Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:7]=1C=O)#[N:2].[C:22](O)(=O)[CH2:23][C:24]([OH:26])=[O:25]>N1CCCCC1.N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:10]2[C:11]([Cl:21])=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][C:15]=2[Cl:16])[C:7]=1[CH:22]=[CH:23][C:24]([OH:26])=[O:25])#[N:2]
Reactant: O=C(O)CC(=O)O
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C=CC(=O)O
Yield: 56.7 %

Procedure:
By the method of Example 5, Step H, 1.5 g (0.0045 mole) of 4-cyano-5-formyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole and 1.0 g (0.0096 mole) of malonic acid were reacted in the presence of 5 mL of pyridine and 10 drops of piperidine, yielding 0.96 g of 3-[4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazol-5-yl]acrylic acid. The nmr spectrum of this solid was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[Cl:8].[O-]S([O-])(=S)=O.[Na+].[Na+]>I>[Cl:8][C:7]1[CH:6]=[N:5][N:4]([CH3:9])[C:3](=[O:10])[CH:2]=1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Agent: I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: Cn1ncc(Cl)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4,5-Dichloro-2-methylpyridazin-3(2H)-one (1 g) is dissolved in aqueous HI solution (57%, 8.5 mL) and the mixture is heated to reflux for 12 hours. After cooling to room temperature the mixture is treated with aqueous Na2S2O3 solution (30%, 100 mL) and stirred for 1 hour. The mixture is then extracted three times with dichloromethane. The combined organic phases are washed with brine, dried (MgSO4) and concentrated. The residue is triturated with diisopropylether. Yield: 414 mg; Mass spectrum (ESI+): m/z=145 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].Br[CH2:12][C:13]1[N:18]=[C:17]([CH2:19][N:20]2[C:24]3[N:25]=[C:26]([NH2:34])[N:27]=[C:28]([C:29]4[O:30][CH:31]=[CH:32][CH:33]=4)[C:23]=3[N:22]=[N:21]2)[CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[NH2:34][C:26]1[N:27]=[C:28]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[C:23]2[N:22]=[N:21][N:20]([CH2:19][C:17]3[N:18]=[C:13]([CH2:12][N:2]([CH3:1])[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5])[CH:14]=[CH:15][CH:16]=3)[C:24]=2[N:25]=1
Reactant: CNC(=O)C(F)(F)F
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(CBr)n3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)n1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-methyl-2,2,2-trifluoroacetamide (197 mg, 1.55 mmol) in DMF (5 mL) at 0° C. was treated with sodium hydride (60% dispersion in mineral oil; 62 mg, 1.55 mmol), stirred for 15 min, treated with 3-(6-bromomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (120 mg, 0.310 mmol), stirred at 50° C. for 1 h, cooled to room temperature, poured into water (20 mL), extracted with EtOAc (3×10 mL) and the combined organic phase dried (MgSO4) and concentrated in vacuo to give N-(6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-pyridylmethyl)-N-methyltrifluoroacetamide. A solution of this product in MeOH (20 mL) was treated with a solution of sodium (71 mg, 3.10 mmol) in MeOH (10 mL), stirred for 16 h, concentrated in vacuo, treated with EtOAc (20 mL), filtered through Celite and concentrated in vacuo. The resulting solid was suspended in MeOH (2 mL), treated with HCl (4-M in dioxane, 1.0 mL), stirred for 10 min, concentrated in vacuo and triturated with Et2O to give the title compound (80 mg, 58%) as a yellow solid.
Reaction SMILES: C(OC(N1C[CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1CC[CH:34]([O:37][CH2:38][C:39]([NH2:41])=[O:40])[CH2:33]C1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][N:11]3[CH2:12][CH2:33][CH:34]([O:37][CH2:38][C:39]([NH2:41])=[O:40])[CH2:9][CH2:10]3)=[CH:20][CH:19]=2)[CH2:22]1
Reactant: NC(=O)COC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Product: NC(=O)COC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 274 is synthesized from Intermediate C and 2-(piperidin-4-yloxy)acetamide according to General Method K. (LC/MS method 16: ES+ m/z 384.3 [M+H]+, Rt=0.32 min)
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[SH:33])([CH3:26])[CH3:25].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:24]([CH3:26])[CH3:25]
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: CC(C)c1ccccc1S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)c1ccccc1SC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.50 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 1.60 mmol of 2-isopropylbenzenethiol, and 1.60 mmol of piperidine in 30 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 66°-67° C.). 1H NMR (DMSO-d6) δ 1.16 (t, 6 H), 2.21-2.35 (m, 3 H), 2.60 (m, 1 H), 3.21 (m, 1 H), 3.42 (q, 2 H), 5.88 (d, 1 H), 6.56 (t, 1 H), 6.94 (t, 1 H), 7.13 (m, 4 H), 7.25 (m, 2 H), 7.45 (m, 5 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 55 °C
Reaction time: 4 h
Yield: 13.2 %

