Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[CH3:22]>>[CH3:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Cc1ccc(-c2nnc(N)nc2-c2ccccc2)cc1C
Yield: 66.6 %

Procedure:
6-(3,4-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine (55 mg, 67%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,4-dimethylphenylboronic acid (51.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6]([CH2:9]Br)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6]([CH2:9][NH:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NC(CO)CO
Reactant: BrCc1noc2cc(Br)ccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCC(CO)NCc1noc2cc(Br)ccc12
Yield: 24.5 %

Procedure:
A solution of 6-bromo-3-bromomethyl-1,2-benzisoxazole (Intermediate 1, 130 mg), serinol (50 mg) and DIPEA (0.05 ml) in DMF (0.2 ml) was stirred at 60° under nitrogen for 3 h. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried through a hydrophobic filter and concentrated. The residue was purified on a Varian Bond Elut SPE cartridge (silica, 2 g) eluting with dichloromethane followed by dichloromethane-methanol (9:1) to give the title compound as a yellow gum (33 mg).
Reaction SMILES: C1COCC1.CO.C[Si]([C:12]#[C:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:33])[C:19]3[C:24]([C:25]=2[CH:26]=1)=[CH:23][C:22]([C:27]#[C:28][Si](C)(C)C)=[CH:21][CH:20]=3)(C)C.[OH-].[Na+]>C(Cl)Cl.O>[C:27]([C:22]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:33])[C:17]3[C:25]([C:24]=2[CH:23]=1)=[CH:26][C:14]([C:13]#[CH:12])=[CH:15][CH:16]=3)#[CH:28]
Reactant: Cn1c2ccc(C#C[Si](C)(C)C)cc2c2cc(C#C[Si](C)(C)C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#Cc1ccc2c(c1)c1cc(C#C)ccc1n2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
A mixed solution containing dist. THF and dist. MeOH (dist. THF/dist. MeOH=3/1: 4 mL) as well as dist. H2O (0.1 mL) were added to and dissolved into 3,6-bis(trimethylsilylethynyl)-9-methylcarbazole (173 mg, 0.46 mmol) obtained in Synthesis example 12. Then, NaOH (35 mg, 0.88 mmol) was added, and the resultant mixed solution was stirred under a nitrogen atmosphere at room temperature for 4 hours to obtain a reaction mixture. After that, the reaction mixture was diluted with CH2Cl2. Then, an organic layer was washed with dist. H2O and sat. NaCl, and was dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product. Subsequently, the obtained crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=5/1) to obtain 3,6-diethynyl-9-methylcarbazole (86 mg, 81% yield).
Reaction SMILES: [Cl:1]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(NC(C)C)(C)C.[F:20][C:21]([F:64])([F:63])[C:22]1[CH:23]=[C:24]([C@H:32]2[O:36][C:35](=[O:37])[N:34]([CH2:38][C:39]3[C:44]([N:45]([CH2:48][C@H:49]4[CH2:54][CH2:53][C@H:52]([CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:51][CH2:50]4)[CH2:46][CH3:47])=[CH:43][CH:42]=[CH:41][N+:40]=3[O-])[C@H:33]2[CH3:62])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:20][C:21]([F:64])([F:63])[C:22]1[CH:23]=[C:24]([C@H:32]2[O:36][C:35](=[O:37])[N:34]([CH2:38][C:39]3[C:44]([N:45]([CH2:48][C@H:49]4[CH2:54][CH2:53][C@H:52]([CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:51][CH2:50]4)[CH2:46][CH3:47])=[CH:43][CH:42]=[C:41]([Cl:1])[N:40]=3)[C@H:33]2[CH3:62])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc[n+]([O-])c2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(Cl)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triphosgene (360 mg, 1.21 mmol) and diisopropylamine (123 mg, 170 μL, 1.21 mol) were added successively to a stirred solution of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-1-oxidopyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate (156.6 mg, 0.243 mmol) in dry CH2Cl2 (9 mL) at −20° C. under N2. The reaction was stirred at room temperature for 6 h. Additional triphosgene (360 mg, 1.21 mmol) and diisopropylamine (123 mg, 170 μL, 1.21 mmol) were added successively and the reaction was stirred at room temperature overnight. The reaction was diluted with saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-60% EtOAc in hexanes gradient) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate. Rf=0.32 (20% EtOAc/hexanes). LCMS calc.=664.2; found=664.4 (M+1)+. 1H NMR (500 MHz, CDCl3): δ 7.87 (s, 1 H); 7.81 (s, 2 H); 7.41 (d, J=8.4 Hz, 1 H); 7.19 (d, J=8.4 Hz, 1 H); 5.83 (d, J=8.4 Hz, 1 H); 4.97 (d, J=16.9 Hz, 1 H); 4.47-4.43 (m, 1 H); 4.29 (d, J=16.9 Hz, 1 H); 4.12-4.06 (m, 2 H); 2.98-2.88 (m, 2 H); 2.81-2.74 (m, 2H); 2.13 (d, J=6.8 Hz, 2 H); 1.84-1.68 (m, 5 H); 1.36-1.24 (m, 1 H); 1.22 (t, J=7.1 Hz, 3 H); 0.99 (t, J=7.0 Hz, 3 H); 0.95-0.81 (m, 4 H); 0.73 (d, J=6.6 Hz, 3 H).
Reaction SMILES: CO[C:3](=[O:15])[CH2:4][N:5]1[CH2:9][CH:8]2[CH2:10][CH2:11][C:12](=[O:13])[N:7]2[C:6]1=[O:14].[NH3:16]>CO>[O:14]=[C:6]1[N:7]2[C:12](=[O:13])[CH2:11][CH2:10][CH:8]2[CH2:9][N:5]1[CH2:4][C:3]([NH2:16])=[O:15]
Reactant: N
Reactant: COC(=O)CN1CC2CCC(=O)N2C1=O
Solvent: CO
Product: NC(=O)CN1CC2CCC(=O)N2C1=O
Reaction time: 24 h

