Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([C:21]1[CH:22]=[CH:23][C:18]([O:24][CH3:25])=[CH:19][CH:20]=1)=[O:9]
Reactant: COc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Reaction time: 1.5 h

Procedure:
To a stirred suspension of commercial 5-bromo-2-chlorobenzoic acid (506 mg, 2.12 mmol) in 10 mL of CH2Cl2 containing oxalyl chloride (2.4 mmol) was added 2 drops of DMF. Once the vigorous evolution of gas ceased, the reaction was stirred 1.5 hr prior to removal of the volatiles using a rotary evaporator. After dissolving the crude 5-bromo-2-chlorobenzoyl chloride in 8 ml of CS2, the stirred mixture was cooled to 4° prior to adding anisole (240 mg, 2.12 mmol) followed by AlCl3 (566 mg, 4.25 mmol). The reaction, after warming to 20° over 1 hr, was stirred for 20 hr prior to quenching with 1N HCl. Subsequently, the suspension was diluted with 50 ml H2O and stirred until all solids were in solution. The mixture was extracted 3× with EtOAc. The combined organic extracts were washed 1× with 1N HCl, H2O, aq NaHCO3, and brine prior to drying over Na2SO4. After removal of the volatiles, the residue was chromatographed on silica gel using 15% EtOAc/hexane to elute 450 mg of 5-bromo-2-chloro-4′-methoxybenzophenone.
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.[CH2:24]([S:26]([C:29]1[S:33][C:32]([C:34](O)=[O:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>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:34]([C:32]5[S:33][C:29]([S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=5)=[O:35])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)s1
Yield: 71.8 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol), 5-(ethylsulfonyl)thiophene-2-carboxylic acid (110 mg, 0.50 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (98 mg, 0.51 mmol), 1-hydroxybenzotriazole (69 mg, 0.51 mmol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 318, the title compound (180 mg, 71%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([O:32]CC)=O)[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>CCO>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:36][CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)=[O:32])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccncc1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCc3ccncc3)c(O)c3ncc(Cc4ccccc4)cc32)cc1
Temperature: 120 °C

Procedure:
A mixture of ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (40 mg, 0.080 mmol) and 4-(aminomethyl)pyridine (122 μL, 1.2 mmol) in EtOH (1 mL) was heated at 120° C. in a sealed tube in a microwave for 30 min. The reaction mixture was concentrated at reduced pressure, reconstituted in CH2Cl2 and washed with a mixture of 1N HCl and brine. Drying and evaporation of the organic phase gave the product as a pale green solid: 1H NMR (CDCl3) δ 10.81 (1H, br t, J=6 Hz), 8.69 (2H, d, J=7 Hz), 8.65 (1H, d, J=1 Hz), 7.83 (2H, d, J=8 Hz), 7.76 (2H, d, J=6 Hz), 7.31 (3H, m), 7.19 (2H, d, J=8 Hz), 7.11 (1H, s), 7.03 (2H, m), 5.43 (2H, br s), 4.86 (2H, d, J=6 Hz), 4.08 (2H, s), 3.03 (3H, s); HRMS calcd for C30H26N4O5S+H+: 555.1702. Found: 555.1699.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16](OCC(C2C=CC3C4C=C5CCC(Br)C(=O)C5=CC=4OCC=3C=2)=O)=O)[CH2:5]1.COC(N[C@H](C(N1[C@@H](C)CC[C@H]1C1[NH:63][C:62]2[C:64]3[C:69]([CH:70]=[CH:71][C:61]=2[N:60]=1)=[CH:68][C:67]1[C:72]2[C:77]([CH2:78][O:79][C:66]=1[CH:65]=3)=[CH:76][C:75]([C:80]1[NH:84]C([C@@H]3C[C@H](COC)CN3C(OC(C)(C)C)=O)=[N:82][CH:81]=1)=[CH:74][CH:73]=2)=O)C(C)C)=O.[C:100]([O:104][C:105]([N:107]1[CH2:111][C@@H:110]([CH2:112][O:113][CH3:114])[CH2:109][C@H:108]1[C:115](O)=O)=[O:106])([CH3:103])([CH3:102])[CH3:101]>>[C:12]([O:11][C:9]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:16]1[NH:63][C:62]2[C:64]3[C:69]([CH:70]=[CH:71][C:61]=2[N:60]=1)=[CH:68][C:67]1[C:72]2[C:77]([CH2:78][O:79][C:66]=1[CH:65]=3)=[CH:76][C:75]([C:80]1[NH:84][C:115]([C@@H:108]3[CH2:109][C@H:110]([CH2:112][O:113][CH3:114])[CH2:111][N:107]3[C:105]([O:104][C:100]([CH3:101])([CH3:102])[CH3:103])=[O:106])=[N:82][CH:81]=1)=[CH:74][CH:73]=2)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N(C(=O)OC(C)(C)C)C1
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7C[C@H](COC)CN7C(=O)OC(C)(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1

