Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25](C=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.Cl.[N:32]1([CH2:38][CH2:39][O:40][NH2:41])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:41][O:40][CH2:39][CH2:38][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: NOCCN1CCCCC1
Reactant: O=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(COc2ccc(Nc3ncnc4c3CC(=NOCCN3CCCCC3)C=C4)cc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
In a mixture of tetrahydrofuran (2 ml) and water (0.1 ml) were dissolved 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1, 50 mg) and 2-(1-piperidyl)ethoxyamine dihydrochloride (36.5 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed sequentially with aqueous saturated sodium bicarbonate solution, and aqueous sodium chloride solution, and dried over magnesium sulfate. After concentration, the residue was purified by chromatography (eluting with hexane:ethyl acetate=2:3) using an amino column, and further re-purified by thin layer chromatography to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(2-(1-piperidyl)ethoxyimino)quinazoline (V-1, 13 mg).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:38])=[C:17]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[C:32]5[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:31]=5[O:30][N:29]=4)[CH2:24][CH2:23]3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[C:50]([N:57](Br)[CH2:58][CH3:59])([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>CC(C)=O>[Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:38])=[C:17]([CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[C:32]5[CH:33]=[CH:34][C:35]([O:37][CH2:59][CH2:58][NH:57][C:50](=[O:51])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[CH:36][C:31]=5[O:30][N:29]=4)[CH2:26][CH2:27]3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(O)ccc34)CC1)CCCC2O[Si](C)(C)C(C)(C)C
Reactant: CCN(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(OCCNC(=O)OC(C)(C)C)ccc34)CC1)CCCC2O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 9-((tert-butyldimethylsilyl)oxy)-3-(2-(4-(6-hydroxybenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, prepared as described in the previous step, (50 mg, 0.093 mmol) in acetone (0.5 mL) and DMF (0.5 mL) was treated with potassium carbonate (33.3 mg, 0.24 mmol) and N-Boc-2-bromoaminoethane (27 mg, 0.12 mmol), and the reaction mixture was stirred for 17 h at 60° C. under argon. The reaction mixture was evaporated at 40° C. under reduced pressure and dissolved in water (10 mL) and extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over Na2SO4, filtered, and the solvent was evaporated yield the crude title compound. (ESI-MS (M+1) 682)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]2[CH2:15][NH:14][C:13](=[O:16])[NH:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.O>CS(C)=O>[CH:23]1([O:1][C:2]2[CH:3]=[C:4]([CH2:10][CH:11]3[CH2:15][NH:14][C:13](=[O:16])[NH:12]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(CC2CNC(=O)N2)cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC2CNC(=O)N2)cc1OC1CCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To the solution of 22.22 g (100 mmoles) of the product obtained in Example 3, step (a) in 220 ml of dimethylsulphoxide, 27 g of powdered anhydrous potassium carbonate are added and the suspension is stirred at 60° C. for 30 minutes, then 12.9 ml (120 mmoles) of cyclopentyl bromide are portionwise added during 60 minutes while the temperature is kept at 60° C. The suspension is further stirred at 60° C. for 20 hours, then cooled to 25° C. and poured into 800 ml of water. The aqueous emulsion is extracted four times with 400 ml of chloroform. The collected organic phases are washed twice with 50 ml of 1 N sodium hydroxide solution, dried over anhydrous magnesium sulphate and evaporated in vacuo. To the oily residue 200 ml of benzene are added and the evaporation is repeated. The residue is triturated with 150 ml of ether and the crystals obtained are filtered after 30 minutes and washed with 50 ml of ether to give 21.30 g (73.4%) of the title compound, m.p. 104°-107° C. After recrystallization from acetone this melting point rises to 115°-116° C. On the basis of its physical properties, this product is identical with the compound obtained in Example 2, step (d).
