Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[N:16]=[C:17]([CH3:20])[S:18][CH:19]=3)[CH:10]=2)[N:3]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].C(N(C(C)C)CC)(C)C.Cl>C1COCC1.CO.O1CCOCC1.CCOCC>[ClH:1].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[N:16]=[C:17]([CH3:20])[S:18][CH:19]=3)[CH:10]=2)[N:3]=1
Reactant: CN(C)CCCN
Reactant: Cc1nc(-c2cccc(Nc3nccc(Cl)n3)c2)cs1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(Nc3nccc(NCCCN(C)C)n3)c2)cs1
Temperature: 25 °C

Procedure:
4-chloro-N-(3-(2-methylthiazol-4-yl)phenyl)pyrimidin-2-amine, 12, (400 mg, 1.30 mmol), N1,N1-dimethylpropane-1,3-diamine (0.25 mL, 2.0 mmol), and diisopropylethylamine (0.46 mL, 2.6 mmol) are dissolved in THF (10 mL) and heated to reflux for 20 hours. The reaction is cooled to room temperature and partitioned between EtOAc and water. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (5% MeOH ramped to 6% MeOH in CH2Cl2 with 0.7% added triethylamine) to give an oil. The oil is dissolved in MeOH (0.5 mL) and Et2O (20 mL) and cooled to 0° C. To this solution is added a solution of 4M HCl in dioxane (0.25 mL) in one portion. The white precipitate which forms is collected by filtration and dried at reduced pressure to afford the desired compound as a white solid: 1H NMR (CD3OD, 300 MHz) δ 2.03-2.08 (m, 2H), 2.79 (s, 6H), 2.80 (s, 3H), 3.10-3.15 (m, 2H), 3.65 (t, J=6.6 Hz, 2H), 6.30 (d, J=7.5 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.70 (d. J=7.5 Hz, 1H), 7.77 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 8.19 (s, 1H); HRMS calcd for C19H24N6S, 369.1861 m/z (M+H)+; observed 369.1855 m/z.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].C([Li])(C)(C)C.[CH3:11][O:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19]>C1COCC1>[CH2:1]([O:3][C:4]([C:18]([OH:20])([CH3:19])[CH2:17][CH2:16][CH2:15][O:14][CH2:13][O:12][CH3:11])=[CH2:5])[CH3:2]
Reactant: COCOCCCC(C)=O
Reactant: C=COCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=C(OCC)C(C)(O)CCCOCOC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl vinyl ether (19.47 g, 270 mmol) in THF was added 106 mL of tert-butyl lithium (1.7 M, 180 mmol) dropwise at −78° C. The solution was warmed to 0° C. with an ice bath, stirred for another one hour and then re-cooled to −78° C. To this lithiated enol ether was added dropwise a solution of 5-methoxymethoxy-2-pentanone (13.16 g 90 mmol) in 10 mL of THF. The resulting mixture was stirred for one hour at −78° C. and one and a half hour at 0° C., and then slowly warmed up to room temperature. The reaction mixture was quenched with 70 mL of saturated NH4Cl aq. The organic layer was separated and the aqueous layer was extracted with 3×100 mL of diethyl ether. The combined organic layer was dried over Na2SO4 and concentrated via rotary evaporation to afford 2-ethoxy-3-hydroxy-6-methoxymethoxy-3-methyl-1-hexene in quantitative yield (19.4 g). The crude product was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1C=CC=CC=1>[C:1]1([CH2:7][C:8](=[O:13])[CH:9]([C:24](=[O:25])[NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:26])=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CC(=O)CC(=O)Cc1ccccc1
Solvent: c1ccccc1
Product: CC(=O)C(C(=O)Cc1ccccc1)C(=O)NS(=O)(=O)c1ccc(C)cc1