Procedure:
A solution of tetrahydro-3,5-dioxo-1H-pyrrolo-[1,2-c]imidazole-2(3H)-acetic acid methyl ester (1.0 g, 0.004 mol) in methanol, 150 ml, is saturated with anhydrous ammonia. The mixture is allowed to stand 24 hours at room temperature. The solution is concentrated at reduced pressure to yield tetrahydro-3,5-dioxo-1H-pyrrolo[1,2-c]imidazole-2(3H)-acetic acid amide.
Reaction SMILES: COC(=O)[C:4]1[C:9]([OH:10])=[C:8]([N+:11]([O-:13])=[O:12])[C:7]([OH:14])=[N:6][C:5]=1[CH2:15][O:16][CH3:17]>Cl>[CH3:17][O:16][CH2:15][C:5]1[N:6]=[C:7]([OH:14])[C:8]([N+:11]([O-:13])=[O:12])=[C:9]([OH:10])[CH:4]=1
Reactant: COCc1nc(O)c([N+](=O)[O-])c(O)c1C(=O)OC
Agent: Cl
Product: COCc1cc(O)c([N+](=O)[O-])c(O)n1
Temperature: 120 °C

Procedure:
4,6-Dihydroxy-2-methoxymethyl-5-nitro-nicotinic acid methyl ester (2.00 g, 7.75 mmol) is placed in concentrated hydrochloric acid (100 mL) and heated in a bomb at 120° C. overnight. The reaction mixture is cooled in an ice bath and poured onto ice (200 g). A white precipitate formed. The precipitate is collected and dried in a vacuum oven to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9](Cl)=[O:10]>>[Cl:7][CH2:8][C:9]([N:1]1[CH2:6][CH2:5][N:4]([C:9](=[O:10])[CH2:8][Cl:7])[CH2:3][CH2:2]1)=[O:10]
Reactant: C1CNCCN1
Reactant: O=C(Cl)CCl
Product: O=C(CCl)N1CCN(C(=O)CCl)CC1

Procedure:
By reacting 8.6 g of piperazine with 23 g of chloroacetic chloride in the same manner as described in Synthesis Example 1, 36 g of crystals of the title compound were obtained.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH2:24][CH2:25][Cl:26]>>[Cl:26][CH2:25][CH2:24][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: ClCCBr
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2CCCl
Temperature: 55 °C
Yield: 67.3 %