Procedure:
tert-Butyl (2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate was prepared from (2S,4S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate by the same method employed in the synthesis of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate, replacing (2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylic acid with (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[C:10]2[CH:11]=[N:12][C:13]([NH:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[O:17])=[CH:14][C:9]=2[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([SiH](CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:10]2[CH:11]=[N:12][C:13]([NH:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[O:17])=[CH:14][C:9]=2[NH:8][N:7]=1
Reactant: COC/C=C/c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
To the solution of crude (R,E)-1-(3-(3-methoxyprop-1-en-1-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (142 mg, 0.239 mmol) in DCM (0.8 mL) TFA (0.3 mL) and triethylsilane (0.1 mL) were added. The mixture was stirred at room temperature for 30 min and additional TFA (0.5 mL) and triethylsilane (0.3 mL) were added. The mixture was stirred at room temperature for 30 min, evaporated in vacuo and purified by MS-directed reverse phase preparative-HPLC (C-18 stationary phase, eluting with a H2O/MeCN gradient with 0.1% TFA), to afford (R)-1-(3-(3-methoxypropyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (21.7 mg, 0.046 mmol, 19%). MS ESI calc'd. for C19H24N5O2 [M+H]+ 354, found 354. 1H NMR (600 MHz, DMSO-d6) δ 12.92 (s, 1H), 9.38 (s, 1H), 8.80 (s, 1H), 7.88 (s, 1H), 7.46 (s, 1H), 7.38-7.15 (m, 5H), 4.85 (m, 1H), 3.33 (t, J=6.3 Hz, 2H), 3.19 (s, 3H), 2.91 (t, J=7.6 Hz, 2H), 1.99-1.85 (m, 2H), 1.39 (d, J=6.9 Hz, 3H),
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[NH:36]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH2:37]1.C(=O)([O-])O.[Na+]>ClCCl>[N:43]1[CH:44]=[CH:45][CH:46]=[C:41]([CH:38]2[CH2:39][CH2:40][N:36]([C:28]([N:4]3[C:5]4[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:6]=4[O:1][CH2:2][CH2:3]3)=[O:34])[CH2:37]2)[CH:42]=1
Reactant: c1cncc(C2CCNC2)c1
Reactant: COC(=O)c1ccc2c(c1)NCCO2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)N(C(=O)N1CCC(c3cccnc3)C1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 139.9 %