Procedure:
Reaction of equimolar amounts of 1-phenyl-2,4-pentanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 1-PHENYL-3-(N-p-TOLUENESULFONYLCARBAMOYL)-2,4-PENTANEDIONE, m.p. 119.5°-120.5° C. (corr.).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23](=O)[CH2:22]1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:23]3[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:21][CH2:22]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: O=C1COc2ccccc21
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3COc4ccccc43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 2,3-dihydrobenzofuran-3-one using decaborane yielded a mixture of epimers of the title compound as a colorless waxy solid. MS (ESI): m/z=397.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 1.16 g, 26.5 mmol) in THF (30 mL) was added a solution of [3-(4-chloro-phenyl)-isoxazol-4-yl]-methanol (24.1 mmol) in THF (60 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (4.65 g, 26.5 mmol) in THF (60 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=4:1 to 2:1) afforded 6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72%) which was obtained as a light yellow solid. To a suspension of 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.0 mmol) in THF (3 mL) and methanol (3 mL) was added a solution of lithium hydroxide monohydrate (85.1 mg, 2.0 mmol) in water (3 mL) and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (1 N, 30 mL) and the resulting mixture was filtered. The solid was dried to afford the title compound (100%) which was obtained as a light yellow solid. MS: m/e=331.1 [M−H]−.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7].CS(O)(=O)=O>C1COCC1>[CH3:3][C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][OH:7]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: CS(=O)(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(CO)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 ml of THF and 76.5 gm NaBH4 was stirred for 30 min. at ambient temperature. Solution of 2-Methyl-3-nitro benzoic acid in THF (250 g in 750 ml) was added and stirred for 0.5 hour at ambient temperature. Further, methanesulphonic acid (90 ml) was added to the reaction mixture and stirred until the completion of reaction. The reaction mixture is extracted with ethyl acetate by addition of Hydrochloric acid and product organic layer is separated out. Ethyl acetate is evaporated to give 2-Methyl-3-nitrobenzyl alcohol as yellow oil, which is further treated with cyclohexane and crystallized to give 2-Methyl-3-nitrobenzyl alcohol (Yield: ˜210 g., 84%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19][CH2:20][CH3:21])=[CH2:18])CCC>O1CCOCC1.CCOC(C)=O.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>[CH2:20]([O:19][C:17]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[CH2:18])[CH3:21]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=C(OCC)c1ccc(C(=O)OC)nc1
Yield: 84.9 %

Procedure:
To a solution of methyl 5-bromopyridine-2-carboxylate (25 g, 116 mmol) in dioxane (30 mL) was added Pd(PPh3)4 (6.7 g, 5.8 mmol) and tributyl(1-ethoxyvinyl)tin (46 g, 127.0 mmol). The resulting solution was heated to reflux under N2 for 12 h. Upon completion of the reaction as judged by LC/MS analysis, the reaction was diluted with EtOAc, washed with KF solution (10% aqueous), filtered through Celite, dried over MgSO4, filtered, concentrated and purified on silica gel to afford the title compound (20.4 g). LC/MS: m/e 208.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][N:7]=[C:8]([C:10]1[C:19]2[C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:16](Cl)=[C:15]([C:24]([OH:26])=[O:25])[C:14]=2[C:13]([C:27](=[N:29][NH:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[OH:28])=[CH:12][C:11]=1Cl)[OH:9].[NH2:39][CH2:40][CH2:41][CH2:42][OH:43]>>[CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][CH2:5][NH:6][N:7]=[C:8]([C:10]1[C:19]2[C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:16]([NH:39][CH2:40][CH2:41][CH2:42][OH:43])=[C:15]([C:24]([OH:26])=[O:25])[C:14]=2[C:13]([C:27](=[N:29][NH:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[OH:28])=[CH:12][C:11]=1[NH:39][CH2:40][CH2:41][CH2:42][OH:43])[OH:9]
Reactant: NCCCO
Reactant: CN(C)CCCNN=C(O)c1cc(Cl)c(C(O)=NNCCCN(C)C)c2c(C(=O)O)cc(Cl)c(C(=O)O)c12
Product: CN(C)CCCNN=C(O)c1cc(NCCCO)c(C(O)=NNCCCN(C)C)c2c(C(=O)O)cc(NCCCO)c(C(=O)O)c12

Procedure:
Compound 7 (45 mg, 0.089 mmol) was suspended in 3-amino-propanol (0.5 ml) in a microwave reaction vessel. The tube was flushed with nitrogen, sealed and treated at 150° C. for 10 min in the microwave. The mixture was then diluted down with water (25 ml), basified with 2M sodium carbonate and extracted with chloroform (5×5 ml). The organics were treated in the usual manner to afford a blue solid. The crude product was purified by HPLC to obtain 9 as a blue solid. Yield 9 (4.13 mg, 0.0071 mmol, 7.9%): 1H NMR (MeOD) δ: 1.98-2.07(m, 8H), 2.61(s, 12H), 2.84(m, 4H), 3.53(t, 4H, J=6.9 Hz), 3.84(t, 4H, J=6.0 Hz), 4.09(t, 4H, J=7.1 Hz), 7.68(s, 2H); 13C NMR (MeOD) δ: 25.98(2×CH2), 33.15(2×CH2), 39.15(2×CH2), 41.29(2×CH2), 44.71(4×CH3), 57.66(2×CH2), 60.63(2×CH2), 102.06(2×C), 118.41(2×CH), 121.52(2×C), 126.06(2×C), 146.49(2×C), 163.80(2×C═O), 166.72(2×C═O); HRMS (ES+) calcd C30H42N6O6 [M+H]+ 583.3239. Found: 583.3260.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:6][C:7]=1Cl.[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C(=O)([O-])[O-].[K+].[K+].C(O)CCO.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[OH-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[S:23]1[CH:27]=[CH:26][C:25]([C:2]2[N:3]=[CH:4][C:5]([N:9]3[CH2:14][C@@H:13]4[CH2:15][C@H:10]3[CH2:11][N:12]4[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:6][CH:7]=2)=[CH:24]1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cnc(Br)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: OCCCO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cnc(-c2ccsc2)cn1

