Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:23]C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]=1.Cl>CO>[NH2:23][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:10]=2)=[C:2]([F:1])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)c2)c(F)c1
Agent: Cl
Solvent: CO
Product: Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)c2)c(F)c1
Yield: 87.6 %

Procedure:
A mixture of N-(3-fluoro-4-(2-(4-fluorophenylamino)pyridin-4-yloxy)phenyl)acetamide (18 mg, 0.051 mmol), 6 M HCl (0.1 mL, 0.60 mmol) and MeOH (1.5 mL) was heated at reflux for 2 h. The mixture was concentrated in vacuo and the residue made basic with saturated aq. NaHCO3 solution then extracted with EtOAc. The extract was dried (MgSO4) and concentrated in vacuo to give the title compound (14 mg, 88%) as a red gum. 1H NMR (DMSO-d6) δ 8.97 (s, 1H), 7.98 (d, 1H, J=5.8 Hz), 7.64-7.60 (m, 2H), 7.05 (dd, 2H, J=9.1, 8.8 Hz), 6.97 (dd, 1H, J=9.4, 8.8 Hz), 6.51 (dd, 1H, J=13.3, 2.6 Hz), 6.40 (ddd, 2H, J=9.0, 6.2, 2.1 Hz), 6.08 (d, 1H, J=2.0 Hz), 5.44 (br s, 2H); MS (ESI+) m/z 314.17 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27](O)=[O:28]>>[F:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1ccc(F)c(C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(C)ccc2F)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Fluoro-5-methyl-benzoic acid.
Reaction SMILES: C(NCC)C.[C:6]([OH:12])(=[O:11])[CH2:7][CH2:8][C:9]#[CH:10].[I:13][C:14]1[S:15][CH:16]=[C:17](I)[CH:18]=1>>[I:13][C:14]1[S:15][C:16]([C:10]#[C:9][CH2:8][CH2:7][C:6]([OH:12])=[O:11])=[CH:17][CH:18]=1
Reactant: Ic1csc(I)c1
Reactant: C#CCCC(=O)O
Solvent: CCNCC
Product: O=C(O)CCC#Cc1ccc(I)s1
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To 75 ml of diethylamine was added with stirring 3.76 g of 4-pentynoic acid, 22 g of 2.4-diiodothiophene, and 300 mg of tetrakis-(triphenylphosphine)palladium(o). The slurry was degassed with argon and 960 mg of CuI was added. The slurry was maintained under argon and allowed to stir overnight, producing a dark brown solution. Thereafter, the solvent was removed under reduced pressure and 100 ml of 10% HCl was added to the residue. The residue was filtered and then extracted 3x with ethyl acetate. The combined extracts were washed lx with water, dried over anhydrous MgSO4, filtered and stripped. The resulting residue was flash chromatographed on a column of silica gel. Elution with a mixture of 30/70/2 parts ethyl acetate/hexane/acetic acid produced 3.5 g of the titled product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].C1(S(O[CH2:25][CH2:26][Cl:27])(=O)=O)C=CC=CC=1>[Na].CO>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH2:25][CH2:26][Cl:27])=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=S(=O)(OCCCl)c1ccccc1
Reactant: COC(=O)c1cc2cc(O)ccc2s1
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc2cc(OCCCl)ccc2s1
Reaction time: 8 h
Yield: 38.7 %

Procedure:
5-Hydroxybenzo[b]thiophene-2-carboxylic acid methyl ester (1.47 g.) was dissolved in a solution of sodium (0.163 g.) in methanol (15 ml.) and 2-(benzenesulphonyloxy)ethyl chloride (1.57 g.) was added. The resulting solution was heated under reflux for 8 hours and then allowed to cool and stood overnight. The solution was then evaporated and the residue was partitioned between water and ether. The aqueous layer was separated and washed several times with ether. The combined organic layer and ethereal extracts were washed with water, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 5-(2-chloroethoxy)benzo[b]thiophene-2-carboxylic acid methyl ester, (0.74 g.), m.p. 116°-117° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].C(N(CC)CC)C.[N:19]1([C:25]2[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:26]=1)=[O:6]
Reactant: Cc1ccc(C(=O)Cl)cc1I
Reactant: Nc1cccc(N2CCOCC2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1I
Temperature: 80 °C
Yield: 68.1 %

