Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[F:39])=[O:30])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[F:39])=[O:30])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: CCCCCCCN(CCCCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCCN(CCCCCSc1nc(-c2ccc(O)cc2)c(-c2ccc(O)cc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-[5-[4,5-bis(4-methoxyphenyl)-1H-imidazol-2-ylthio]pentyl]-N'-(2,4-difluorophenyl)-N-heptylurea (0.78 g, 0.0012 mol) in methylene chloride (30 mL) cooled to -78° under a nitrogen atmosphere, 1M boron tribromide in methylene chloride (3.6 mL) was added. The reaction mixture stirred for 1 hour at 0°, was poured over ice (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with 10% aqueous NaHCO3 (50 mL), water, brine, dried over magnesium sulfate, and concentrated in vacuo to give the crude oil. The product was purified by flash chromatography on silica gel (100 mL) eluting with hexane:ethyl acetate (40:60 v:v) to give a white foam, mp 110°-12° (0.5 g, 0.00008 mol). 1H NMR (DMSO-d6) δ12.22 (bs,1H), 9.55(bs,1H), 9.32(bs,1H),7.92(s,1H), 7.45-6.6(m,11H), 3.24(m,4H), 3.06(t,2H), 1.77-1.17(m,16H), 0.88(t,3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)=O)(C)(C)C.Cl[C:17]1N=C(Cl)N=[C:19](OC)[N:18]=1.CN1CCOCC1.CNC.FC(F)(F)C(O)=O>O1CCCC1.ClCCl.O>[CH3:17][N:18]([CH3:19])[C:13]([CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: COc1nc(Cl)nc(Cl)n1
Agent: CNC
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C)C(=O)C1CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To a solution of pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (980 mg, 4.55 mmol) in tetrahydrofuran (20 ml) was added 2,4-dichloro-6-methoxy-[1,3,5]triazine (800 mg, 4.55 mmol) and N-methyl morpholine (1.0 ml, 0.91 mmol). The mixture was stirred at room temperature for 1 hour. Dimethylamine (2.0 M in tetrahydrofuran, 11 ml, 22.0 mmol) was added in one portion. The mixture was stirred at room temperature for an additional 15 hours. Water (2.0 ml) was added, and the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (20 ml) and 1 N hydrochloric acid (15 ml). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (10 ml) and brine (10 ml), then dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product (260 mg, 20%). The crude material was dissolved in dichloromethane (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The mixture was stirred at room temperature for 90 minutes, and then concentrated in vacuo. The residue was taken into saturated aqueous sodium bicarbonate (10 ml) and extracted three times with chloroform (10 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 180 mg (20% over 2 steps) of pyrrolidine-3-carboxylic acid dimethylamide.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:19][CH2:18][C:17](=O)[CH2:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([C@H:28]([NH2:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C@H:28]([NH:30][CH:17]2[CH2:18][CH2:19][C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])=[CH:10][CH:11]=3)[CH2:16]2)[CH3:29])[CH:25]=[CH:26][CH:27]=1
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: O=C1CC[C@H](c2ccc(C(=O)N3CCOCC3)cc2)C1
Product: C[C@@H](NC1CC[C@H](c2ccc(C(=O)N3CCOCC3)cc2)C1)c1cccc(Cl)c1