Procedure:
(1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (525 mg, 2.65 mmol) and potassium phosphate (1686 mg, 7.94 mmol) were combined in a 75 mL medium pressure flask and purged in a 50° C. vacuum oven for 10 mins and placed under N2 (g) atmosphere. THF (30 mL) was added, followed by 1-bromo-2-chloroethane (1.124 mL, 13.24 mmol) and the mixture was heated to 55° C. for 18 h. The reaction mixture was cooled to rt, treated with more 1-bromo-2-chloroethane (0.043 mL, 0.517 mmol) and heated back up to 55° C. for 68 h. The reaction was filtered and washed with DCM. The liquid filtrate was concentrated to viscous brown oil which was purified by column chromatography (SiO2, 40 g cartridge, eluted with 95:5 DCM:MeOH), dried under vacuum with stirring to give (1S,4S)-tert-butyl 5-(2-chloroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (465 mg, 1.783 mmol, 67.3% yield) as viscous light brown oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.37 (s, 1H), 4.36 (br. s., 1H), 4.24 (br. s., 1H), 3.44 (d, J=9.5 Hz, 1H), 3.17 (t, J=8.8 Hz, 1H), 3.08-2.94 (m, 1H), 2.93-2.85 (m, 2H), 2.67 (d, J=9.5 Hz, 1H), 2.53 (d, J=9.5 Hz, 1H), 1.82 (d, J=6.4 Hz, 1H), 1.71 (dd, J=15.9, 9.8 Hz, 1H), 1.46 (s, 9H).
Reaction SMILES: ClC1C=NC=C(Cl)C=1N[C:9]([C:11]1[C:20](=O)[C:19]2C(=N[CH:16]=[CH:17][CH:18]=2)N(N2CCN(C)CC2)C=1)=[O:10].[Cl:30][C:31](OC)=[O:32]>>[Cl:30][C:31]([O:10][CH2:9][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:32]
Reactant: COC(=O)Cl
Reactant: CN1CCN(n2cc(C(=O)Nc3c(Cl)cncc3Cl)c(=O)c3cccnc32)CC1
Product: O=C(Cl)OCc1ccccc1

Procedure:
The same reaction was carried out as in Example 23, except for using N-(3,5-dichloropyridin-4-yl)-1-(4-methylpiperazin-1-yl)-1,4-dihydro[1,8]naphtyridin-4-one-3-carboxamide, instead of ethyl 1-(1-benzylpiperidin-3-yl)-1,4-dihydro[1,8]naphtyridin-4-one-3-carboxylate and using methyl chloroformate, instead of benzyl chloroformate, to obtain 85 mg (53%) of the above-identified compound as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:27]([CH3:29])[CH3:28].C(Cl)Cl.CCOCC.CO>CN(C)C=O>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:27]([CH3:29])[CH3:28])=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1
Reactant: CC(C)Br
Reactant: Cc1cccc(CNc2nc(F)nc3[nH]cnc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cccc(CNc2nc(F)nc3c2ncn3C(C)C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2-fluoro-N-(6-methylpyridin-2-yl)methyl-9H-purin-6-amine (0.3 g, 1.17 mmol) in dimethylformamide (10 ml) at room temperature under an argon atmosphere, was added powdered, anhydrous K2CO3 (0.8 g, 5 eq, 5.85 mmol), followed by 2-bromopropane (1.15 ml, 11.7 mmol). The reaction mixture was stirred at room temperature for 24 h, when DCM:ether:MeOH (55:40:5), indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between EtOAc (100 ml) and water (100 ml). The aqueous phase was extracted with more EtOAc (2×50 ml) and the combined organic phase washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with CHCl3:MeOH (98:2) to afford the title compound as a slightly yellow film (180 mg, 51%). δH (CDCl3, 500 MHz) 1.6 (6 H, d, J 7.5, CH[CH3]2), 2.54 (3 H, s, CH3), 4.86-4.73 (3 H, m, NHCH2 and CHMe2), 7.06 (1 H, d, J 10, ArH), 7.14 (1H, d, J 10, ArH), 7.53 (1 H, t, J 10, ArH), 7.8 (1 H, s, ArH); δC (CDCl3, 500 MHz) 158.42 (C), 158.04 (C), 156.16 (C), 156 (C), 155.49 (C), 150.12 (C), 137.67 (CH), 136.93 (CH), 121.89 (CH), 118.1 (C), 118.53 (CH), 47.15 (CH), 45.52 (CH2), 24.38 (CH3), 22.58 (2×CH3); m/z 301.2 (M+H); 19F NMR δ −50.22
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[F:30].O>CN(C=O)C>[F:30][C:22]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (1120 mg, 6 mmol) in DMF (25 mL) was added K2CO3 (828 mg, 6 mmol) and 1,2-difluoro-4-nitrobenzene (795 mg, 5 mmol) at room temperature. The reaction was stirred at 80° C. for 24 hours. After that, the reaction was poured into 50 mL of water and extracted with EA (3×25 mL), washed with H2O (25 mL) and brine (25 mL), dried over Na2SO4 and concentrated to give yellow solid. MS (m/z): 226 (M−99)+
Reaction SMILES: [OH:1][CH:2]([CH2:16][OH:17])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=O)[CH2:6][CH2:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:15][CH2:13][CH2:12][CH2:11][CH2:10][CH:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([OH:1])[CH2:16][OH:17])[CH2:9][CH2:8]1
Reactant: NC(=O)CCCC1CCN(CC(O)CO)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCCCC1CCN(CC(O)CO)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
Compound 10 (263 mg, 1.07 mmol) was dissolved in tetrahydrofuran (12 mL) under a nitrogen atmosphere. Lithium aluminum hydride (3.7 mL of a 1 M solution in THF) was added dropwise over 20 min. The reaction was refluxed for 8 h, and then cooled to room temperature. It was quenched by successively adding water (1 mL, dropwise), 20% sodium hydroxide solution (1 mL), and then 25% ammonium hydroxide solution (2 mL). The resulting mixture was stirred for 30 min and then filtered through diatomaceous earth. The filtrate was dried over sodium sulfate and concentrated under vacuum to give the amine 11 (183 mg, 74% yield) as a red oil which was carried on without further purification: 1H NMR (500 MHz, CDCl3) δ 1.21-1.68 (m, 12H), 1.88-1.95 (m, 3H), 2.20-2.33 (m, 4H), 2.49-2.53 (m, 1H), 2.66-2.70 (m, 1H), 2.78-2.82 (m, 1H), 2.96-3.02 (m, 1H), 3.48-3.94 (m, 3H). m/z (ESI): 231 [C12H26N2O2+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:17])[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(Cl)Cl.Cl>[Ti](Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:17])[C:7](=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C(=O)OCC)=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21