Procedure:
3-Iodo-4-methylbenzoyl chloride (Intermediate 6) (19.5 g) was added portion-wise to a mixture of triethylamine (48 ml) and 3-(4-morpholinyl)benzenamine (Intermediate 8) (12.6 g) in DMF (150 ml) and the mixture was heated at 80° C. for 16 h. The solvent was removed under vacuum and the residue was dissolved in chloroform (200 ml). The organic layer was washed with water (2×100 ml), 2M sodium hydroxide solution (100 ml) and brine (100 ml), dried over magnesium sulphate, filtered and concentrated under vacuum The resulting yellow solid was triturated with diethyl ether and collected by filtration to yield the title compound as an off-white solid (20.0 g). The product was used in subsequent reactions without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][N:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:11][C:9]1[O:10][C:6]2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=[C:2]([O:1][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][N:19]=3)[C:7]=2[CH:8]=1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cn2)c2cc(C)oc2c1
Temperature: 100 °C
Yield: 97.4 %

Procedure:
A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (500 mg, 2.27 mmol), 2-bromo-5-methanesulfonyl pyridine (590 mg, 2.57 mmol), Cs2CO3 (1.1 g, 4.12 mmol) and CuI (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via gradient silica gel chromatography on silica gel using EtOAc/Hex (10/90 to 30/70) to afford the title compound (830 mg, 88%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (t, J=7.16 Hz, 3 H) 2.48 (s, 3 H) 3.01-3.19 (m, 3 H) 4.41 (q, J=7.16 Hz, 2 H) 6.23 (d, J=0.94 Hz, 1 H) 7.02-7.18 (m, 2 H) 7.64 (d, J=1.13 Hz, 1 H) 7.85-7.96 (m, 1 H) 8.02-8.10 (m, 1 H); (ESI, pos): 376.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[Br-:6].[K+:7].[Br:8]Br>O>[Br:6][C:2]([Br:8])([C:1]#[N:5])[C:3]#[N:4].[Br-:6].[K+:7]
Reactant: N#CCC#N
Reactant: BrBr
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: N#CC(Br)(Br)C#N
Reaction time: 2 h

Procedure:
A mixture of 99 g of malononitrile and 75 g of potassium bromide in 900 ml of water was cooled to 5°-10° and 158 ml of bromine were slowly added at 5°-10° during 21/2 hours. After addition was completed, the mixture was stirred for 2 hours at 5°-10°, then was filtered. The collected solid was washed with 150 ml of ice-water and air-dried on the filter. A second crop was obtained by filtering the filtrate after a short quiescent period. The isolated solids were combined and dried to constant weight in a desiccator over phosphorus pentoxide (the presence of bromine vapors necessitated replenishing the phosphorus pentoxide) to give 337.5 g of the complex, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[CH:21][N:20]=[CH:19]1.[CH2:25]=[O:26]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[CH:21][N:20]=[C:19]1[CH2:25][OH:26]
Reactant: Cc1cncn1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: C=O
Solvent: Cc1ccccc1C
Product: Cc1cnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 2'-chloro-5-nitro(5-methylimidazol-1-yl)benzophenone is heated in a bomb with paraformaldehyde in xylene to 140° C. to give 2'-chloro-5-nitro-2-[5-methyl-2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>CN(C1C=CN=CC=1)C.ClCCl>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH:24][CH2:22][CH3:23])=[O:26])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CCN=C=O
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)NCC)cc1
Reaction time: 3 h
Yield: 49 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.40 g) obtained in Example 1d) and DMAP (0.34 g) in dichloromethane (14 ml) was added ethyl isocyanate (0.79 ml) at room temperature and the mixture was stirred for 3 hr. The reaction mixture was diluted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate), and the obtained product was recrystallized from ethyl acetate-diethyl ether to give the title compound as a white powder (0.12 g, 49%).
Reaction SMILES: O.[CH:2]1([O:7][C:8]2[C:13]([O:14][CH:15]([F:17])[F:16])=[CH:12][N:11]=[C:10](OC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:38](O)(=[O:40])C>>[CH:2]1([O:7][C:8]2[C:13]([O:14][CH:15]([F:16])[F:17])=[CH:12][N:11]=[C:10]([CH2:38][OH:40])[CH:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: FC(F)Oc1cnc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1OC1CCCC1
Reactant: CC(=O)O
Solvent: O
Product: OCc1cc(OC2CCCC2)c(OC(F)F)cn1
Temperature: 60 °C