Procedure:
1.8 g of methyl 3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate, 93.2 ml of dichloromethane and 4.62 ml of diisopropylethylamine are placed in a 250 ml round-bottomed flask under a nitrogen atmosphere. 1.38 g of triphosgene are added at 0° C. and then the reaction mixture is left stirring at ambient temperature for three hours. 1.62 ml of diisopropylethylamine and 1.45 g of 3-(pyrrolidin-3-yl)pyridine are subsequently added and the reaction mixture is stirred for eighteen hours. A saturated aqueous sodium hydrogencarbonate solution and dichloromethane are added. The aqueous phase is extracted three times with dichloromethane. The organic phases are combined, washed with water and with a saturated aqueous sodium chloride solution and dried over sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is chroratographed on silica gel with a dichloromethane/methanol 95/5 mixture. 2.39 g of methyl 4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=O.C(=O)(O)[O-].[Na+]>C(O)CC>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[N:1]=[C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]3[CH:13]=2)=[CH:17][CH:18]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Nc1ccc2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: Clc1ccc(-c2cn3c(ccc4ccccc43)n2)cc1

Procedure:
17.7 g (0.123 mole) of 2-aminoquinoline, 28.7 g (1 equivalent of α-bromo-p-chloroacetophenone and 20.6 g (2 equivalents) of sodium bicarbonate are mixed in 180 ml of n-propanol and heated under reflux for 20 hours. The precipitate obtained is filtered off, washed with ethanol and water and dried. A white solid is obtained which is recrystallized from nitromethane.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[Br:12]N1C(=O)CCC1=O>>[Br:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]=1
Reactant: Cc1ccc2nnn(C)c2c1
Reactant: O=C1CCC(=O)N1Br
Product: Cn1nnc2ccc(CBr)cc21

Procedure:
The dimethyl compound (a) is reacted with N-bromosuccinimide, yielding the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:6][C:7](=[O:9])[CH3:8])(=[O:5])[CH3:4].[CH2:10](Br)[CH:11]=[CH2:12]>CO>[CH2:12]([CH:6]([C:7](=[O:9])[CH3:8])[C:3](=[O:5])[CH3:4])[CH:11]=[CH2:10]
Reactant: CC(=O)CC(C)=O
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(C(C)=O)C(C)=O
Temperature: 0 °C
Yield: 48 %

Procedure:
NaOH (4.51 g, 113 mmol) was dissolved in anhydrous MeOH. After cooling the mixture to 0° C. using an ice-bath, acetylacetone (10.0 g, 99.8 mmol) was added while stirring over a period of several minutes. Allyl bromide (10.4 mL, 123 mmol) was then added without cooling over a period of 10 min. After addition was complete, the reaction mixture was refluxed for an additional 2 h. The mixture was cooled and filtered to remove excess NaBr. MeOH and the excess allyl bromide were removed by distillation. The product, 5, was isolated as a yellow oil, 6.72 g (48% yield), between 81-87° C.
Reaction SMILES: [Cl-].[Li+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]1[CH2:27][CH2:26]N2C(=NCCC2)[CH2:19][CH2:18]1.C1(C=O)CCC1>CC#N>[CH:18]1(/[CH:19]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:17][CH2:27][CH2:26]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: C1CCC2=NCCCN2CC1
Agent: O=CC1CCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: CCOC(=O)/C=C/C1CCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a suspension of lithium chloride (2.22 g, 52.2 mmol) in MeCN (80 mL) were added ethyl 2-(diethoxyphosphoryl)acetate (available from Aldrich) (8.37 mL, 41.8 mmol) and DBU (16.7 mL, 111 mmol) at room temperature. The mixture was cooled to 0° C., and to it was added cyclobutanecarbaldehyde 70.B (2.93 g, 34.8 mmol) dropwise. The resulting cloudy mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford (E)-ethyl 3-cyclobutylacrylate 70.C as a colorless liquid (5.00 g, 94%).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:14]=3[CH:15]=2)=[O:10])[CH2:3]1.[CH:21]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([O:20][CH:27]4[CH2:28][CH2:29][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:25][CH2:26]4)=[CH:16][C:14]=3[CH:15]=2)=[O:10])[CH2:3]1
Reactant: CC(C)N1CCC(O)CC1
Reactant: C[C@@H]1CN(C(=O)c2cc3cc(O)ccc3o2)C[C@H](C)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3oc(C(=O)N4C[C@@H](C)O[C@@H](C)C4)cc3c2)CC1
Reaction time: 3 h
Yield: 64.1 %