Procedure:
A mixture of 3-bromobenzaldehyde (51.8 g), 1-undecyne (48.6 g), bis(triphenylphosphine)palladium(II)chloride (3.37 g), copper iodide (457 mg), and triethylamine (196 ml) in dry tetrahydrofuran (300 ml) was stirred for 4 hrs at 55° C. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate, and the solution was washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on 300 g of silica gel (1:4-ethyl acetate:hexane). The appropriate fractions were collected and evaporated. Distillation of a 40-g sample of the residue (81.3 g) gave 9.5 g (13%) of the product, bp 172°-174° C. (0.5 mm mercury).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:15]=1[NH2:16].F[C:24]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]>>[F:13][C:14]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:15]=1[NH:16][C:24]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Nc1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1cc(F)c(F)cc1F
Yield: 88.1 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (21 mL, 53 mmol), diisopropylamine (7.2 mL, 51 mmol), 2,4,5-trifluoro-aniline (2.5 g, 17 mmol), and 2,4,5-trifluorobenzoic acid (3.0 g, 17 mmol) provided 4.54 g of the crude title compound.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:27]([O:26][C:24]([C:4]1[CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]=1[CH2:2][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37])=[O:25])[CH3:28]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
A mixture of ethyl 6-(bromomethyl)-2-(thiazol-2-yl)-4-(2-(trifluoromethyl)phenyl)-1,4-dihydropyrimidine-5-carboxylate (3.8 g, 8 mmol), morpholine-3-carboxylic acid hydrochloride (2.62 g, 16 mmol) and potassium carbonate (4.2 g, 30 mmol) in ethanol (130 mL) was stirred at 25° C. for 12 hours. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=30/1) to give the title compound as a yellow solid (2.1 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[O:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(C)c(C)o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(CBr)oc1C
Temperature: 76 °C
Yield: 7.8 %

Procedure:
A mixture of 2,4,5-trimethyloxazole (0.50 mL, 4.3 mmol), N-bromosuccinimide (0.77 g, 4.3 mmol) and benzoyl peroxide (0.21 g, 0.86 mmol) in carbon tetrachloride (4 mL) was heated at 76° C. under nitrogen atm for 3 hrs. After cooling to rt, the solid was removed by filtration. The filtrate solution was washed with saturated aqueous NaHCO3 (20 mL) and concentrated. The residue was purified by flash column chromatography (SiO2 ; hexanes:ethyl acetate/4:1) to afford 2-(bromomethyl)-4,5-dimethyloxazole (64 mg) as an yellow oil. 1H NMR (CDCl3) 67 4.4 (s, 2 H), 2.25 (s, 3 H), 2.05 (s, 3 H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH:14]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:37].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH:14]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[CH2:15][F:37])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCC(Oc2cnn(C(C)(C)C)c(=O)c2Cl)c2ccc(C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(CF)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-chloro-5-(2-p-toluenesulfonyloxy-1-(4-tert-butylphenyl)-1-ethyl)oxy-3(2H)-pyridazinone (0.2 g, 0.375 mmol) is added 3.75 ml of tetrabutylammonium fluoride solution (1M in THF, 3.75 mmol). The mixture is first stirred at room temperature for 15 minutes after which it is heated for 15 minutes at 100° C. The solution is then cooled to room temperature and to it is added dichloromethane followed by water. The layers were separated and the organic layer is washed with water and then dried. The organic layer is then concentrated and subjected to purification using silica gel flash chromatography (ethyl acetate/hexanes) to obtain the above compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([F:18])([F:17])[F:16].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])[C:24](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]2[NH:19][C:24]([C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[F:21])=[N:20][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(Cl)cc2C(F)(F)F)cc1N
Product: FC(F)(F)c1cc(Cl)ccc1-c1cc2[nH]c(C(F)(F)C(F)(F)F)nc2cc1Cl
Yield: 77 %