Procedure:
Water (4 drops is added to a solution of 4-cyclopentyloxy-5-difluoromethoxy-2-trityloxypyridine (900 mg) in glacial acetic acid (20 mL) and the mixture heated at 60° C. for 18 hours. After cooling the mixture is evaporated to dryness and the residue partitioned between water and ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated to give a pale yellow solid which is purified by flash chromatography (gradient elution using n-pentane/ethyl acetate 7:3 v/v to n-pentane/ethyl acetate 2:3 v/v on silica) to give 4-cyclopentyloxy-5-difluoromethoxy-2-hydroxymethylpyridine (250 mg) as a white solid, m.p. 85-6° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([CH2:10]Br)[C:6]([CH3:12])=[C:5]([CH2:13]Br)[C:4]=1[CH3:15].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:23][C:19]1[N:18]=[C:17]([NH:16][CH2:2][C:3]2[C:8]([CH3:9])=[C:7]([CH2:10][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=3)[C:6]([CH3:12])=[C:5]([CH2:13][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=3)[C:4]=2[CH3:15])[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1c(CBr)c(C)c(CBr)c(C)c1CBr
Reactant: Nc1cccc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(CNc2cccc(N)n2)c(C)c(CNc2cccc(N)n2)c(C)c1CNc1cccc(N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A mixture of 1,3,5-tris(bromomethyl)-2,4,6-trimethyl-benzene (0.72 g, 1.8 mmol), 2,6-diamino-pyridine (1.20 g, 11 mmol), and K2CO3 (0.79 g) in CH3CN (100 mL) was stirred at room temperature for 24 h and then heated under reflux for 2 h. After filtration of the reaction mixture and evaporation of CH3CN, the obtained powder was suspended in CHCl3. The suspension was filtrated, the chloroform solution was washed several times with water, dried, and the solvent was removed under reduced pressure. The crude product was crystallized from THF/hexane. Yield 60%. M.p. 130-132° C.; 1H NMR (500 MHz, CDCl3): δ=2.38 (s, 9H), 4.01 (t, 3H, J=4.4 Hz), 4.15 (s, 6H), 4.35 (d, 6H, J=4.4 Hz), 5.81-5.84 (m, 6H), 7.24 (d, 3H). 13C NMR (125 MHz, CDCl3): δ=15.83, 41.65, 95.70, 96.81, 133.78, 136.84, 139.25, 157.68, 157.99. HR-MS calcd for C27H33N9: 483.2859; found: 483.2867.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)=[O:4].[NH2:14][CH2:15][CH2:16][OH:17]>C(Cl)Cl>[OH:17][CH2:16][CH2:15][NH:14][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
Into an ice-cooled and stirred solution of 4-methoxycarbonylbenzoyl chloride 1 (53.6 g, 0.270 mol) in methylene chloride was dropwisely added a solution of 2-aminoethanol (36.3 g, 0.594 mol) in methylene chloride (40 ml) under nitrogen during 1 hr, and the mixture was stirred for 3 hr at room temperature. The resulting precipitate was collected by vacuum filtration, washed thoroughly with water and dried in vacuo at 50° C. to give N-(2-hydroxyethyl)-4-methoxycarbonylbenzamide 2 (53.3 g, 88% yield) as white powder: 1H NMR (CD3SOCD3)δ3.45 (t of t, 2H, J=5.4 and 5.9 Hz, CH2N), 3.64 (t, 2H, J=5.9 Hz, CH2O), 3.90 (s, 3H, CH3O), 4.87 (brs, 1H, OH), 8.02 (d, 2H, J=9.3 Hz, 2,6-Ar-H), 8.05 (d, 2H, J=9.3 Hz, 3,5-Ar-H), 8.65 (t, 1H, J=5.4 Hz, NH).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[C:10]([NH:13][C:14]1[NH:18][N:17]=[C:16]([S:19](Cl)(=[O:21])=[O:20])[C:15]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:12])[CH3:11]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:10]([NH:13][C:14]1[NH:18][N:17]=[C:16]([S:19]([NH:4][C:3]2[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=2[F:9])(=[O:20])=[O:21])[C:15]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:12])[CH3:11]