Procedure:
In a 250 milliliter round-bottomed flask equipped with a pressure equalizing dropping funnel, there was discharged 10 grams of 1,8-dichloroanthraquinone, 16.5 milliliters of diethyl malonate, and 150 milliliters of methylene chloride under a nitrogen atmosphere. The resulting mixture was then mechanically stirred and cooled with an ice bath. Thereafter, 24 milliliters of titanium tetrachloride was added dropwise through the dropping funnel over a period of 20 minutes, followed by the addition of 45 milliliters of pyridine. The reaction mixture was then stirred at room temperature for 65 hours. Subsequently, 150 milliliters of a dilute aqueous hydrochloric acid solution was slowly added with stirring. The organic phase resulting was separated, washed twice with water, and dried with anhydrous magnesium sulfate. Evaporation of the dried organic solution yielded a yellowish solid which when recrystallized from methanol afforded 7.5 grams of the pure Compound (VIII), mp., 166°-167° C.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N+:29]([O-])=O)[CH2:16][CH2:15]3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[F-].[K+].C([SiH](CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][NH:21][CH2:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:7][CH2:8]2)=[O:13])[CH2:19][CH2:18]1
Reactant: O=C(C1CC1)N1CCN(C(=O)[C@H]2CC[C@H](CNCc3ccccc3[N+](=O)[O-])CC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Product: Nc1ccccc1CNC[C@H]1CC[C@H](C(=O)N2CCN(C(=O)C3CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(4-Cyclopropanecarbonyl-piperazin-1-yl)-{trans-4-[(2-nitrobenzylamino)-methyl]-cyclohexyl}methanone (272 mg, 0.63 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol) were weighed into a flask and flushed with nitrogen for 5 minutes. THF (10 mL) was added, followed by a solution of KF (73 mg, 1.26 mmol in 1.2 ml of H2O). Then triethylsilane (0.40 mL, 2.52 mmol) was added drop wise and the reaction was left stirring for 3 h at room temperature. The mixture was filtered on a celite bed to remove palladium and the solution was concentrated under reduced pressure. The residue was suspended in DCM (4 mL) and washed with H2O (4 mL). The organic phase was collected and concentrated, the crude product was purified by SiO2 column, eluting with AcOEt:MeOH 80:20, affording 146 mg of the titled compound (57% yield).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CO.[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[C:29]1[CH2:36][C@@H:35]2[C@@H:31]([CH2:32][C:33]3([O:40][CH2:39][CH2:38][O:37]3)[CH2:34]2)[CH2:30]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH2:36][C@@H:35]2[C@@H:31]([CH2:32][C:33]3([O:37][CH2:38][CH2:39][O:40]3)[CH2:34]2)[CH:30]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C(CCCCOCc1ccccc1)=C1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCO
Product: C1=C(CCCCCOCc2ccccc2)C[C@H]2CC3(C[C@@H]12)OCCO3
Reaction time: 2.5 h
Yield: 102.2 %

