Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[OH:17])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH-].[K+].Br[CH:21]([CH3:39])[C:22]([C:24]1[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27]([OH:34])=[C:26]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:25]=1)=[O:23].Cl>CN1CCCC1=O.O>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH:21]([CH3:39])[C:22]([C:24]2[CH:29]=[C:28]([C:30]([CH3:31])([CH3:33])[CH3:32])[C:27]([OH:34])=[C:26]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:25]=2)=[O:23])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(Br)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(OC(C)C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A mixture of 5.5 g (24 mmol) of 2-benzotriazol-2-yl-4-methyl-phenol, 4.7 g (72 mmol) of potassium hydroxide and 100 ml of n-methylpyrrolidone is stirred for 2 hours at room temperature. Then 8.0 g (24 mmol) 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-propan-1-one dissolved in 40 ml of n-methylpyrrolidone is added and stirring is continued at room temperature for 20 hours. After the addition of 50 ml of water and 15 ml 2N hydrochloric acid the precipitated solid is filtered off and recrystallized from ethanol to give 8.9 g (76%) of compound 117; m.p. 161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:17](Cl)(=O)[CH2:18][CH2:19][CH2:20][CH3:21].Cl>C1COCC1>[CH2:18]([C:17]1[N:6]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][CH:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:7]=2)[N:1]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)Cl
Reactant: NC(=O)c1cc(C(F)(F)F)ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1nc(O)c2cc(C(F)(F)F)ccc2n1
Reaction time: 4 h
Yield: 83.1 %

Procedure:
Preparation D11, Step 1: 2-amino-5-(trifluoromethyl)-benzamide (100 mg, 0.49 mmol, 1 eq) was suspended in THF (5 mL) at 0° C. then 1.000N NaOH (0.73 mL, 0.735 mmol, 1.5 eq) was added. Valeryl chloride (87 μL, 0.735 mmol, 1.5 eq) was slowly dripped into the mixture. After 4 hours, little reaction. Added more 1.000N NaOH (5.84 mL, 5.88 mmol, 12 eq) followed by more valeryl chloride (0.70 mL, 5.88 mmol, 12 eq). After the reaction was complete, added conc. HCl until pH=3. Stripped off the THF. Extracted the aqueous 3 times with ethyl acetate. The organic layers were combined, dried (sodium sulfate) and stripped to give an oil. Purified over silica gel in 9:1 to 1:1 hexanes/ethyl acetate to give 2-butyl-6-(trifluoromethyl)quinazolin-4-ol (110 mg) as a white solid. Yield=78%. LCMS detects (M+H)+=271.21.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C([NH:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][N:26]=1)=[O:24])C1C=CC=CC=1>>[CH2:9]([C:33]1[C:25]([C:23]([NH2:22])=[O:24])=[N:26][CH:27]=[C:28]([C:29]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:31])[CH:32]=1)[C:3]1[CH:4]=[CH:5][CH:7]=[CH:8][CH:2]=1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccccc2)nc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: NC(=O)c1ncc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1Cc1ccccc1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to benzylamine via Procedure G. Crude methyl 6-(benzylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 300 mg of 6-(benzylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(benzylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield-benzyl-N5-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide. MS (Q1) 443.1 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CC(C)=O>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Br:1])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(O)c(Br)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
A solution of 2-bromo-4-methylphenol (Alfa; 3.00 g; 16.0 mmol) in acetone (30 mL) was treated with potassium carbonate (2.44 g; 17.6 mmol), stirred for 10 minutes then treated with tert-butyl bromoacetate (2.37 mL; 16.0 mmol). The reaction mixture was stirred at 65° C. for 18 hours, then the mixture was filtered, the solid was washed with acetone and the filtrate was concentrated to dryness under vacuum to give the title compound as a pale yellow liquid (4.8 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(#N)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: O
Product: Clc1cc(-c2cccnc2)cc(Cl)n1
Yield: 92.1 %

Procedure:
2,6-dichloro-4-iodopyridine (500 mg, 1.77082 mmol), 3-pyridylboronic acid pinacol ester (487 mg, 1.3 equiv., 2.30207 mmol), PCy3 (112 mg, 0.22 equiv., 0.389581 mmol), and Pd2(dba)3 (84 mg, 0.050 equiv., 0.0885411 mmol) were mixed in acetonitrile (13 mL, 140 equiv., 247.915 mmol) and K3PO4 (1.27 M, 1.95 mL, 1.4 equiv., 2.47915 mmol), and the reaction was kept at 110° C. for 2 h. Brine and 10% citric acid was used to adjust the pH around 8. The mixture was extracted with EtOAc three times. After evaporation of the organic layers, the residue was purified via chromatography (0-70% EtOAc/Heptane) to yield 367 mg yellow powder 1H NMR (400 MHz, CDCl3) δ (delta) 8.86 (d, J=2.4 Hz, 1H), 8.74 (dd, J=4.8, 1.6 Hz, 1H), 7.92-7.86 (m, 1H), 7.47 (s, 2H), 7.45 (dd, J=7.9, 4.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ (delta) 151.45, 151.24, 150.72, 148.02, 134.40, 131.63, 123.96, 120.75. LCMS: m/z 225 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH2:9]([OH:14])[CH2:10][CH2:11][C:12]#[CH:13]>C(#N)C.[Cu]I.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>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]#[C:12][CH2:11][CH2:10][CH2:9][OH:14]
Reactant: C#CCCCO
Reactant: Fc1ccccc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: OCCCC#Cc1ccccc1F