Reactant: COC(=O)c1c(S(=O)(=O)Cl)n[nH]c1NC(C)=O
Reactant: Nc1c(F)cccc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1c(S(=O)(=O)Nc2c(F)cccc2F)n[nH]c1NC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
23.63 g (177.5 mmol) of 97% 2,6-difluoroaniline and 1.48 g N,N-dimethyl-4-aminopyridine was dissolved in 225 ml pyridine and 25.0 g (88.75 mmol) 5-acetamido-4-methoxycarbonylpyrazole-3-sulphonyl chloride added portionwise. The mixture was stirred for 48 hours at 25° C. The pyridine was distilled and the residue dissolved in 510 ml methylene chloride washed twice with 370 ml 5N hydrochloric acid and twice with 370 ml water, dried over magnesium sulphate and concentrated. The residue was triturated with ether, the product suction filtered, washed with ether and dried.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[Cl:31][CH2:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:31][CH2:32][CH2:33][CH2:34][S:35]([NH:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:37])=[O:36]
Reactant: CCCCCCCCCCCCCCCCOCC(CN)OC
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOCC(CNS(=O)(=O)CCCCl)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
To a solution of 3.368 g (10.22 mM) of 3-hexadecyloxy-2-methoxypropylamine IVa3 in 35 ml of dichloromethane and 1.85 ml (13.29 mM) of triethylamine is added 1.99 g (11.24 mM) of 3-chloropropanesulfonyl chloride with ice-cooling and the mixture is stirred at room temperature for 4 hours and then heated for 30 minutes with stirring. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (3:1) mixture as an eluent. The product is recrystallized form methanol to give 4.15 g (8.827 mM) of 3-(3-chloropropylsulfonylamino)-1-hexadecyloxy-2-methoxypropane IIIa3 as a colorless powder in 86% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25](=[O:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[O:11][N:10]=[C:9]([CH3:20])[C:8]=3[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=2)=[CH:29][CH:28]=1)[CH3:23]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)(C)C)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[C:6]([C:19]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=2[I:33])[C:26]([O:28][CH3:29])=[O:27])=O)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[Br-].[CH3:35]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[I:33][C:32]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:22][CH:21]=[C:19]([C:6]1[C:5]([CH3:4])=[CH:14][C:13]2[C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:17])([CH3:18])[C:8]=2[CH:7]=1)[CH3:35]
Reactant: COC(=O)c1ccc(I)c(OCC(=O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)c(OC=C(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1

