Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:27][C:22]1[CH:21]=[C:20]([C@H:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH:8]([NH2:7])[CH3:9])[CH2:19]2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(NC(=O)OC(C)(C)C)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of tert-butyl-1-((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2-yl)ethylcarbamate 49b (100 mg, 0.24 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The reaction mixture was stirred for 2 h before being concentrated. The residue was subjected reverse phase column chromatography (CH3CN/H2O/0.1% Formic acid=5% to 100%) to give 1-((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2-yl)ethanamine 45 (65 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.0 Hz, 1 H), 7.23 (d, J=2.4 Hz, 1 H), 7.19 (d, J=7.2 Hz, 1 H), 7.14-7.08 (m, 2 H), 6.98 (dd, J=2.4, 8.4 Hz, 1H), 6.82 (d, J=7.2 Hz, 1 H), 6.46 (s, 1 H), 4.08 (t, J=8.4 Hz, 1 H), 3.61 (q, J=6.4 Hz, 1 H), 2.69 (dd, J=7.6, 16.8 Hz, 1 H), 2.46 (dd, J=8.8, 16.8 Hz, 1 H), 2.10 (broad, 2 H), 1.14 (d, J=8.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 144.75, 143.04, 136.16, 134.41, 132.52, 130.53, 130.41, 127.96, 127.80, 127.62, 127.52, 126.80, 121.07, 52.17, 43.68, 32.41, 21.53; ESI MS m/z 318.0.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]([C:12]([OH:14])=O)[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C([Cl:18])=O>CCOCC>[CH2:1]([C:9]1[CH:10]([C:12]([Cl:18])=[O:14])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCC1=CC1C(=O)O
Solvent: CCOCC
Product: CCCCCCCCC1=CC1C(=O)Cl
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of 2-octylcycloprop-2-ene-1-carboxylic acid (350 mg, 1.8 mmol) in ether was treated with 0.45 g (3.5 mmol) of oxalyl chloride at room temperature. The reaction mixture was stirred for one hour then stripped to give 330 mg of 2-octylcycloprop-2-ene-1-carbonyl chloride.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28](OC(C)(C)C)[CH2:27][C:26]3=C=O)=[CH:21][CH:20]=2)[C:15](=C=O)[CH2:14]1)(C)(C)C>C(Cl)Cl>[N:16]1([C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[CH2:15][CH2:14][NH:13][CH2:18][CH2:17]1
Reactant: CC(C)(C)ON1CCN(c2ccc(N3CCN(OC(C)(C)C)CC3=C=O)cc2)C(=C=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(N2CCNCC2)ccc1N1CCNCC1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution in methylene chloride (1 ml) of 1,4-bis(4-tert-butoxy-carbonyl-1-piperazinyl)benzene (59 mg; 0.13 mmol) synthesized by the above process under ice cooling, and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the resultant concentrated residue (81 mg) was dissolved in methanol-chloroform (1:2). The solution was applied to a column packed with alumina (3 g), and the column was eluted with methanol-chloroform (1:2). The eluate was concentrated under reduced pressure, thereby obtaining 31 mg (yield: 88%) of the title compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>CN(C)C=O>[CH2:25]([NH:28][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1)[CH2:26][CH3:27]
Reactant: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCCN
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)no1
Yield: 73.4 %

Procedure:
1.4 g (4 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature for 1 hour with 5.2 g (90 mmol) of propylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.07 g (73%) of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a]-[1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][C:13](=[O:16])[C:12]=2[CH:17]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13](=[O:16])[C:12]=2[CH:17]=1
Reactant: O=C1COc2ccc(Br)cc21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1Oc2ccc(Br)cc2C1=O

Procedure:
Potassium carbonate (1.66 g, 12 mmol) is added to a solution of 5-bromo-1-benzofuran-3(2H)-one (2.13 g, 10 mmol) in acetone (25 mL). The stirred mixture is treated dropwise with ethyl chloroformate (1.05 mL, 11 mmol). The mixture is then heated at reflux for 18 h. The solids are filtered off and the filtrate concentrated in vacuo. The residue is partitioned between EtOAc and saturated aqueous NaHCO3. The layers are separated and the organic layer washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[S:40][CH:41]=[C:42]([C:44]([NH:46][CH:47]2[CH2:49][CH2:48]2)=[O:45])[N:43]=1>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>[CH:47]1([NH:46][C:44]([C:42]2[N:43]=[C:39]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:7]5[O:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:9][N:8]=5)[CH:11]=4)[NH:15][CH:14]=3)[S:40][CH:41]=2)=[O:45])[CH2:48][CH2:49]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: O=C(NC1CC1)c1csc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(-c4nc(C(=O)NC5CC5)cs4)c3c2)o1
Yield: 29.9 %