Procedure:
1-Bromo-2-fluorobenzene [1072-85-1] (3.0 g, 17 mmol, 1.0 equiv) and pent-4-yn-1-ol [5390-04-5] (2.3 mL, 25 mmol, 1.5 equiv) were dissolved in acetonitrile (40 mL). CuI (0.13 g, 0.68 mmol, 0.04 equiv) and TEA (3.4 mL, 25 mmol, 1.5 equiv) was added to the stirred solution followed by tetrakis(triphenylphosphine)palladium(0) (0.39 g, 0.34 mmol, 0.02 equiv). The solution was heated at reflux for 16 hours. The solution was cooled, filtered through Celite, the Celite pad rinsed with EtOAc and the solvent removed by rotoevaporation. Column chromatography (9:1 hexanes:ethyl acetate) of the residue afforded pure 5-(2-fluorophenyl)pent-4-yn-1-ol Intermediate 60 (1.3 g, 43%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:36])[C:11]([CH2:32][C:33](O)=[O:34])=[CH:12][N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:38]([N:40]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN>CN(C)C=O.CO.C(Cl)(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:15]([C:14]1[N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:12]=[C:11]([CH2:32][C:33](=[O:34])[NH:40][CH3:38])[C:10](=[O:36])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(Cn1cc(CC(=O)O)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNC(=O)Cc1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetic acid (25 mg) obtained in Example 191, Step 1 in dimethylformamide (0.2 ml), were successively added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg), 1-hydroxybenzotriazole hydrate (15 mg) and methylamine (2M tetrahydrofuran solution) (0.073 ml), and the mixture was stirred at room temperature for 2 hr. The obtained reaction mixture was applied as it was to silica gel thin layer chromatography (chloroform:methanol=10:1) and crystallized from ethyl acetate-diisopropyl ether to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-methylcarbamoylmethyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (22 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[F:21][C:22]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:30][C:28]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([F:21])[CH:29]=1
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1F

Procedure:
N-Bromosuccinimide and AIBN were added to a carbon tetrachloride solution of 2-fluoro-4-methylbenzonitrile, followed by heating under reflux to obtain 4-(bromomethyl)-2-fluorobenzonitrile. By allowing this to react with morpholine in DMF in the presence of potassium carbonate, 2-fluoro-4-(morpholin-4-ylmethyl)benzonitrile was obtained. In DMF and in the presence of potassium carbonate, this was allowed to react with cyclohexanamine at 160° C. for 30 minutes while carrying out microwave irradiation. By post-treating the reaction liquid, 2-(cyclohexylamino)-4-(morpholin-4-ylmethyl)benzonitrile was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(N(CC)CC)C.C(Cl)(Cl)Cl.CO>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([Cl:12])[CH:14]=2)[N:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Clc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-Dichloropurine (3.78 g; 0.02 mol) was reacted with 3-chloroaniline (3.83 g; 0.03 mol) in n-butanol (40 ml) in the presence of triethylamine (7 ml; 0.05 mol) at 110° C. for 3 hours. After cooling to room temperature the reaction mixture was stirred at 0° C. for 2 hours. The yellow precipitate was filtered off, washed with cold n-butanol (2×10 ml), water (3×10 ml) and dried in the drying oven at 60° C. into constant weight. Yield: 3.69 g yellow crystalline powder (65.8%). The crude product was crystallized from isopropanol to give 2.85 g of pure substance. TLC (chloroform-methanol; 85:15): one single spot; free of starting material. HPLC purity: 98+%
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=3)=[O:16])[C:10](=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:36])=O>C(Cl)Cl.O>[Cl:36][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][N:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][C:10]2=[O:25])=[CH:18][CH:19]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Cn1ccc(OCc2ccc(F)cc2)cc1=O)c1ccc(CO)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cn1ccc(OCc2ccc(F)cc2)cc1=O)c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1.20 g (3.27 mmol) 4-(4-fluoro-benzyloxy)-1-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 31.1) in 20 mL DCM is added 0.29 mL (3.59 mmol) pyridine and 0.26 mL (3.59 mmol) thionylchloride at 0° C. The reaction mixture is stirred 1 h at 0° C., is warmed to RT and is then diluted with water. The organic phase is washed with saturated aqueous KHSO4-solution and then with water, dried over MgSO4, filtered over charcoal and the solvent is evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:16])([CH3:15])[CH2:10][O:11][CH2:12]OC)[CH:4]=1.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH2:12][O:11][CH2:10][C:9]2([CH3:16])[CH3:15]
Reactant: COCOCC(C)(C)c1cccc(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)COC2
Temperature: -78 °C
Reaction time: 2 h
Yield: 136.1 %