Procedure:
Sodium methoxide (0.62 ml, 3.17 mmol) is added over 8 hours to a mixture of methyl 3-(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl-methyloxy)-4-iodobenzoate (1.6 g, 3.1 mmol) and methyltriphenylphosphine bromide (1.51 g, 4.2 mmol) in THF (15 ml).
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:15](=[O:17])[N:14]([CH2:18][C:19]4[N:28]=[C:27]([CH3:29])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[C:13]4=[N:30][CH2:31][CH2:32][N:12]4[C:11]=3[N:10]=[CH:9]2)=CC=1.C1C(=O)N([Br:42])C(=O)C1>CC#N>[Br:42][C:9]1[NH:8][C:16]2[C:15](=[O:17])[N:14]([CH2:18][C:19]3[N:28]=[C:27]([CH3:29])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[C:13]3=[N:30][CH2:31][CH2:32][N:12]3[C:11]=2[N:10]=1
Reactant: COc1ccc(Cn2cnc3c2C(=O)N(Cc2nc(C)c4ccccc4n2)C2=NCCN23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1nc(CN2C(=O)c3[nH]c(Br)nc3N3CCN=C23)nc2ccccc12
Reaction time: 1.5 h

Procedure:
To 5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 13 (386 mg, 1.16 mmol) in CH3CN (10 ml) was added NBS (268 mg, 1.51 mmol) at 0° C., stirred for 1.5 hr. Another 41 mg of NBS was added, stirred for 30 minutes. The reaction was quenched by adding water (15 ml), washed with DCM (2×15 ml). The organic phase was washed with HCl (1 M, 10 ml). The combined aqueous phase was concentrated and purified by flash chromatography (MeOHIDCM, MeOH contains 1% Et3N) to afford 2-bromo-5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 14.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.O.[NH2:10][NH2:11]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:10][NH2:11])[CH2:4][CH2:3]1
Reactant: NN
Reactant: CN1CCC(=O)CC1
Solvent: CO
Solvent: O
Product: CN1CCC(=NN)CC1

Procedure:
1-Methyl-piperidin-4-one (22.6 g, 0.2 mol) and methanol (200 mL) were charged to a 500 mL three-necked flask fitted with an addition funnel. The vessel was cooled in an ice bath and kept under a nitrogen atmosphere while a solution of hydrazine monohydrate (5 g, 0.1 mol) in 50 mL of methanol was added drop-wise over a period of one hour. A white precipitate formed after about half of the hydrazine was added. Stirring was continued overnight, and subsequent TLC indicated one product. The methanol was removed in vacuo, and the residue was slurried in hexane and filtered to provide N,N′-bis-(1-methyl-piperidin-4-ylidene)-hydrazine. 1H NMR (300 MHz, CDCl3)δ(ppm): 2.6 (m, 8H), 2.5 (m, 8H), 2.33 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([C:10]([C:12]1[CH:16]=[C:15]([Cl:17])[O:14][N:13]=1)=O)=[CH:6][N:7](C)C)[CH3:2].Cl.[C:20]([NH:24]N)([CH3:23])([CH3:22])[CH3:21].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][N:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=1[C:12]1[CH:16]=[C:15]([Cl:17])[O:14][N:13]=1)=[O:18])[CH3:2]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)on1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1-c1cc(Cl)on1
Temperature: 90 °C
Yield: 20960.6 %

Procedure:
A solution of 2-(5-chloro-isoxazole-3-carbonyl)-3-dimethylamino-acrylic acid ethyl ester (294.8 mg, 1.08 mmol) in absolute ethanol (1.4 mL, 0.77M) was treated with tert-butylhydrazine hydrochloride (137.3 mg, 1.10 mmol) and sodium acetate (108.6 mg, 1.32 mmol). The resulting mixture was heated to 90° C. overnight. At this time, the reaction was cooled to 25° C. and was concentrated in vacuo. The reaction was partitioned between water (200 mL) and dichloromethane (2×50 mL). The combined organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Biotage chromatography (40S column 60% ethyl acetate/hexanes) followed by ISCO CombiFlash (4 g column 0-20% ethyl acetate/hexanes) afforded 1-tert-butyl-5-(5-chloro-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (67.4 g, 21%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(COC)OC>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]2[CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:1]=[C:2]2[CH:11]=1
Reactant: COc1ccc2c(Cl)cc(N)nc2c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(cc(Cl)c3ccc(OC)cc32)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 g of 2-amino-4-chloro-7-methoxyquinoline were dissolved in 20 ml of dimethoxyethane and 1.3 g of ethyl bromopyruvate were added thereto. The mixture was stirred at room temperature for 2 hours and the crystalline intermediate thus formed was filtered off, washed with ether and then was dissolved in 20 ml of ethanol. The resultant solution was refluxed for 3 hours and ethyl 5-chloro-8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 215°-216° C. was isolated by the procedure of Example 9.