Procedure:
The title compound (34 mg, 30% yield) as a yellow crystalline solid was prepared according to Example 275, using N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (145 mg, 0.278 mmol), 2-bromo-N-cyclopropylthiazole-4-carboxamide (75 mg, 0.305 mmol), and Pd(PPh3)4 (Strem Chemicals, 16 mg) as the starting materials and reagent. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (1H, br.), 8.57 (1H, s), 8.29 (2H, m), 8.15 (1H, s), 7.74 (1H, d, J=7.4 Hz), 7.65 (2H, d, J=8.6 Hz), 3.77 (1H, m), 2.90 (1H, m), 1.25 (6H, d, J=6.1 Hz), 0.75 (2H, m.), 0.69 (2H, m). MS (ESI, pos. ion) m/z 409.1 (M+H)+.
Reaction SMILES: Cl.Cl.CO[C:5]1[CH:10]=[C:9]([NH2:11])[C:8](C)=[CH:7][C:6]=1[NH2:13].N.N[C:16]1[C:17](C)=[C:18]([OH:23])[C:19](C)=[CH:20][CH:21]=1.OO>O>[CH:16]1[C:21](=[N:13][C:6]2[CH:5]=[CH:10][C:9]([NH2:11])=[CH:8][CH:7]=2)[CH:20]=[CH:19][C:18](=[O:23])[CH:17]=1
Reactant: COc1cc(N)c(C)cc1N
Reactant: Cc1ccc(N)c(C)c1O
Agent: Cl
Agent: N
Agent: OO
Solvent: O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Reaction time: 4 h
Yield: 78.2 %

Procedure:
0.2 mole (4.5 g) 2-methoxy-5-methyl paraphenylenediamine dihydrochloride is dissolved in 200 cc water and the pH thereof is adjusted to 8 by the addition thereto of ammonia. This solution is immediately added to 0.02 mole (2.74 g) 3-amino-2,6-dimethyl phenol, previously dissolved in 200 cc water. To the resulting mixture there are added 60 cc ammonia 22° Be and 260 cc hydrogen peroxide to make 20 volumes. The mixture is allowed to stand at room temperature for four hours. On filtering the reaction mixture on a suction filter, then are obtained 3.1 g of said indoaniline in crystalline form, which after recrystallization from a mixture of pyridine and water, exhibits a melting point of 145°.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][C:6]1([CH3:19])[CH3:18])(=[O:3])[CH3:2]>CO.[H][H].[OH-].[OH-].[Pd+2]>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][C:6]1([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NC1CCN(Cc2ccccc2)CC1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC1CCNCC1(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 4-acetylamino-1-benzyl-3,3-dimethyl piperidine (1.8 g, 6.92 mmol) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) at 35° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-acetylamino-3,3-dimethylpiperidine. Yield 1.0 g (90%), C9H18N2O, m/z 171 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[C:10]([O:14][C:15](=[O:28])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C)C=O>[C:10]([O:14][C:15](=[O:28])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=2)=[C:21]([O:26][CH3:27])[CH:20]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: Fc1cccc(CCl)c1
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CCNC(=O)OC(C)(C)C)ccc1OCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
34.6 g (0.23 mol) of 1-chloromethyl-3-fluoro-benzene in 50 ml of dry dimethylformamide were added to a suspension of 55.9 g (0.209 mol) of [2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester, 43 g of K2CO3 and 3.4 g of potassium iodide in 400 ml of dry dimethylformamide. The reaction was stirred at room temperature overnight. Solvent was removed, water was added to the residue and the product was extracted with ethyl acetate. The crude oil obtained was triturated with diethyl ether. The solid was filtered and 58.2 g (74% yield) of the title product were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][CH:20]([F:31])[O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH:20]([F:31])[F:19])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-difluoromethoxy-pyridine-2-carboxylic acid (CAS1174323-34-2, WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=431.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][NH:11][CH2:10][NH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][NH:11][CH2:10][NH:9][C:8]2=[S:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NCNCC1(c1ccccc1)c1ccccn1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: S=C1NCNCC1(c1ccccc1)c1ccccn1