Procedure:
General procedure B was followed using (3S)-3-[4-(Morpholine-4-carbonyl)phenyl]-cyclopentanone (preparation 15) as the ketone and (R)-1-(3-chlorophenyl)ethanamine as the amine. 1H NMR (600 MHz, DMSO) δ 7.44-7.42 (m, 1H), 7.35-7.22 (m, 7H), 3.76 (q, J=6.6 Hz, 1H), 3.57 (br m, 4H), 3.33 (br m, 4H), 3.27-3.19 (m, 1H), 3.02 (m, 1H), 2.07 (m, 1H), 1.93 (m, 1H), 1.77-1.41 (m, 4H), 1.23 (d, J=5.3 Hz, 3H).
Reaction SMILES: [OH:1][C@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:3]1[OH:22].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>COC(OC)(C)C>[OH:22][C@H:3]1[C@H:2]([O:1][CH3:23])[C:11]2[CH:10]=[CH:9][N:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)[C@H]3O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: CO[C@@H]1c2ccn3cc(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 0.62 g (2.10 mmol) (7S,8R,9R)-7,8-dihydroxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine in dimethoxypropane is added 0.51 g (26.2 mmol) p-toluenesulphonic acid and acetone (4.0 ml). The mixture is stirred for 6 h at 60° C. and 96 h at 25° C. The reaction is quenched by adding of saturated aqueous sodium hydrogen carbonate solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (dichloromethane/methanol: 100/3) to give 0.12 g (0.34 mmol/16%) of the title compound as an amorphous solid. 1H-NMR (200 MHz,[D6] DMSO): δ=2.29 (s, 3H), 3.25 (s, 3H), 4.05 (q, 1H), 4.32 (d, 1H), 4.47 (dd, 1H), 6.61 (d, 1H), 7.19-7.46 (m, 5H), 7.54 (s, 1H), 7.72 (d, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:12])[CH:9]([Br:11])[Br:10])[C:5]([OH:7])=O.P(Cl)(Cl)(Cl)=O.[NH2:18][CH:19]1[C:30](=[O:31])[N:21]2[CH:22]([C:27]([OH:29])=[O:28])[CH:23]([OH:26])[CH2:24][S:25][C@H:20]12.C[Si](CC(N)=O)(C)C>C(Cl)Cl.O.CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:8](=[O:12])[CH:9]([Br:11])[Br:10])[C:5]([NH:18][CH:19]1[C:30](=[O:31])[N:21]2[CH:22]([C:27]([OH:29])=[O:28])[CH:23]([OH:26])[CH2:24][S:25][C@H:20]12)=[O:7]
Reactant: CON=C(C(=O)O)C(=O)C(Br)Br
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12)C(=O)C(Br)Br
Yield: 92.8 %

Procedure:
A solution of 2-methoxyimino-3-oxo-4,4-dibromobutyric acid (syn isomer, 10 g) in methylene chloride (10 ml) was added to a solution of N,N-dimethylformamide (2.89 g) and phosphoryl chloride (6.07 g) in methylene chloride (30 ml) at -15° to 10° C., and stirred for an hour. The solution was added to a solution of 7-amino-3-hydroxycepham-4-carboxylic acid (4.8 g) and trimethylsilylacetamide (23.1 g) in methylene chloride (100 ml) at -15° to -10° C., and stirred for 2 hours. To the resultant solution was added water (40 ml) under ice-cooling and stirred for 10 minutes, and then the solvent was removed under reduced pressure therefrom. To the residue was added a saturated aqueous solution of sodium chloride (40 ml) and allowed to stand in a refrigerator overnight. The precipitates were collected by filtration, washed with a saturated aqueous solution of sodium chloride and water in turn, and dried under reduced pressure to give 7-(2-methoxyimino-3-oxo-4,4-dibromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 10.27 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][C@@H:12]([NH:16]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:13][S:14][CH3:15])[C:6]=2[CH:36]=1.CC(O)C.Cl>CO>[ClH:1].[NH2:16][C@@H:12]([CH2:13][S:14][CH3:15])[CH2:11][O:10][C:7]1[C:6]2[CH:36]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: CSC[C@@H](COc1noc2ccc(Cl)cc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CSC[C@H](N)COc1noc2ccc(Cl)cc12

