Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[N+:12]([C:3]1[C:2]([OH:11])=[CH:1][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)([O-:14])=[O:13]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc2c(cc1O)CCCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5,6,7,8-tetrahydro-2-naphthol (44 g) in 300 ml of acetic acid was added dropwise fuming nitric acid (12 ml in 12 ml of acetic acid) over a period of 30 minutes. The reaction mixture was then stirred for an additional 5 hours at room temperature. After evaporation of the solvent, the crude product was purified by column chromatography (silica gel) to give 16 g of pure product, m.p. 88°-89° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:8]=2[CH:21]=1)([OH:3])=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:8]2[CH:21]=[C:4]([C:1](=[O:3])[NH:33][S:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)(=[O:31])=[O:32])[CH:5]=[CH:6][C:7]=2[N:11]=[C:10]1[CH3:12]
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Reactant: COc1ccc(S(N)(=O)=O)cc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)NC(=O)c2ccc3nc(C)n(Cc4ccccc4Cl)c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
N,N'-carbodiimidazole (0.431 g) was added at a time to a solution of 0.400 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 15 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 0.498 g of 4-methoxybenzenesulfonamide and 0.405 g of diazabicycloundecene in 5 ml of N,N-dimethylformamide was added thereto, and the mixed solution was stirred at 100° C. for 67 hours. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. Water and chloroform were added to the residue, and 10% hydrochloric acid was added thereto while being cooled until the aqueous layer was acidified. The resulting mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, and the solvent was distilled off under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of chloroform and methanol at a ratio of 100:2 to 100:10). The resulting product was concentrated, and was crystallized from a mixed solution of ethyl acetate and diethyl ether. The crystals were separated through filtration, and were dried to give 0.450 g of 1-(2-chlorobenzyl)-6-(4-methoxybenzenesulfonylcarbamoyl)-2-methylbenzimidazole (217).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[C:24]([F:39])=[C:25]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[C:24]([F:39])=[C:25]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[C:31](=[CH:20][C:3]2[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=2[CH3:1])[C:32](=[O:38])[NH:33]3)[CH:26]=[CH:27][CH:28]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4F)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 62.1 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (54 mg, 62.1%) as a yellow solid.
Reaction SMILES: O[C:2]1[CH:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:7])[O:5][CH:6]=1.O.[NH2:15][NH2:16]>C(O)C>[OH:5][CH2:6][C:2]1[N:16]=[N:15][C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NN
Reactant: O=C1OC=C(O)C1c1ccccc1
Solvent: O
Solvent: CCO
Product: O=C1N=NC(CO)=C1c1ccccc1

Procedure:
4-Hydroxy-3-phenyl-2-furanone (3 g, 0.017 mol) was dissolved in ethanol (17 ml) with hydrazine hydrate (0.83 ml, 0.017 mol) and heated at reflux for 10 days (over this time the solvent evaporated). The residue was redissolved in ethanol (17 ml) and heated at reflux then allowed to cool and the solid that crystallised out was collected by filtration (2.2 g, mp=173° C.). Data for the title compound: 1H NMR (360 MHz, d6-DMSO) δ 4.45 (1H, s), 5.31 (1H, s), 7.14 (1H, t, J=7.3 Hz), 7.34 (2H, t, J=7.3 Hz), 7.55 (2H, d, J=7.3 Hz); MS (ES+) m/e 191 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23].P>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)CCc1cc(Nc3ccc(F)cc3F)ccc1C2=O
Yield: 66 %