Reaction SMILES: [S@:1]1(=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[CH2:3][O:2]1.[O-:11]I(=O)(=O)=O.[Na+].O>C(#N)C.C([O-])(O)=O.[Na+].CCOC(C)=O.O.[Ru](Cl)(Cl)Cl>[S:1]1(=[O:11])(=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@@H:4]2[CH2:3][O:2]1
Reactant: O=[S@]1OCC2CCCCN21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=S1(=O)OC[C@H]2CCCCN21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-hexahydro-[1,2,3]oxathiazolo[3,4-a]pyridine 1-oxide (1.09 g, 6.76 mmol) in anhydrous acetonitrile (10 mL) was added sodium (meta)periodate (1.6 g, 7.436 mmol), followed by ruthenium(III) chloride hydrate (14 mg, 0.0676 mmol), and then H2O (10 mL). The mixture was stirred at 0° C. for 10 min and at rt for 20 min, then diluted with saturated NaHCO3 (30 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (80 mL) and dichloromethane (80 mL). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography (silica gel, 2% EtOAc in dichloromethane) to afforded the title product as a clear, colorless oil (0.890 g, 69%).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[S:15][C:16]([CH3:21])=[CH:17][C:18]=1[C:19]#[N:20]>O1CCCC1>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:13][C:14]1[S:15][C:16]([CH3:21])=[CH:17][C:18]=1[C:19]#[N:20])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1cc(C#N)c(N)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
To a stirred slurry of sodium hydride (14.4 g, 50% dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoro-nitrobenzene (28.2 g, 0.2 mol) and 2-amino-5-methylthiophene-3-carbonitrile (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3×500 mL). The combined extracts were washed with 2N hydrochloric acid (2×200 mL), water (2×200 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([S:13](Cl)(=[O:15])=[O:14])[CH:9]=[CH:10][C:11]=1[Cl:12].O>N1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([S:13]([NH:4][O:2][CH3:3])(=[O:14])=[O:15])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CONS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 18 h
Yield: 94.6 %

Procedure:
To a suspension of methoxylamine hydrochloride (0.93 g (11.1 mmol)) in pyridine (5.0 ml), 3,4-dichlorobenzenesulfonyl chloride (2.73 g (11.1 mmol)) was added with stirring under cooling with ice and the resulting mixture was stirred for one hour under cooling with ice, and at room temperature for 18 hours. Water (50.0 ml) was then added to the reaction mixture to bring about separation of crystals. The crystals were filtered and washed with water to give 2.69 g (95%) of 3,4-dichloro-N-methoxybenzenesulfonamide as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][CH2:5][C:6]([CH:8]=[CH2:9])=[CH2:7].[C:11]1([SiH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1([SiH](CC(=CC)CCC=C(C)C)C2C=CC=CC=2)C=CC=CC=1>>[C:18]1([SiH:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH:8]=[C:6]([CH3:7])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:10])[CH3:1])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc([SiH2]c2ccccc2)cc1
Reactant: C=CC(=C)CCC=C(C)C
Agent: CC=C(CCC=C(C)C)C[SiH](c1ccccc1)c1ccccc1
Product: CC(C)=CCCC(C)=CC[SiH](c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 0.170 ml (1.0 mmol) of myrcene, 0.186 ml (1.2 mmol) of diphenylsilane, and 6.0 mg (0.01 mmol) of tetraethylammonium μ-hydridebis(pentacarbonylmolybdenum) was heated in a sealed tube at 100° C. for 24 hours while being stirred. GLC analysis of the reaction mixture revealed that 6-(diphenylsilyl)methyl-2-methyl-2,6-octadiene and 8-diphenylsilyl-2,6-dimethyl-2,6-octadiene were produced at a ratio of about 75:25 in a total yield of 95%. 6-(Diphenylsilyl)methyl-2-methyl-2,6-octadiene:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:24]([N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])(=[O:26])[CH3:25]>>[C:24]([N:27]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:28]1=[O:32])(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)cc2)C1=O
Yield: 70.2 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 165 and 1-acetylimidazolidin-2-one (115 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (178 mg) was obtained.