Procedure:
A solution of 4-chloro-5-[4-chloro-2-(trifluoromethyl)phenyl]benzene-1,2-diamine (100 mg, 0.31 mmol) in pentafluoropropanoic acid (5 ml) was stirred overnight at 80° C. in an oil bath and then quenched with ice-water (50 ml). The pH value of the solution was adjusted to 8 with saturated aqueous sodium carbonate and extracted with ethyl acetate ((50 ml×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-[4-chloro-2-(trifluoromethyl)phenyl]-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a off-white solid (129.8 mg, 77%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[N:10][OH:11])[CH2:4][C:3]1([CH3:13])[CH3:12].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:10]([OH:11])[CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:13])([CH3:12])[CH2:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1C(C)(C)CC(=NO)CC1(C)C
Reactant: BrCc1ccccc1
Product: CN1C(C)(C)CC(N(O)Cc2ccccc2)CC1(C)C
Yield: 40 %

Procedure:
Following the procedure of Example 1, the title compound is prepared from 1,2,2,6,6-pentamethylpiperidin-4-one oxime (5.0 g, 27 mmol) and benzyl bromide (4.6 g, 27 mmol) in a 40% yield to give 3.0 g of a white solid which melts at 107°-108° C. after recrystallization from ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]3[CH2:20][CH2:19][CH2:18][CH:17]4[C:12]3([CH2:13][CH2:14][NH:15][CH2:16]4)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH:21]1([CH2:27]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:21]1([CH2:27][N:15]2[CH2:14][CH2:13][C:12]34[C:8]5[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=5[O:10][CH:11]3[CH2:20][CH2:19][CH2:18][CH:17]4[CH2:16]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrCC1CCCCC1
Reactant: CCOc1cccc2c1OC1CCCC3CNCCC231
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc2c1OC1CCCC3CN(CC4CCCCC4)CCC231

Procedure:
Treating 9-ethoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline with cyclohexylmethyl bromide in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide gives 3-cyclohexylmethyl-9-ethoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline ##STR77##
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][OH:7].Br[CH2:9][C:10]#[N:11].CCN(CC)CC>C1COCC1>[OH:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][N:1]1[CH2:9][C:10]#[N:11]
Reactant: N#CCBr
Reactant: OCC1CCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCN1CCCC1CO
Yield: 63.9 %

Procedure:
The method follows that of S3 using 2-pyrrolidinemethanol (24.27 g, 0.241 mol), BrCH2CN (31.81 g, 0.265 mol), Et3N (37 mL, 0.265 mol) and dry THF (150 mL). The product was obtained as a straw-coloured oil (21.60 g, 64%) after purification by flash chromatography using ether/CH3OH (19:1). δH (250 MHz; CDCl3); 1.5-2.0 (m, 5H, CH2CH2CH2, CH2CH2CH, OH), 2.7 (m, 1H), 2.85 (m, 1H), 3.05 (m, 1H), 3.45 (2×d, 1H, J=4 Hz and J=11 Hz, 1×CHCH2OH), 3.65 (2×d, 1H, J=4 Hz and 11 Hz, 1×CHCH2OH) and 3.75 (d, 2H, NCH2CN); δC(62.9 MHz; CDCl3); 23.37, 27.45, 40.96, 53.95, 62.43, 63.06 and 115.48(CN); IR υmax/cm−1; 3375 (NH2), 3300 (NH2), 3200 (OH), 2970-2800 (CH2, CH3), 1600, 1475, 1375, 1230 and 1060; FAB MS, m/z(M+H)+ 141.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][O:16][CH2:14][CH3:15])=[CH:27][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCCOc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 3 h
Yield: 58.5 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 1.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 1.3 g of 4-(2-ethoxyethoxy)-benzyl bromide, and then 1.0 g of anhydrous potassium carbonate was added thereto. The mixture was heated with stirring on an oil bath at 90° to 100° C. for 3 hours, poured into water, extracted with benzene, washed with water and dried over anhydrous sodium sulfate. Benzene was distilled off under reduced pressure and the resulting oil was purified by means of column chromatography (on silica gel, eluting with benzene/ethyl acetate=18/1) and recrystallization (from n-hexane-benzene) to obtain 1.1 g of the aimed compound, m.p. 82.0°~83.0° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:13][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CN
Reactant: O=Cc1ccc2occc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1ccc2occc2c1
Reaction time: 3 h
Yield: 90.8 %