Procedure:
In accordance with general method O, 0.52 g (1.9 mmol) of 2-chloro-8-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.30 g (2.3 mmol) of 2,4-difluoroaniline, 0.04 g of Pd(OAc)2, 0.16 g of phosphine ligand and 0.86 g (8.9 mmol) of Na—O-tert-butylate are reacted in 10 ml of toluene and 2 ml of tert-BuOH. Purification is carried out by column chromatography (flash; SiO2; hexane 90%/ethyl acetate 10%). Yield: 66%; m.p.: 157° C.
Reaction SMILES: C[Mg]Br.[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[C:5]1=[O:14])[CH2:11]2.[CH2:15](Cl)Cl>C(OCC)C.O1CCCC1>[CH3:15][C:5]1([OH:14])[CH:6]2[CH2:12][CH:10]3[CH2:9][CH:8]([CH2:13][CH:4]1[CH2:11]3)[CH2:7]2
Reactant: ClCCl
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
110 ml of a solution of methyl magnesium bromide (3.0 M) in diethyl ether was diluted with 100 ml of anhydrous tetrahydrofuran (THF). Then, the solution was put into a 1 liter flask and then maintained at 0° C. 2-adamantanone (45 g, 0.3 mol) was dropped slowly using a dropping funnel and then the reaction was stirred at room temperature for about 12 hours. After completion of the reaction, excess THF was removed using a rotary evaporator and then the resultant product was poured into water. Then, the resultant product was neutralized with dilute sulfuric acid and extracted using diethyl ether and was then dried over magnesium sulfate. The obtained crude product was recrystallized using n-hexane and a methylene chloride cosolvent to yield the desired product 2-methyl-2-adamantanol (yield: 80%).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][CH:8](Cl)Cl.C[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18]([CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)[CH2:17][CH2:16]2.[OH-].[NH4+]>C(Cl)Cl.O>[NH:26]1[CH:27]=[C:23]([CH2:22][CH:18]2[C:19]3[C:15](=[CH:14][C:8]([O:7][CH3:6])=[C:21]([CH:13]=[O:12])[CH:20]=3)[CH2:16][CH2:17]2)[N:24]=[CH:25]1
Reactant: COc1ccc2c(c1)CCC2Cc1c[nH]cn1
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)C(Cc1c[nH]cn1)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tin(IV)chloride (800 mg) is added dropwise to a stirred solution of dichloromethyl methyl ether (343 mg) in methylene chloride (8 ml) with ice cooling under a nitrogen atmosphere. The solution is stirred at 0° C. for one hour before adding a solution of 4-(5-methoxyindan-1-ylmethyl)-1H-imidazole (300 mg) in methylene chloride (4 ml). The resulting mixture is allowed to warm to ambient temperature while being stirred for 4 hours. The mixture is then poured into cold water and is made basic with ammonium hydroxide solution. Work-up of the mixture gives the crude product which is purified by flash chromatography and recrystallized from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=2)=[N:6]1.[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:40]([O:39][C:37]([N:31]1[CH2:36][CH2:35][N:34]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:4][C:3]3[C:26]([Cl:30])=[CH:27][CH:28]=[CH:29][C:2]=3[Cl:1])[N:6]=[C:7]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=3)[CH:8]=2)[CH2:33][CH2:32]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3c(Cl)cccc3Cl)n2)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1cc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(Cc3c(Cl)cccc3Cl)n2)ccc1F
Yield: 90.8 %

Procedure:
Following the procedure of Example 1(10), 2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 90.8%).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>O.CO>[C:3]([O:7][C:8]([N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CCCCN(C(=O)OC(C)(C)C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCCC(=O)O)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
NaOH (240 mg, 6 mmol) was dissolved in water (3 mL) and MeOH (10 mL). This solution was added to methyl 5-[(tert-butoxycarbonyl)(pyridin-2-yl)amino]pentanoate (200 mg, 0.64 mmol) dissolved in MeOH (15 mL). The mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 2N HCl to pH 7. The solvent was removed under reduced pressure. A citric acid solution (10 mL) was added and the mixture was extracted with ethyl acetate, dried (MgSO4) and concentrated to give 128 mg (68%) of the product. 1H NMR (CDCl3) 8.36–8.34 (m, 1H), 7.65–7.52 (m, 2H), 7.02–6.98 (m, 1H), 3.97–3.91 (m, 2H), 2.38–2.32 (m, 2H), 1.69–1.62 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]([CH2:29][C:30](OCC)=[O:31])=[O:28])([F:26])([F:25])[F:24]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:30](=[O:31])[CH2:29][C:27](=[O:28])[C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2ccc(N)cc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(Cc2ccc(NC(=O)CC(=O)C(F)(F)F)cc2)cc1
Temperature: -15 °C
Yield: 88.4 %