Procedure:
Treatment of 1,2,3,6-tetrahydro-5-phenyl-5-(2-pyridyl)-4(5H)-pyrimidinone with phosphorus pentasulfide as described in the procedure of Example 1 gives 1,2,3,6-tetrahydro-5-phenyl-5(2-pyridyl)-4(5H)-pyrimidinethione.
Reaction SMILES: N.ClC1[N:4]=CN(C2C=CC(N=C=S)=CC=2OC)C=1.[Cl:19][C:20]1[N:24]=[CH:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[CH:27][C:26]=2[O:34][CH3:35])[N:21]=1>>[Cl:19][C:20]1[N:24]=[CH:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:4])=[S:33])=[CH:27][C:26]=2[O:34][CH3:35])[N:21]=1
Reactant: COc1cc(N=C=S)ccc1-n1cnc(Cl)c1
Reactant: COc1cc(N=C=S)ccc1-n1cnc(Cl)n1
Agent: N
Product: COc1cc(NC(N)=S)ccc1-n1cnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
Step E (5): Methanolic ammonia (1.0 M, 25 mL, 25 mmol) was added to a flask charged with 3-chloro-1-(4-isothiocyanato-2-methoxyphenyl)-1H-1,2,4-triazole 4-chloro-1-(4-isothiocyanato-2-methoxy-phenyl)-1H-imidazole (525 mg, 1.968 mmol) in a ice-water bath. After the addition was complete, the resulting slurry was stirred for 10 min and then allowed to warm to rt. After 24 h, the reaction mixture was concentrated to dryness in vacuo to afford 1-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)thiourea (560 mg, 100% yield) as a white solid. LC-MS (M+H)+ 284.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:21].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[O:21])=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccccc1Sc1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(c1ccc(Cl)nc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
2-Chloro-5-[(2-fluorophenyl)thio]pyridine (Example 1 Step 1, 1.0 g, 4.17 mmol) was taken up in dichloromethane (20 mL) and 3-chloroperoxybenzoic acid (50%; 1.44 g, 4.17 mmol). The reaction was stirred at room temperature under nitrogen for 1 hour. 4N sodium hydroxide solution was added and the products extracted into dichloromethane (×2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using toluene followed by 10% ethyl acetate/toluene gave 2-chloro-5-[(2-fluorophenyl)sulfinyl]pyridine (0.65 g, 61%). δH (500 MHz, d6 DMSO) 8.71 (1H, s), 8.07 (1H, d, J 8.2), 7.83 (1H, t, J 6.7), 7.68 (1H, d, J 8.2), 7.63-7.59 (1H, m), 7.46 (1H, t, J 7.3), 7.33 (1H, t, J 9.1); m/z (ES+) 256, 258 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14]C2CCCCO2)[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].CCCCCC>CCO>[Br:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: O=Cc1ccc(OC2CCCCO2)cc1OCc1ccccc1Br
Solvent: CCO
Solvent: CCCCCC
Product: O=Cc1ccc(O)cc1OCc1ccccc1Br
Reaction time: 1 h
Yield: 109.4 %

Procedure:
2-(2-Bromobenzyloxy)-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (4.4 g) obtained in step 1) was dissolved in a mixture of 10% HCL (30 mL) and EtOH (20 mL), followed by stirring for 1 hour and extraction with ethyl acetate. The extract was dried over MgSO4 and concentrated. The solid thus formed was cleansed with hexane to afford the object compound (3.78 g, 91%).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[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][C:16]([OH:18])=[O:17].C(O[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O>CCCCCCCC>[CH2:24]([O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)CCCCCCCCCCCCCCC(=O)O
Reactant: O=COCc1ccccc1
Solvent: CCCCCCCC
Product: O=C(O)CCCCCCCCCCCCCCC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 50 h

Procedure:
Hexadecanedioic acid (20.0 g, 69.8 mmol) and DowexR were suspended in n-octane and heated to reflux. Benzyl formate (22.0 g, 162 mmol) was added. After 6 hours additional benzyl formate (22.0 g, 162 mmol) was added. The heating was continued for 50 hours. The reaction mixture was filtered at 80° C. The filtrate was cooled to 20° C., and the precipitate was collected by filtration. The crude product (20.2 g) was suspended in dichloromethane (220 ml) at 20° C. for 4 hours. The suspension was filtered, and the filtrate was evacuated to dryness at 20-30° C. The resulting solid (13.9 g) was recrystallised from 2-propanol (140 ml). The product was isolated by filtration, and dried to constant weight under reduced pressure at 30-40° C. Yield: 10.2 g (39%) of white material.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]2[CH:23]=1)[CH2:11][C:12]#[CH:13]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([CH:23]=[C:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:18]=1
Reactant: C#CCCc1cn2cc(F)ccc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCc2cn3cc(F)ccc3n2)n1

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (220 mg, 1.10 mol) and 2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (220 mg, 1.14 mmol). The crude residue was purified over C18 chromatography (prepacked 35 g silicagel column, H2O/CH3CN: from 95/5 to 55/45 as eluent) to afford 155 mg of 6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine (Yield: 46%) as a white powder (Mp=140-141.8° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1.[Br:25]N1C(=O)CCC1=O>C(#N)C.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[C:6]=1[Br:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a stirred solution of (4-benzyloxy-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (350 mg, 1.08 mmol) in acetonitrile (10 mL) was added N-bromosuccinimide (385 mg, 2.16 mmol). After being stirred at room temperature for 1 hour, the resulting mixture was diluted with water (20 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (15 mL) and brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 0-20% ethyl acetate in hexanes) to afford (4-benzyloxy-1-bromo-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (400 mg, 92%) as a white solid.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][OH:9]>C(Cl)(Cl)Cl.O>[O:9]1[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH3:7])[CH2:8]1
Reactant: CO
Reactant: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCC1CO1