Procedure:
A mixture of 2-[5-bromo-6-chloro-2-pyrazinyl]-(1S,4S)-5-tert-butoxycarbonyl-2,5-diazabicyclo-[2.2.1]-heptane (4.0 g, 10.3 mmol), 3-thiophene boronic acid, aqueous potassium carbonate (15.4 ml, 2 M), 1,3-propandiol (2.34 g, 30.8 mmol), palladacycle (96 mg, 0.10 mmol), tri-tert-butylphosphine (83 mg, 0.41 mmol), palladium acetate (46 mg, 0.20 mmol) and dioxane (40 ml) was stirred at reflux for 5 days. Aqueous sodium hydroxide (50 ml, 1 M) was added and the mixture was extracted with ethyl acetate (2×30 ml). Chromatography on silica gel with ethyl acetate and petroleum (1:1) gave the title compound as an oil. Yield 1.46 g (41%). This single step also includes 6-dechlorination.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].Cl[CH2:24][C:25]#[N:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:22][CH2:24][C:25]#[N:26]
Reactant: N#CCCl
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Product: N#CCOc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (50.0 mg, 0.16 mmol) was alkylated with chloroacetonitrile (24.6 μL, 29.4 mg, 0.39 mmol) as described in Example 47, affording[2-fluoro-5-(7-trifluoromethyl[1,8]-naphthyridin-4-yl)phenoxy]acetonitrile (33.4 mg, 59%). δH (400 MHz, CDCl3) 4.94 (2H, s), 7.23-7.29 (2H, m), 7.40 (1H, dd, J 8.2 and 10.6), 7.56 (1H, d, J 4.3), 7.85 (1H, d, J 8.6), 8.53 (1H, d, J 8.6), 9.28 (1H, d, J 4.7). m/z (ES+) 348 [MH]+.
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])OCC.[CH3:20][O:21][C:22]([O:27][CH3:28])([CH3:26])[C:23](=[O:25])[CH3:24].C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:18]([O:17][CH:10]([O:14][CH2:15][CH3:16])[CH2:24][C:23](=[O:25])[C:22]([O:27][CH3:28])([O:21][CH3:20])[CH3:26])[CH3:19]
Reactant: COC(C)(OC)C(C)=O
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(CC(=O)C(C)(OC)OC)OCC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 119.5 %

Procedure:
Boron trifluoride diethyl etherate (17.03 g, 120.0 mmol) was added dropwise over 15 min to a cooled (−40° C.) solution of triethyl orthoformate (14.82 g, 100.0 mmol) in dichloromethane (150 ml). Stirring was continued for 10 min then the solution was transferred to an ice-water bath and stirred at 0° C. for 20 min. The mixture was cooled to −78° C. and 3,3-dimethoxybutan-2-one (6.61 g, 50.0 mmol) was added followed by dropwise addition of N,N-diisopropylethylamine (19.39 g, 150.0 mmol) over 15 min. After stirring at −78° C. for 15 min the reaction was allowed to reach ambient temperature before pouring the resulting orange solution into a mixture of saturated sodium hydrogencarbonate solution (500 ml) and dichloromethane (200 ml). This mixture was vigorously stirred for 15 min, the organic phase was separated, washed with ice-cold 1M sulphuric acid solution (2×300 ml), ice-cold water (2×300 ml), dried over anhydrous magnesium sulfate and concentrated to give crude 1,1-diethoxy-4,4-dimethoxypentan-3-one (14 g, >100%) as an orange oil: δH (360 MHz, CDCl3) 1.18 (6H, t, J 7), 1.36 (3H, s), 2.93 (1H, d, J 6), 3.23 (3H, s), 3.25 (3H, s), 3.51-3.73 (4H, m), 5.03 (1H, t, J 6).
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:34]([CH3:38])[C:35](=[O:37])[CH3:36]>C(#N)C>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:34]([CH3:38])[C:35](=[O:37])[CH3:36])[CH2:20][CH2:21]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: CC(=O)C(C)Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(C)C(C)=O)CC2)CC1
Yield: 88.6 %