Procedure:
A solution of [4-(4-aminobenzyl)phenyl]carbamic acid tert-butyl ester (1.26 g, 4.2 mmol) in PhMe (15 mL) was treated with a PhMe (10 mL) solution of CF3COCH2CO2Et (0.79 g, 4.3 mmol), before being heated under reflux for 1 h. More CF3COCH2CO2Et (0.40 g, 2.2 mmol) was added, & the mixture was heated under reflux for 1.5 h. The precipitate generated when the mixture was cooled to −15° C. was collected to give {4-[4-(4,4,4-trifluoro-3-oxobutyrylamino)benzyl]phenyl}carbamic acid tert-butyl ester (1.62 g, 90%): m/z (ES−)=435.3 [M−H]−. This compound (1.00 g, 2.3 mmol) was added portionwise with stirring to cold H2SO4 (5 mL) to generate a brown solution. This solution was heated at 90° C. for 1 h, then the cooled mixture was poured onto crushed ice. The aqueous phase was treated with solid NaOH until basic, & the mixture was extracted with Et2O (200 mL). The Et2O extracts were dried (MgSO4), concentrated to a small volume, & triturated with PE to furnish the title compound (0.66 g, 91%): δH ((CD3)2SO)=3.80 (s, 2H), 4.85 (s, 2H), 6.45 (d, 2H), 6.85 (d, 2H), 6.95 (s, 1H), 7.35 (d, 1H), 7.40–7.50 (m, 2H); m/z (ES+)=319.1
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH:13][CH3:14].O>C1COCC1>[CH3:12][N:13]([CH3:14])[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In THF (250 ml) was dissolved 4-nitrobenzyl bromide (25.0 g), and to the mixture was added 50% dimethylamine solution (29 ml) at 0° C. The reaction mixture was stirred at room temperature for 60 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give dimethyl-4-nitrobenzylamine (20.7 g) as orange oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[O:19][C:18]([CH:20]=[CH:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[O:1]([CH2:8][CH2:9][CH2:10][N:26]1[CH:25]=[CH:24][N:23]=[C:22]1[CH:21]=[CH:20][C:18]1[O:19][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ncc[nH]2)o1
Reactant: BrCCCOc1ccccc1
Product: O=[N+]([O-])c1ccc(C=Cc2nccn2CCCOc2ccccc2)o1

Procedure:
Using the same general procedure of Example 1, the captioned compound was prepared using 3-phenoxypropyl bromide and 2-[2-(5-nitro-2-furyl)vinyl]imidazole. The resulting orange product after recrystallization from ethanol-water melted at 85°-86°.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2Br)[N:11]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[C:27](=[O:28])[C:10]=12)C1C=CC=CC=1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[Cl:39].C([O-])([O-])=O.[Na+].[Na+].ClCCl>CO.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>[Cl:32][C:33]1[CH:34]=[C:35]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][C:12]2[N:11]3[CH2:24][CH2:25][N:26]([CH:29]([CH3:30])[CH3:31])[C:27](=[O:28])[C:10]3=[C:9]([OH:8])[C:14](=[O:15])[N:13]=2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)N1CCn2c(Cc3ccccc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccc(Cl)c(Cl)c3)nc(=O)c(O)c2C1=O
Reaction time: 8 h
Yield: 15.2 %

Procedure:
9-Benzyloxy-6-(2-bromobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (71) (0.1 g, 207 μmol, Eq: 1.00, ˜40% pure), 3,4-dichlorophenylboronic acid (47.5 mg, 249 μmol, Eq: 1.2), Na2CO3 (65.9 mg, 622 μmol, Eq: 3) and tetrakis(triphenylphosphine)palladium (0) (24.0 mg, 20.7 μmol, Eq: 0.1) were stirred in methanol (0.9 ml)/dichloromethane (300 μl) in the microwave at 115° C. for 30 minutes. The reaction mixture stood at room temperature overnight. The supernatant was pipetted off, concentrated and purified by SiO2 flash chromatography (4 g SiO2, dichloromethane/methanol 0-5% methanol) to afford 6-(3′,4′-dichloro-biphenyl-2-ylmethyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (72) (0.016 g, 31.4 μmol, 15.2% yield, 90% pure) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[O:34][CH3:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[O:34][CH3:35])=[CH:6][CH:7]=1
Reactant: COc1c(CBr)ccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Product: COc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(F)cc2)ccc2ccccc12

Procedure:
In an analogous manner to that described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3(b)] with 2-bromomethyl-1-methoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-[1-methoxy-naphthalen-2-yl-methoxy]-piperidine-1-carboxylate as a colourless resin; MS: 465 (M)+.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].C(N(CC)CC)C.Cl[CH2:20][CH2:21][N:22]([CH2:33][CH2:34]Cl)[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C)C=O>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][N:1]([C@H:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][C@H:3]3[OH:11])[CH2:34][CH2:33]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCN([C@H]3c4ccccc4C[C@H]3O)CC2)cc1
Temperature: 80 °C