Procedure:
1.50 g of p-toluenesulfonic acid and 2.9 ml of ethylene glycol were added to 17.8 g of 3-(5-benzyloxypentylidene)- 7,7-ethylenedioxy-cis-bicyclo[3,3,0]octane (prepared as described in Preparation 3) in 300 ml of benzene, and the mixture was heated, with stirring, for 2.5 hours whilst removing water as an azeotropic mixture. Upon completion of the reaction, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off from the reaction mixture under reduced pressure, to give 18.20 g of the title compound as an oil. This mixture was used for the subsequent reaction of Preparation 5 without purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(O[CH:16]([C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[F:31])[C:17]1[N:18]([CH3:23])[C:19]([Cl:22])=[CH:20][N:21]=1)=O)(C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([SH:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39][CH:16]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:17]2[N:18]([CH3:23])[C:19]([Cl:22])=[CH:20][N:21]=2)=[CH:35][CH:34]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cn1c(Cl)cnc1C(OC(=O)OC(C)(C)C)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cn1c(Cl)cnc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
Trifluoroacetic acid (10 ml) was added to the 2-[(t-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole (404 mg, 1.13 mmol) obtained in Referential Example 14. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in thionyl chloride (2.0 ml) and to the resulting solution was added a drop of dimethylformamide. The mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in dimethylformamide (5.0 ml). To the resulting solution were added 4-chlorobenzenethiol (244 mg, 1.69 mmol) and potassium carbonate (936 mg, 6.78 mmol). The resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was allowed to stand until it became room temperature. Ethyl ether (60 ml) was added. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 5:1) to give the title compound (195 mg, 89%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([C:11](O)([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:26])[C:19]([O:21][Si](C)(C)C)=[CH2:20])[CH3:16].[Sn+6].[Cl-].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:15]([O:17][C:18](=[O:26])[C:19](=[O:20])[CH2:21][C:11]([C:5]1[C:6]2[O:10][CH2:9][O:8][C:7]=2[C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:13])[CH3:12])[CH3:16]
Reactant: CC(C)(O)c1ccc(Br)c2c1OCO2
Reactant: C=C(O[Si](C)(C)C)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(Br)c2c1OCO2
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 129.1 %

Procedure:
1.77 g of 2-(7-bromobenzo[1,3]dioxol-4-yl)-propan-2-ol and 2.82 g of 2-trimethylsilyloxy-acrylic acid-ethyl ester (WO 00/32584) in 36 ml of dichloromethane are mixed at −70° C. with 1.10 ml of tin(VI)chloride. It is stirred for 20 minutes at −70° C. and then added to saturated sodium carbonate solution. It is extracted with dichloromethane, washed with water, dried and concentrated by evaporation in a vacuum. 3.15 g of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid-ethyl ester is obtained as a crude product. The latter is reacted for 4 hours at room temperature in 57 ml of a mixture that consists of 1N sodium hydroxide solution in ethanol/water. The batch is added to water, extracted with ether and then the aqueous phase is acidified with hydrochloric acid. It is extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 2.1 g of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid is obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH:12]1([CH:18]=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:18]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=CC1CCCCC1
Solvent: O
Solvent: CCO
Product: O=C1CC(C2CCCCC2)Oc2ccc(Br)cc21
Yield: 84.4 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (50 g, 0.23 mol), cyclohexanecarbaldehyde (26 g, 0.23 mol) and borax (89 g, 0.23 mol) in ethanol (300 mL) and H2O (500 mL) was refluxed overnight. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product, which was purified by column chromatography to give 6-bromo-2-cyclohexylchroman-4-one (60 g, 83%). 1H-NMR (CDCl3): 1.05-1.33 (m, 5H), 1.67-1.81 (m, 5H), 1.95 (d, 1H), 2.64 (m, 2H), 4.15 (m, 1H), 6.86 (d, 1H), 7.51 (m, 1H), 7.94 (s, 1H).