Reaction SMILES: [NH2:1][C:2](=[N:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:24]2[N:28]=[C:27]([O:29][CH2:30]Cl)[N:26]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:25]=2)[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH2:20][CH2:21][OH:22])[C:12]=2[F:23])=[CH:5][CH:4]=1.[CH3:47][C:48]([CH3:60])([CH3:59])[CH2:49][O:50][C:51](=[O:58])[C:52]([CH3:57])([CH3:56])[C:53]([OH:55])=[O:54].[I-].[Na+].C(=O)([O-])O.[K+]>C(OCC)(=O)C.CC(N(C)C)=O>[CH3:47][C:48]([CH3:60])([CH3:59])[CH2:49][O:50][C:51](=[O:58])[C:52]([CH3:57])([CH3:56])[C:53]([O:55][CH2:30][O:29][C:27]1[N:26]([C:32]2[N:33]=[CH:34][CH:35]=[CH:36][N:37]=2)[N:25]=[C:24]([CH:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([NH2:1])=[N:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:4][CH:5]=2)[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH2:20][CH2:21][OH:22])[C:12]=2[F:23])[N:28]=1)=[O:54]
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nc(OCCl)n(-c3ncccn3)n2)c1
Reactant: CC(C)(C)COC(=O)C(C)(C)C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 79.6 %

Procedure:
A mixture of N-[1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]benzamide (500 mg), 2,2-dimethylmalonic acid mono-(2,2-dimethylpropyl)ester (1.56 g), sodium iodide (1.16 g), potassium hydrogen carbonate (543 mg), and DMA (50 mL) was stirred at 50° C. for 7 hours. After cooling the mixture to room temperature, ethyl acetate was added thereto, and the resulting mixture was sequentially washed twice with water and with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (500 mg).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].CC(C)([O-])C.[K+].I[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:32]1([C:30]([NH:29][C:27]2[N:28]=[C:23]3[CH:22]=[CH:21][C:20]([O:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1]([O:10][CH2:11][CH3:12])=[O:9])=[N:25][N:24]3[CH:26]=2)=[O:31])[CH2:33][CH2:34]1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: CCOC(=O)c1ccccc1O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 17.6 %

Procedure:
To a solution of ethyl salicylate (1010 mg, 6.1 mmol) in N,N-dimethylformamide (8 mL) was added potassium tert-butoxide (840 mg, 6.4 mmol) at 0° C., and the mixture was stirred at 0° C. for 5 min and at room temperature for 25 min. To the reaction mixture were added N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1.0 g, 3.1 mmol) and potassium carbonate (420 mg, 3.1 mmol), and the mixture was stirred at 100° C. for 24 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give ethyl 2-({2[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoate (200 mg, 18%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8].[Br:11]N1C(=O)CCC1=O>C(Cl)Cl>[Br:11][C:6]1[N:2]([CH3:1])[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:5]=1
Reactant: COC(=O)c1cccn1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a dry flask is added methyl 1-methyl-1H-pyrrole-2-carboxylate (12.0 g, 86.4 mmol) and 150 mL of dry CH2Cl2, and the flask is wrapped in foil and purged with nitrogen. N-bromosuccinimide (16.2 g, 90.7 mmol) is added in one portion and the mixture is stirred at room temperature for 0.5 h. The reaction mixture is washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. Fractional distillation gives 12.0 g of methyl 5-bromo-1-methyl-1H-pyrrole-2-carboxylate as a yellow oil (64% yield). MS for C7H8NO2Br (ESI) (M)+m/z 217.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1C1C(C)=NC=C(C)N=1.Cl[C:18]1[C:19]([CH2:26][CH3:27])=[N:20][CH:21]=[C:22]([CH2:24][CH3:25])[N:23]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:18]1[C:19]([CH2:26][CH3:27])=[N:20][CH:21]=[C:22]([CH2:24][CH3:25])[N:23]=1
Reactant: CCc1cnc(CC)c(Cl)n1
Reactant: Cc1cnc(C)c(-c2ccc(Cl)cc2Cl)n1
Product: CCc1cnc(CC)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Following the procedure for the preparation of 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine but 3-chloro-2,5-diethylpyrazine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.19, 1.35, 2.65, 2.88, 7.29, 7.39, 7.54, 8.47; 13C NMR (CDCl3) δ 13.52, 14.48, 28.03, 28.97, 128.01, 130.22, 132.07, 134.61, 135.77, 137.02, 143.22, 150.44, 154.57, 155.84; MS (ESI+) for C14H14Cl2N2 m/z 282.2 (M+H)+.