Procedure:
Benzofuran-5-carbaldehyde (315 mg, 2.16 mmol) was dissolved in anhydrous methanol (10 mL). Methylamine (0.86 mL of 33% solution in ethanol, 6.91 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a brown oil and then dissolved in anhydrous methanol (10 mL). Sodium borohydride (83.2 mg, 2.20 mmol) was added and the mixture was stirred overnight at room temperature. Water (5 mL) was added and the solution was concentrated. Sodium hydroxide (10 mL, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 mL). Combined organic layers were dried over MgSO4, filtered and concentrated to afford benzofuran-5-yl-N-methylmethanamine (316 mg, 91%) as a light brown oil: 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.56 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 3.70 (s, 2H), 3.17 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[NH:23][C:22]2=[O:35])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]([O:40][CH3:41])(=[O:39])[CH:37]=[O:38].O>C1C=CC=CC=1>[OH:38][CH:37]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:22]1=[O:35])[C:36]([O:40][CH3:41])=[O:39]
Reactant: O=C1NC(SCC#Cc2ccccc2)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C=O
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccccc1
Yield: 64 %

Procedure:
3-(Triphenylmethylamino)-4-(3-phenylprop-2-ynylthio) azetidin-2-one (526mg) and methyl glyoxylate (1.17g) were refluxed in dry benzene (25ml) with provision for the removal of water. After 11/2 hours the solvent was evaporated and the residue was chromatographed on silica to give 1-(1-hydroxy-1-methoxycarbonylmethyl)-3-(triphenyl methylamino)-4-(3-phenylprop-2-ynylthio)azetidin-2-one as an amorphous solid (399 mg). νmax (CHCl3) 3475 (--OH), 1770 (β-lactam), 1750 (ester) cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8]1)=[O:6].CCN(C(C)C)C(C)C.[Br:34][CH2:35][C:36](Br)=[O:37]>C(Cl)Cl>[Br:34][CH2:35][C:36]([N:10]1[CH2:11][CH2:12][N:7]([C:5](=[O:6])[C:4]2[CH:21]=[C:22]([CH3:24])[CH:23]=[C:2]([CH3:1])[CH:3]=2)[CH2:8][CH:9]1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)=[O:37]
Reactant: Cc1cc(C)cc(C(=O)N2CCNC(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: O=C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CBr)C(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a cooled solution of (+,-)-[3,5-dimethylbenzoyl]-3-(3,4-dichlorophenyl)piperazine (11.5 g, 31.65 mmol) in CH2Cl2 (200 mL) at 0° C. was added Hunig's base (4.5 g, 35 mmol) and bromoacetyl bromide (6.4 g, 31.65 mmol). The solution was stirred at 0° C. overnight under N2. After completion the reaction was diluted with CH2Cl2 (400 mL) and washed with brine (300 mL, 2×), dried over MgSO4, filtered and concentrated. The crude material was purified by flash grade silica gel chromatography, eluting with 2% [NH4OH/MeOH (1:9)]/98% CH2Cl2 to give the title compound as a light yellow solid (7.1 g, 47.3%), m.p. 77-79° C., FAB MS [M+1]+35Cl,79Br482.9, 484.9.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)(=O)[CH3:15]>>[CH3:2][C:3]1[CH:8]=[C:7]2[C:6](=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[NH:9][C:14]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)=[CH:15]2
Reactant: Cc1ccc(NN)c([N+](=O)[O-])c1
Reactant: CC(=O)c1cnccn1
Agent: Cl
Product: Cc1cc([N+](=O)[O-])c2[nH]c(-c3cnccn3)cc2c1
Yield: 12 %

Procedure:
(4-Methyl-2-nitrophenyl)hydrazine hydrochloride (2 g, 9.8 mmol) and 2-acetylpyrazine (1.2 ml, 9.8 mmol) were reacted according to the same procedures as Preparations 4 to 5 to give the title compound (0.3 g, Yield 19%).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[C:11]([CH3:19])[C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[C:11]([CH3:19])[C:12]([O:15][CH:16]([CH3:17])[CH3:18])=[N:13][CH:14]=1
Reactant: COC(=O)c1c(OCc2ccccc2)cnc(OC(C)C)c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1c(O)cnc(OC(C)C)c1C
Yield: 88.8 %

Procedure:
A mixture of methyl 5-(benzyloxy)-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131b, 1.1 g, 3.5 mmol) and Pd/C (0.5 g) in MeOH (60 mL) was hydrogenated under an H2 balloon at room temperature for 2 hours. The reaction mixture was filtered through CELITE® and the filtrate was concentrated under vacuum to give methyl 5-hydroxy-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131c, 0.7 g, 89%) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C:26]5[CH:30]=[CH:31][CH:32]=[C:33]([C:34]([F:35])([F:36])[F:37])[C:25]=5[F:24])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(C(F)(F)F)c1F
Yield: 76.1 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (309 mg, 1.00 mmol), 2-fluoro-3-(trifluoromethyl)benzoic acid (312 mg, 1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg, 1.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (380 mg, 76%) was obtained as a white powder.