Procedure:
To 8 g of (1S,2R)-1-aminoindan-2-ol (53.6 mmol) dissolved in 80 ml of dimethyl-formamide there are added 15 ml of triethylamine (107.2 mmol) and 15.8 g of N,N-bis(2-chloroethyl)-p-toluenesulphonamide (53.6 mmol). The mixture is heated at 80° C. for 24 hours and then the dimethylformamide is evaporated off. The residue is taken up in dichloromethane, washed, dried, filtered and evaporated. The oil obtained is purified by flash chromatography on silica (eluant: dichloromethane/ethyl acetate 95/5) to yield the expected product in the form of a meringue.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[N:33]1([CH2:38][C:39]2([OH:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:37]=[CH:36][N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:42]5[CH2:43][CH2:44][C:39]([OH:45])([CH2:38][N:33]6[CH:37]=[CH:36][N:35]=[CH:34]6)[CH2:40][CH2:41]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:31])([F:30])[F:32])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC1(Cn2ccnc2)CCNCC1
Product: O=C1N=C(N2CCC(O)(Cn3ccnc3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-hydroxy-4-imidazol-1-ylmethyl-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-Imidazol-1-ylmethyl-piperidin-4-ol following General Procedure B.
Reaction SMILES: [ClH:1].[C:2](O)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[ClH:14].[C:2]([Cl:1])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of nicotinic acid hydrochloride (0.5 g, 3.1 mmol) in CH2Cl2 (200 mL) at room temperature was added oxalyl chloride (0.42 mL, 4.8 mmol) and three drops of DMF. The reaction mixture was stirred at room temperature for 1 h and then concentrated using a rotary evaporator. The resulting residue was re-dissolved in toluene (50 ml), and then again concentrated using a rotary evaporator to afford nicotinic acid chloride hydrochloride (0.5 g, 90%). To a solution of 2′-hydroxyacetophenone (0.38 g, 2.8 mmol) in THF (50 mL) at room temperature was added nicotinic acid chloride hydrochloride (0.5 g, 2.8 mmol) and triethylamine (1.2 mL, 8.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (50 mL), extracted with CH2Cl2 (3×100 mL), concentrated using a rotary evaporator. The residue was purified by column chromatography (hexane:ethyl acetate 2:1) to provide the corresponding ester (0.42 g, 62%). A solution of the above ester (0.42 g, 1.73 mmol) in THF (50 mL) was mixed with t-BuOK (0.25 g, 2.25 mmol) and was stirred at room temperature for 16 hours. The reaction was quenched with water (50 mL) and the aqueous was acidified with HCl (0.5 N) to pH=6. The reaction mixture was extract with CH2Cl2 (3×100 mL), concentrated using a rotary evaporator, trituration in hexanes to afford a solid. This solid was collected by filtration and washed with hexanes to provide the diketone (0.3 g, 71%). A solution of the above diketone (0.3 g, 1.25 mmol) in HOAc (50 mL) and HCl (conc., 1 mL) was stirred at reflux for 2 hours. The solvent was removed using a rotary evaporator. The residue was purified by column (hexane:ethyl acetate:MeOH 3:3:1) to provide 2-(pyridin-3-yl)-4H-chromen-4-one as a light yellow solid (0.202 g, 73%); MS (ES) m/z: 224.90 (M+1), 223.92 (M); MP 122.8-124.0° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1SC([CH:42]=[O:43])=NC=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([CH2:42][OH:43])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: Cc1cnc(C=O)s1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(CO)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 5-methylthiazole-2-carbaldehyde.
Reaction SMILES: [N+](C1C=CC(C(OCCCC[C@@H](O[N+]([O-])=O)CO[N+]([O-])=O)=O)=CC=1)([O-])=O.[N+](C1C=CC(C([O:36][CH2:37][CH2:38][CH2:39][C@@H:40]([O:46][N+:47]([O-:49])=[O:48])[CH2:41][O:42][N+:43]([O-:45])=[O:44])=O)=CC=1)([O-])=O>>[N+:43]([O-:45])([O:42][CH2:41][C@H:40]([O:46][N+:47]([O-:49])=[O:48])[CH2:39][CH2:38][CH2:37][OH:36])=[O:44]
Reactant: O=C(OCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: O=C(OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])OC[C@@H](CCCO)O[N+](=O)[O-]

Procedure:
The title compound was prepared by following the procedure for example 6 in WO2005070868(A 1), except that the reagent (5R)-5,6-bis(nitrooxy)hexyl 4-nitrobenzoate was replaced by (4R)-4,5-bis(nitrooxy)pentyl 4-nitrobenzoate. 1H NMR (500 MHz, CD3CN) δ 5.42 (dq, J=2.6, 6.6 Hz, 1H), 4.84 (dd, J=2.6, 12.9 Hz, 1H), 4.48 (dd, J=6.2, 13.0 Hz, 1H), 3.54 (t, J=6.3 Hz, 2H), 1.82 (q, J=7.4 Hz, 2H), 1.54-1.68 (m, 2H).