Procedure:
To a solution of 0.50 g of sixth generation PAMAM in 5 ml of methanol was added 0.56 g of epoxyoctane. After 6 days at room temperature, the solvent was evaporated in vacuo to give 0.80 g of colorless oil. The material was soluble in chloroform, toluene or methanol, but not soluble in water. The 13C-NMR spectrum was in accord with a dendrimer with C-8 alkyl groups attached to its terminal amines.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][OH:12])[CH:7]=[C:8]([F:10])[CH:9]=1.[CH3:13]I>CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][O:12][CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CI
Reactant: OCc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
NaH (60% dispersion in mineral oil, 245 mg, 6.12 mmol) was added to a solution of (3-bromo-5-fluorophenyl)methanol (1.195 g, 5.83 mmol) in 2-Me THF (20 mL). After gas evolution had ceased, MeI (0.455 mL, 7.29 mmol) was added and the resulting mixture was stirred at r.t. for 16 h. Another portion of NaH (50 mg, 2.1 mmol) and MeI (0.10 mL, 1.6 mmol) were added and the mixture was heated to 60° C. for 2 h. The cooled mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (gradient of 0-15% EtOAc in heptane) to give 0.810 g (63% yield) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (s, 3 H), 4.38-4.46 (m, 2 H), 7.18 (m, 1 H), 7.37 (s, 1 H), 7.44-7.50 (m, 1 H); MS (EI) m/z 218 M+.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:6]2)[NH2:2].[F:20][CH:21]([F:27])[C:22](OCC)=O.FC(F)C(O)=O.O>CN1C(=O)N(C)CC1>[F:20][CH:21]([F:27])[C:22]1[N:4]2[C:5]3[CH:6]=[C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]2=[N:1][N:2]=1
Reactant: CCOC(=O)C(F)F
Reactant: NNc1ccc2[nH]c(=O)c(-c3ccccc3)cc2n1
Agent: O=C(O)C(F)F
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=c1[nH]c2ccc3nnc(C(F)F)n3c2cc1-c1ccccc1
Temperature: 200 °C

Procedure:
A mixture of 6-hydrazino-3-phenyl-1,5-naphthyridin-2(1H)-one (7-2) (21 g, 83 mmol), ethyl difluoroacetate (31 g, 250 mmol), and difluoroacetic acid (200 mg, 2.08 mmol) in DMI (100 mL) was heated under microwave irradiation at 200° C. for 1 h. To the cooled mixture was added water, and the resulting solid was collected by filtration to give 1-(difluoromethyl)-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridin-7(6H)-one (10-1) as pale yellow solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)#[N:20].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:18][C@H:15]2[CH2:14][CH2:13][C@H:12]([C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[O:11])[CH2:17][CH2:16]2)=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@@H](O)CC2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C#N)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 1.0 g (3.93 mmol) of cis-(4-isopropyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone, 0.515 g (4.3 mmol) of 4-cyanophenol, 1.28 g (4.88 mmol) of triphenylphisphine in 6 ml THF, 1.11 g (4.82 mmol) of di-tert-butyl azodicarboxylate in 6 ml of THF was added at 0° C., and stirred for 72 hr at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with cyclohexane and ethyl acetate=from 1:1 to 1:3, then dichloromethane and methanol=19:1. The combined product fractions were evaporated to dryness to yield 0.26 g (19% yields) of the titled compound. MS (m/e): 356.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:12])=[C:6]([CH:8]=[CH:9][C:10]=1[CH3:11])[NH2:7])([O-:3])=[O:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:1]([C:4]1[C:5]([CH3:12])=[C:6]([NH:7][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=[CH:9][C:10]=1[CH3:11])([O-:3])=[O:2]
Reactant: Cc1ccc(N)c(C)c1[N+](=O)[O-]
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Nc2ccccn2)c(C)c1[N+](=O)[O-]
Temperature: 20 °C
Yield: 41.4 %

Procedure:
3.3 g of 3-Nitro-2,4-dimethylaniline and 3.2 g of 2-bromo-pyridine are mixed and the resulting mixture heated for 8 hours to 170° C. After cooling to 20° C., the greasy mass formed was dissolved in water and the solution pH then raised by addition of sodium carbonate. The resulting precipitate was recrystallized from ethanol. 2 g of the product melting at 178° to 179° C. were obtained. Another 2.1 g of the substance were obtained from the aqueous phase by concentration.