Procedure:
1-methoxy-3-[2-(methoxymethoxy)-1,1-dimethyl-ethyl]benzene (Intermediate 40, 300 mg, 1.3375 mmol) was dissolved in DCM (8 mL), the solution was cooled to −78° C. and titanium tetrachloride (37.928 mg, 0.2000 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. water (15 mL) was added and the mixture extracted with EtOAc (25 mL). Organics were dried over Na2SO4, filtered and evaporated to afford a crude that was purified by flash chromatography (Biotage system) on silica gel using a SNAP 25 g as column and cyclohexane/ethyl acetate from 100:0 to 90:10 as eluent affording the title compound (350 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].[CH2:8]([NH2:10])[CH3:9]>>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH:10][CH2:8][CH3:9])=[O:5]
Reactant: CN(C)CC(=O)O
Reactant: CCN
Product: CCNC(=O)CN(C)C
Reaction time: 72 h
Yield: 94.9 %

Procedure:
N,N-dimethylglycine (0.8 g, 6.8 mmol) was dissolved in an aqueous solution of 70% ethylamine (5.7 g, 68 mmol), and the solution was placed in a closed vessel and stored at 5° C. for 3 days. The solution was concentrated under reduced pressure, and the resultant oily product was subjected to column chromatography, followed by extraction with a chloroform/methanol mixed solvent, to thereby obtain Exemplified Compound (6) (0.84 g, 94.4%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.[F:12][C:13]1[C:18]([CH2:19]Br)=[C:17]([F:21])[C:16]([F:22])=[C:15]([F:23])[C:14]=1[F:24]>>[F:12][C:13]1[C:18]([CH2:19][O:1][C:2]2[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([O:8][CH2:19][C:18]3[C:17]([F:21])=[C:16]([F:22])[C:15]([F:23])=[C:14]([F:24])[C:13]=3[F:12])[CH:7]=2)=[C:17]([F:21])[C:16]([F:22])=[C:15]([F:23])[C:14]=1[F:24]
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: CC(=O)c1cc(O)cc(O)c1
Product: CC(=O)c1cc(OCc2c(F)c(F)c(F)c(F)c2F)cc(OCc2c(F)c(F)c(F)c(F)c2F)c1
Yield: 98 %

Procedure:
Synthesized by 1:2 ratio of 3',5'-dihydroxyacetophenone to pentafluorobenzyl bromide. Yield: 98%. m.p. 102°-103° C. 1H NMR, δ: 2.60 (s, 3H, CH3CO), 5.22 (s, 4H, CH2O), 6.83 (bs, 1H, H-C4'), 7.24 (d, 2H, J=1.8 Hz, H-C2' & H-C6') ppm; 13C NMR, δ: 26.0 (CH3CO), 57.4 (CH2O), 106.4 (C4'), 107.4 (C2' & C6'), 109.7 (C1", 2JC-F =17 Hz) 137.4 (C2" & C6", JC-F =249 Hz), 139.2 (C1'), 141.7 (C4", JC-F =256 Hz), 145.7 (C3" & C5", JC-F =251 Hz), 159.2 (C3' & C5'), 196.7 (C=O) ppm. MS (EI): 331 ([M-PFBz]+); MS (ECNI): 331 ([M-PFBz]-, 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Cl.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:19][CH:20]4[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: OC1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 30.7 %

Procedure:
To a solution of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (300 mg, 1.14 mmol) and trans-4-aminocyclohexanol hydrogenchloride (327 mg, 2.84 mmol) in NMP (2.0 mL) was added NaHCO3 (286 mg, 3.41 mmol), the mixture was stirred at 180° C. for 45 mins under microwave irridation. The mixture was purified by flash chromatograph to give 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanol (120 mg, 0.350 mmol, 31%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=S)[NH:10][CH:11]2[CH:16]3[CH2:17][CH:13]4[CH:14]([CH2:15]3)[CH:12]24)=[CH:4][CH:3]=1.[NH3:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:19])[NH:10][CH:11]2[CH:16]3[CH2:17][CH:13]4[CH:14]([CH2:15]3)[CH:12]24)=[CH:4][CH:3]=1
Reactant: N
Reactant: S=C(Nc1ccc(Cl)cc1)NC1C2CC3C(C2)C31
Solvent: CCO
Product: N=C(Nc1ccc(Cl)cc1)NC1C2CC3C(C2)C31