Reaction SMILES: [OH-].[Na+].Cl.[O:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16]Cl)[C:11]=2[Cl:18])[CH2:6][CH2:5]1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]=[C:26]([SH:28])[NH:27][C:23]=2[CH:22]=1>>[O:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:28][C:26]3[NH:25][C:24]4[CH:29]=[CH:30][C:21]([O:20][CH3:19])=[CH:22][C:23]=4[N:27]=3)[C:11]=2[Cl:18])[CH2:6][CH2:5]1
Reactant: ClCc1nccc(N2CCOCC2)c1Cl
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]c(SCc3nccc(N4CCOCC4)c3Cl)nc2c1
Reaction time: 8 h

Procedure:
5 N Sodium hydroxide (5.68 ml) was added dropwise to a stirred solution of 4 -morpholino-3 -chloro-2 -chloromethylpyridine hydrochloride (3.66 g) and 5 -methoxy-2 -mercaptobenzimidazole (2.33 g). After standing overnight the solution was evaporated under reduced pressure and the residue triturated with water. The solid thus obtained was recrystallised from ethanol to give 2 -(4 -morpholino-3 -chloro-2 -pyridyl-methylthio)-5 -methoxy-(1H)-benzimidazole, 4.38 g, m.p. 124°-25°.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][CH:35]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:36][CH:37]=O>>[CH3:34][CH:35]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:36][CH:37]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(CC=O)CC(C)(C)C
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(CC=CCc1ccccc1)CC(C)(C)C
Yield: 65.2 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (2.80 g, 6.26 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.9 mL, 6.26 mmol, 1.0 equiv.) and 3,5,5-trimethylhexanal (1.33 g, 9.39 mmol, 1.5 equiv.), 0.94 g (65%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:4]=[C:3]([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[CH:2]=1.[ClH:47]>>[ClH:47].[C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH:4]=[C:3]([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCNCCCNCc1cc(CNCCCNCCCNC(=O)OC(C)(C)C)cc(-c2ccccc2)c1
Agent: Cl
Product: NCCCNCCCNCc1cc(CNCCCNCCCN)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To the crude di-tert-butyl ((((([1,1′-biphenyl]-3,5-diylbis(methylene))bis(azanediyl))bis(propane-3,1-diyl))bis(azanediyl))-bis(propane-3,1-diyl))dicarbamate from Step 2 was subjected to acidification with methanolic HCl (200 mL, 1.0M). The reaction mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure, and the solid was collected by vacuum filtration and washed with Et2O (50 mL) and hot MeOH (50 mL) to afford the desired product (6.8 g, 60%) as a white solid. 1H NMR (500 MHz, D2O) δ 7.85 (s, 2H), 7.74 (d, J=7.5 Hz, 2H), 7.59-7.56 (m, 3H), 7.50-7.49 (m, 1H), 4.38 (s, 4H), 3.29 (t, J=8.0 Hz, 4H), 3.23 (q, J=5.0 Hz, 8H), 3.14 (t, J=8.0 Hz, 4H), 2.25-2.19 (m, 4H), 2.17-2.11 (m, 4H). LRMS [M+H]+441.4.