Procedure:
The above prepared ((cis)-2,6-dimethyl-morpholin-4-yl)-(5-hydroxy-benzofuran-2-yl)-methanone (0.150 g, 0.545 mmol) was dissolved in 2.7 mL of THF and treated successively at 10° C. with 1-isopropyl-piperidin-4-ol (0.156 g, 2 eq.), triphenylphosphine (0.285 g, 2 eq.) and DIAD (0.212 mL, 2 eq.), and the mixture then kept at ambient temperature for another 3 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by two flash chromatographies (SiO2, NEt3/AcOEt=4/96 and CH2Cl2/MeOH=9/1), yielded eventually 0.140 g of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][N:23]([CH3:25])[NH2:24].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:22][N:23]([CH3:25])[NH:24][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:13][CH:14]=1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Reactant: CN(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NN(C)C)cn1
Yield: 33.6 %

Procedure:
To a stirred solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) in DMF (5 mL) at room temperature under argon was added N,N-dimethylhydrazine (23 mg, 0.38 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (122 mg, 0.38 mmol) and N,N-diisopropylethylamine (223 mg, 1.7 mmol). After 15 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 1:0 to 97.5:2.5) afforded the title compound (38 mg, 33%) as a colourless gum. MS: m/e=333.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:20][O:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH:16][C:23]([N:22]([O:21][CH3:20])[CH3:26])=[O:24])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)Cc2cc(Oc3ccc(N)cc3)ccc2O1
Reactant: CON(C)C(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)Nc1ccc(Oc2ccc3c(c2)CC(C)(C)O3)cc1
Reaction time: 1.5 h
Yield: 86 %

Procedure:
6.5 g of 4-(2,3-dihydro-2,2-dimethyl-5-benzofuranyloxy)aniline was dissolved in 30 ml of pyridine, and 3.8 g of N-methoxy-N-methylcarbamoyl chloride was gradually dropwise added thereto over a period of 30 minutes under cooling with ice. Stirring was continued for 1.5 hours, and then pyridine was distilled off under reduced pressure. The residual oily substance was dissolved in 100 ml of toluene, and washed sequentially with water, a dilute hydrochloric acid aqueous solution and a saturated sodium chloride aqueous solution. Then, toluene was distilled off. The residue was purified by silica gel column chromatography by using a solvent mixture of ethyl acetate/n-hexane=1/3 as the developer, to obtain 7.5 g of compound No. 19 as identified in Table 1.
Reaction SMILES: [CH:1]1([C:6]2[C:7]3[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=3)[N:9]=[C:10]([CH3:12])[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([CH:19]([C:22]1[C:23]2[N:24]([C:29](I)=[C:30]([CH3:32])[N:31]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:20][CH3:21])[CH3:18]>>[CH:1]1([C:6]2[C:7]3[N:8]([C:13]([C:29]4[N:24]5[N:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH:19]([CH2:17][CH3:18])[CH2:20][CH3:21])[C:23]5=[N:31][C:30]=4[CH3:32])=[C:14]([CH3:16])[N:15]=3)[N:9]=[C:10]([CH3:12])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1cn2nc(C)cc(C3CCCC3)c2n1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C5CCCC5)cc(C)nn34)c(C)nc12
Yield: 53.8 %