Procedure:
To a solution of 3-[3-(p-chlorophenyl)thioureido]tricyclo[2,2,1,02,6 ]heptane (0.25 g.) in ethanol saturated with ammonia (10 ml.) was added 0.2 g. of yellow mercuric oxide, and the mixture stirred at room temperature for 16 hours. The solids were filtered off and the clear filtrate evaporated to dryness. The residual solid was recrystallised from toluene to give 3-[3-(p-chlorphenyl)guanidino]tricyclo[2,2,1,02,6 ]heptane, m.p. 204°-205°.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][C:11]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([N:8]([CH2:19][CH2:20][OH:21])[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][C:11]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1cc[n+]([O-])cc1F
Agent: Cl
Solvent: CO
Product: O=C(c1cc[n+]([O-])cc1F)N(CCO)Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a solution of the compound (1.20 g) obtained in step 2 in MeOH (5 mL) was added 6N hydrochloric acid (5 mL), and the mixture was stirred at 60° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a mixture of ethyl acetate and THF. The solution was neutralized with aqueous sodium hydroxide solution, and the resultant product was extracted three times with a mixture of ethyl acetate and THF, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 66% ethyl acetate/hexane→5% ammonia/ethyl acetate) to give N-benzyl-3-fluoro-N-(2-hydroxyethyl)isonicotinamide 1-oxide (0.63 g, 73%) as a white powder.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](=[O:30])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@H:37]([CH:42]([CH3:43])[CH3:44])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl)C(C)C
Agent: Cl
Product: COC(=O)[C@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(4-chloro-3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].C[N-]C.[Ti+4:13].[CH:14]1[CH2:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].[CH:15]1([Ti+3:13])[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: [Ti+4]
Reactant: C1=CCC=C1
Agent: C[N-]C
Solvent: Cc1ccccc1
Product: [Ti+3]C1C=CC=C1

Procedure:
A 250 mL Schlenk flask is charged with titanium tetrakis(dimethylamide), 2.48 g (11.06 mmole), and toluene, 100 mL. Freshly cracked cyclopentadiene monomer, 2.7 mL (33.18 mmole), is added to the magnetically stirred solution. The mixture is refluxed 1 hour giving a deep red solution. All volatiles are removed under vacuum at room temperature leaving a viscous deep red oil. The oil is transferred to a microdistillation apparatus and a low melting solid is distilled at 70° C. under vacuum (0.05 mm Hg). The product is determined to be cyclopentadienyltitanium tris(dimethylamide).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([O:41][CH3:42])[CH:35]=1>>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([O:41][CH3:42])[CH:35]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: COc1cc(CCN)ccc1O
Product: COc1cc(CCNc2nccc(-c3cccc(CN(CCCNC(=O)OC(C)(C)C)S(C)(=O)=O)c3)n2)ccc1O

Procedure:
Intermediate 4 was coupled to 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 586. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (s, 1H) 8.05 (s, 1H) 7.96 (s, 1H) 7.50 (m, 2H) 7.0 (m, 1H) 6.83 (m, 1H) 6.77 (m, 2H) 5.64 (s, 1H) 4.84 (s, 1H) 4.44 (s, 3H) 4.09 (s, 2H) 3.86 (s, 2H) 3.77 (m, 1H) 3.25 (m, 3H) 3.07 (br s, 2H) 2.90 (m, 2H) 2.85 (S, 3H) 1.60 (m, 2H) 1.39 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[Na].[CH3:23]Br>CN(C)C=O>[CH3:23][N:10]([C:2]([CH3:1])([CH3:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: CC(C)(NS(=O)(=O)c1ccccc1)c1ccccc1
Reactant: CBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CN(C(C)(C)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
27.5 g (0.1 mole) of N-(α,α-dimethylbenzyl)benzenesulfonamide was added to 5.8 g (0.12 mole) of 50% sodium hydride in 200 ml of dry N,N-dimethyl formamide. The mixture was stirred at room temperature for 30 minutes to react them. To the resulting sodium salt of N-(α,α-dimethylbenzyl)benzenesulfonamide was added 16.1 g (0.17 mole) of methyl bromide. The mixture was heated to 60° C. and stirred for 1 hours. The N,N-dimethyl formamide was distilled off under reduced pressure, and cold water was added. The resulting white solid was recrystallized from methanol to afford N-methyl-N-(α,α-dimethylbenzyl)benzenesulfonamide in a yield of 87%. This compound is designated as compound No. 64 in Table 2 below, and its melting point and elemental analysis values are shown in Table 2.