Reaction SMILES: C1(C([O:14][C:15](=[O:41])[C@@H:16]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)C2C=CC=CC=2)C=CC=CC=1.[H][H]>C(O)(C)(C)C.[Pd]>[CH3:39][C:37]([CH3:40])([O:36][C:34]([NH:33][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=1)[C:15]([OH:41])=[O:14])=[O:35])[CH3:38]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(c2ccccc2)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CCc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 92.9 %

Procedure:
(S)-2-[[(1,1-Dimethylethoxy)carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)-3-oxo-l-propenyl]phenyl]propanoic acid diphenylmethyl ester (1.6 g. 2.8 mmol) and 10% Pd/C (300 mg) in t-butanol (20 mL) was blanketed with hydrogen (1 atm). To prevent the solvent from freezing, a warm water bath (40° C.) was used to heat the reaction mixture. Upon the consumption of 2 equivalents of hydrogen, the mixture was filtered through celite. The celite pad was washed with ethanol (50 mL) and the filtrates combined and concentrated. The residue was purified by recrystallization from hexanes to give (S)-2-[[(1,1-dimethylethoxy) carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)3-oxopropyl]phenyl]propanoic acid (1.0 g, 2.6 mmol) in 94% yield. mp. 88.5°-90° C., [α]D +21.2° (0.90% in ethanol).
Reaction SMILES: [CH:1]([C@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH2:24]([C:31]1[N:35]=[C:34]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[O:33][N:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([C:31]1[N:35]=[C:34]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:1][C@H:3]3[CH2:5][C@@:4]3([CH2:12][N:13]([CH3:23])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:38][CH2:37]2)[O:33][N:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C[C@@]1(c2ccccc2)C[C@@H]1C=O)S(=O)(=O)c1ccccc1
Reactant: c1ccc(Cc2noc(C3CCNCC3)n2)cc1
Product: CN(C[C@@]1(c2ccccc2)C[C@@H]1CN1CCC(c2nc(Cc3ccccc3)no2)CC1)S(=O)(=O)c1ccccc1

Procedure:
N-{[(1S,2S)-2-formyl-1-phenylcyclopropyl]methyl}-N-methylbenzenesulfonamide and 4-(3-benzyl-1,2,4-oxadiazol-5-yl)piperidine (incorporating by reference as needed WO 00/39125) were reacted as per Preparation 10 to give the title compound. 1H NMR (300 MHz, DMSO-de) δ 7.69-7.54 (m, 5H), 7.35-7.20 (m, 10H), 4.06 (s, 2H), 3.55 (d, J=13.8 Hz, 1H), 2.97-2.85 (m, 1H), 2.78 (d, J=13.8 Hz, 1H), 2.64-2.59 (m, 1H), 2.53 (s, 3H), 2.27-2.21 (m, 1H), 2.02-1.88 (m, 4H), 1.75-1.61 (m, 2H), 1.48-1.41 (m, 1H), 1.17 (m, 1H), 1.07-1.02 (m, 1H), 0.93-0.89 (m, 1H). ES-LCMS m/z 557.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[CH:6][N:7]=1
Reactant: Fc1ccccc1CBr
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccccc1COc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a solution of 6-bromo-3-pyridinol (commercial source, 0.870 g, 5.0 mmol) in acetone (20 ml) were added potassium carbonate (1.04 g, 7.5 mmol) and 1-(bromomethyl)-2-fluorobenzene (Aldrich, 1.2 ml, 10.0 mmol) and the mixture was stirred for three hours at r.t. The solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (1:0 to 98:2) to afford the title compound as a white solid (1.28 g, 90%). MS: (ES/+) m/z: 282, 284 [MH]+ C12H9BrFNO requires 281, 283; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.12-8.20 (m, 1H); 7.43-7.53 (m, 1H); 7.32-7.43 (m, 2H); 7.16-7.24 (m, 2H); 7.07-7.16 (m, 1H); 5.17 (s, 2H).