sodium hydrogencarbonate solution was added. The solution was extracted with dichloromethane three times. The combined extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate-n-hexane to obtain 1.03 g of 4-(4-morpholino-3-nitrophenyl)-2-(-3,4-diethoxyphenyl) thiazole.
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:14]=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:4]1([CH:2]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=[O:15])[CH3:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OCCc2ccccc2)c(O)c1
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Oc1cc(C=O)ccc1OCCc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 95.3 %

Procedure:
(1-Bromoethyl)benzene (0.56 mL, 4.13 mmol, 2 eq) was added to a stirred solution of 3-hydroxy-4-(2-phenylethoxy)-benzaldehyde (500 mg, 2.06 mmol, 1 eq) and cesium carbonate (672 mg, 2.06 mmol, 1 eq) in N,N-dimethylformamide (8 mL). The solution was stirred overnight and then diluted with ethyl acetate (50 mL). The organic solution was washed with 1M HCl (2×100 mL), and brine (100 mL), dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel and elution with petroleum ether:ethyl acetate (6:1) gave the product as a colourless oil (680 mg, 95%). RF (petroleum ether:ethyl actetate, 4:1) 0.51. 1H NMR (CDCl3) δ 9.72 (s, 1H, O═C—H), 6.93 (d, 1H, J 7.9 Hz, ArH), 5.38 (q, 1H, J 6.4 Hz, CHCH3Ph), 4.33 (m, 2H, CH2CH2Ph), 3.21 (t, 2H, J 6.8 Hz, CH2CH2Ph), 1.67 (d, 3H, J 6.4 Hz, CHCH3Ph).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][CH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](=[O:26])[N:14]2[CH:27]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[Br:1][C:27]1[N:14]2[C:15](=[O:26])[N:16]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[CH2:10][Cl:9]
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)c(Br)n12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
N-bromosuccinimide (80.4 mg, 0.45 mmol) was added to a stirred solution of 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one (0.114 g, 0.41 mmol) and benzoyl peroxide (9.94 mg, 0.041 mmol) in DCE (3 mL). The mixture was stirred at RT for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-bromo-2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one (0.102 g, 70% yield) as a white solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH:15]=2)(=O)=O)=CC=1.[CH3:25][O:26][C:27]1[CH:36]=[C:35]2[C:30]([CH:31]=[CH:32][CH:33]=[C:34]2[N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:29][CH:28]=1>ClCCl>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]=[C:14]2[CH2:13][CH2:12][N:40]1[CH2:39][CH2:38][N:37]([C:34]2[C:35]3[C:30](=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:36]=3)[CH:31]=[CH:32][CH:33]=2)[CH2:42][CH2:41]1
Reactant: COc1ccc2cccc(N3CCNCC3)c2c1
Reactant: COc1ccc2c(c1)C(CCOS(=O)(=O)c1ccc(C)cc1)=CC2
Solvent: ClCCl
Product: COc1ccc2c(c1)C(CCN1CCN(c3cccc4ccc(OC)cc34)CC1)=CC2
Temperature: 130 °C
Yield: 164 %

Procedure:
2.07 g (0.006 mol) of 2-(5-methoxy-1H-inden-3-yl)ethyl 4-methylbenzenesulphonate and 2.90 g (0.012 mol) of 1-(7-methoxynaphth-1-yl)piperazine are mixed and the mixture is stirred, is placed under an argon atmosphere and is heated in an oil bath at 130° C. for 2 h. The mixture is taken up in dichloromethane, the solution is washed with water, with dilute sodium hydroxide and then again with water, is dried over magnesium sulphate and is filtered and the filtrate is evaporated under reduced pressure. 4.08 g of an oil are obtained, which oil is purified by chromatography on a column of silica gel, elution being carried out with a 92/8 dichloromethane/acetone mixture.