Procedure:
To a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (610 mg) in acetonitrile (30 ml) are added potassium carbonate (80 mg) and 3-chloro-2-butanone (220 mg), and the mixture is heated under reflux for 16 hours, and concentrated to dryness under reduced pressure. The residue is dissolved in chloroform, and the mixture is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform:methanol=15:1) to give the desired compound (640 mg) as a yellow oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[F:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(F)cnc1Oc1cccc(F)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Oc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(3-fluorophenoxy)nicotinic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.33 (1H, dd, J=8.2, 3.1 Hz), 8.12–7.98 (4H, m), 7.47–7.38 (3H, m), 7.05–6.89 (3H, m), 5.36 (1H, m), 3.90 (3H, s), 1.60 (3H, d, J=6.9 Hz).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(CCBr)c1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3cccc(Cl)c3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)-3-chlorobenzene and isolated as light-yellow gum. MS (m/e): 421.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:15](O)[CH3:16]>Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCO
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(O)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])c(O)c1

Procedure:
A solution of 3-hydroxy-4-nitrophenylacetic acid (4.0 g, prepared according to the procedure described by Meyer et al, J.Med.Chem., 1997, 40, pages 1049-1062) in ethanol (approximately 100 mL) was treated with concentrated hydrochloric acid (5-8 drops) was heated at reflux temperature for 3 hours then evaporated. The residue was dissolved in tert-butyl methylether and the solution was washed with saturated aqueous sodium bicarbonate solution, then with water, then dried, and then evaporated to give the title compound (5.0 g) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Oc2ccc3ccccc3n2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Oc3ccc4ccccc4n3)cc2)ccc1Cl

Procedure:
2-(4-Aminophenoxy)quinoline (2.4 moles, 0.56 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (2.4 moles, 0.57 g) were reacted according to procedure C to yield the title compound, 0.8 g. 70%. Mass Spec (FD) 473. Calculated for C23H15ClF3N3OS: C, 58.29; H, 3.19; N, 8.87. Found: C, 58.47; H, 3.48; N, 8.85.
Reaction SMILES: C([O:4][C:5]1[CH:15]=[C:9]2[C:10]([O:12][C:13](=[O:14])[C:8]2=[CH:7][CH:6]=1)=O)(=O)C.[ClH:16].[NH:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[NH2:18]>C(O)(=O)C>[ClH:16].[OH:4][C:5]1[CH:15]=[C:9]2[C:8](=[CH:7][CH:6]=1)[C:13](=[O:14])[N:18]([NH:17][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[C:10]2=[O:12]
Reactant: NNc1ccncc1
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C1c2ccc(O)cc2C(=O)N1Nc1ccncc1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A solution of 5-acetoxyphthalic anhydride (3.03 g), 4-hydrazinopyridine hydrochloride (2.04 g) and glacial acetic acid (15 ml) was heated under reflux, under nitrogen, for 4 hrs, with stirring. The reaction mixture was cooled to ambient temperature, the precipitate was collected, washed with water and dried at 60° C. under vacuum overnight. Trituration with hot absolute ethanol gave 2.3 g (56%) of product, mp >260° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH:4]([NH:6][C:7](=[O:11])[O:8][CH2:9][CH3:10])[CH3:5].[OH-].[K+].[C:16]1(C)[CH:21]=CC=C[CH:17]=1.C(Br)C=C>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH2:21]([N:6]([CH:4]([CH3:5])[CH:3]([O:2][CH3:1])[O:12][CH3:13])[C:7](=[O:11])[O:8][CH2:9][CH3:10])[CH:16]=[CH2:17]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)NC(C)C(OC)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Product: C=CCN(C(=O)OCC)C(C)C(OC)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
151 g (0.79 mol) of ethyl N-(1,1-dimethoxyprop-2-yl)-carbamate, 175 g of powdered potassium hydroxide and 2.8 g of triethylbenzylammonium chloride are initially introduced into 750 ml of toluene and 94 g (0.777 mol) of allyl bromide are added dropwise at room temperature. After stirring overnight at room temperature, a further 10 g (82.6 mmol) of allyl bromide are added dropwise and the mixture is stirred for one day at room temperature. Water is added until all salts have gone into solution, and the aqueous phase is separated off and extracted twice with 150 ml of toluene each time. The extracts are dried over K2CO3 and concentrated, and the residue is distilled.