Procedure:
Using a procedure analogous to Example 16B, 8-cyclopentyl-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.41, 1.86 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.63 g, 1.86 mmol) give the title compound (0.43 g, 1.0 mmol, 54%). 1H NMR (CDCl3): δ 0.92 (t, J=7.4 Hz, 6H), 1.70-1.96 (m, 10H), 2.25-2.35 (m, 2H), 2.43 (s, 3H), 2.44 (s, 3H), 2.47 (s, 6H), 3.35-3.48 (m, 1H), 3.78-3.90 (m, 1H), 6.68 (s, 1H), 6.76 (s, 1H) ppm. ES-MS (m/z): calcd for C26H34N6 (M+H)+: 431.6. found: 431.3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([NH:14][CH2:15][CH2:16][NH2:17])(=[O:13])[CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:11]([NH:14][CH2:15][CH2:16][NH:17][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:13])[CH3:12]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)NCCNC(=O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
A solution of 1.3 ml (0.01 mol) of 4-chlorobenzoyl chloride in 15 ml of chloroform is added dropwise at 0° to a solution of 1.02 g (0.01 mol) of acetylethylenediamine [J. Amer. Chem. Soc. 61, 822 (1939)] and 1.4 ml (0.01 mol) of triethylamine in 25 ml of chloroform. After 15 minutes, the resulting crystals are filtered off, washed with chloroform and dried. There are obtained 1.9 g of N-(2-acetylaminoethyl)-4-chlorobenzamide, m.p. 222°-224°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)([CH3:10])[CH3:9])=[CH:6][N:7]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=1[OH:37])[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=1[O:37][CH2:2][C:3]1[N:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)([CH3:9])[CH3:10])=[CH:6][N:7]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(CCl)n1-c1ccc(F)cc1
Reactant: COC(=O)c1cc(F)c(O)c(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(F)c(OCc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)cc2)c(Cl)c1
Temperature: 60 °C
Yield: 68 %

Procedure:
A mixture of 2-(chloromethyl)-5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (154 mg, 0.39 mmol), methyl 3-chloro-5-fluoro-4-hydroxybenzoate (118 mg 0.57 mmol), potassium carbonate (79 mg, 0.57 mmol), and 18-crown-6 (11 mg, 0.04 mmol) in CH3CN (4 mL) was heated 8 h at 60° C. After cooling, the reaction mixture was filtered, combined with water and DCM, and then extracted further with DCM. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The material was purified by chromatography (silica, 0-70% EtOAc/Hex) to give methyl 3-chloro-4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)-5-fluorobenzoate as a white solid (150 mg, 68% yield). MS (EI) m/z 567.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.O>CN(C=O)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(OCc3ccc4ccccc4n3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 6-hydroxytetralone, prepared as in step 1, (2.43 g, 15 mmol) and potassium carbonate (2.76 g, 20 mmol) in DMF (65 mL) was added chloromethylquinoline hydrochloride (3.42 g, 16 mmol), and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (100 mL). The extract was dried with MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5:1 methylene chloride-ethyl acetate to provide 2.3 g 3,4-Dihydro-6-(2-quinolylmethoxy)-1(2H)-naphthalenone.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]2[N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:4]2[N:3]=1.[CH2:23]([N:25](CC)[CH2:26][CH3:27])[CH3:24].N1CCCC1.O>CN(C)C(=O)C>[N:25]1([C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:5]3[N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:4]3[N:3]=2)[CH2:26][CH2:27][CH2:24][CH2:23]1
Reactant: CCOC(=O)c1cc2nc(Cl)cc(NC3CCOCC3)n2n1
Reactant: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: C1CCNC1
Solvent: O
Product: CCOC(=O)c1cc2nc(N3CCCC3)cc(NC3CCOCC3)n2n1
Temperature: 60 °C

Procedure:
To a solution of ethyl 5-chloro-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylate (5.88 g, 18.1 mmol) in N,N-dimethylacetamide (50 mL) was added triethylamine (5.50 g, 54.3 mmol) and pyrrolidine (1.59 mL, 19.0 mmol) at 0° C. The mixture was heated at 60° C. for 20 h. And then pyrrolidine (1.59 mL, 19.0 mmol) was added and heated at 60° C. for 24 h. After being cooled to ambient temperature, the reaction mixture was poured into water. The resulting precipitate was collected to give ethyl 5-pyrrolidin-1-yl-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylate. MS (APCI): m/z 360 (M+H).