Procedure:
To a solution of 2.41 g of (R)-5-chloro-3-(3-methylthio-2-tritylaminopropoxy)-1,2-benzoisoxazole in 5 ml of methanol is added 6.0 ml of a 2-propanol solution (6.5M) of hydrogen chloride at room temperature, and they are subjected to reaction at the same temperature for three hours, after which the solvent is removed by distillation under reduced pressure. Ethyl acetate is added to the residue obtained and the crystals precipitated are collected by filtration and dried, to obtain 0.72 g of colorless, crystalline (R)-3-(2-amino-3-methylthiopropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 195.0°-198.2° C. (decomp.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH:10]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[CH:26][CH:25]=1)[C:11]1[N:16]=[C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:13][CH:12]=1)(=[O:9])=[O:8].Cl.O1[CH2:41][CH2:40]OCC1>C(O)CCCCC>[CH2:2]([O:20][C:19](=[O:21])[CH2:18][NH:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:10]([S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[S:31][CH:32]=[CH:33][N:34]=3)=[CH:26][CH:25]=2)[N:16]=1)[CH2:3][CH2:4][CH2:5][CH2:40][CH3:41]
Reactant: O=C(O)CNc1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCCCCCO
Product: CCCCCCOC(=O)CNc1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of (6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-ylamino)acetic acid (110 mg, 0.222 mmol) obtained in Example 3-(b) in 1-hexanol (0.83 ml) was added a 4N hydrogen chloride/1,4-dioxane solution (0.83 ml), followed by stirring at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1→1:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (119 mg) as a colorless oil. (Yield: 92%)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([O:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-].[C]>[F:28][C:25]([F:26])([F:27])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=1)[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([O:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=1)=[O:29]
Reactant: COCCOCOc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COCCOCOc1cc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Yield: 98.4 %

Procedure:
A mixture of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-piperazine (0.38 g) in methanol (6 ml) was hydrogenated over 20% palladium hydroxide-carbon (0.06 g) at room temperature under atmospheric pressure for 8 hours. After removal of the catalyst by filtration through Celite®, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of dichloromethane and methanol (30:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]piperazine (0.32 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)=[CH:20][CH:21]=1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1

Procedure:
215 mg of the target compound (0.55 mmol, 42.4%) was obtained using 1-(2-methoxyphenyl)piperazine (497 mg, 2.58 mmol), 4′-chlorobiphenyl-2-carbaldehyde (280 mg, 1.29 mmol) and NaBH(OAc)3 (832 mg, 3.87 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [N:1]1([NH2:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.C(N(CC)CC)C.Cl[S:15]([C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:17])=[O:16].O>C(OCC)(=O)C>[N:1]1([NH:6][S:15]([CH:18]2[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH2:21][CH2:22][CH2:23]2)(=[O:17])=[O:16])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: Nn1cccc1
Reactant: CCOC(=O)C1=C(S(=O)(=O)Cl)CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1=CCCCC1S(=O)(=O)Nn1cccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of 1.0 g (12.18 mmol) of 1H-pyrrol-1-ylamine and 1.8 ml (13.40 mmol) of triethylamine in 60 ml of ethyl acetate was added dropwise a solution of 3.6 g (12.18 mmol) of ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (compound disclosed in the specification of Japanese Patent Application (Kokai) No. 2000-178246) in 12 ml of ethyl acetate with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=3:1) and the resulting solid was further washed with isopropyl ether to give 1.9 g of the title compound as a white powder (yield: 52%).
Reaction SMILES: [O:1]=[C:2]1[CH:9]2[CH2:10][N:5]([CH2:6][CH2:7][CH2:8]2)[CH2:4][CH:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[BH4-].[Na+]>C(O)C>[OH:1][CH:2]1[CH:9]2[CH2:10][N:5]([CH2:6][CH2:7][CH2:8]2)[CH2:4][CH:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C1CN2CCCC(C2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CN2CCCC(C2)C1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 4-oxo-1-azabicyclo[3.3.1]non-3-yl carboxylate* (22 g, 0.104 moles) in ethanol (200 ml) was cooled in an ice bath to 5° C. and treated portionwise with sodium borohydride (4.0 g). The reaction was then allowed to warm to room temperature and stirred overnight. The solvent was then removed in vacuo, the residue partitioned between dichloromethane (200 ml) and water (75 ml) and the organic layer separated and dried (Na2SO4). Filtration and removal of the solvent afforded the required product as an oil (20.0 g), 85% pure by g.l.c. (OVl, 180° C.) which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCCC1>[CH2:1]([O:3][C:4](=[O:11])[C:5]([CH3:10])([CH3:9])[C:6]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:8])[CH3:2]
Reactant: CCOC(=O)C(C)(C)C(=O)O
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(=O)NCCN1CCOCC1
Temperature: 5 °C

Procedure:
19 g 2,2-Dimethyl-malonic acid monoethyl ester were weighed into a round-bottomed flask and under N2 atmosphere and room temperature, 200 ml tetrahydrofurane, 15.6 ml 4-(2-Aminoethyl)-morpholine and 32.6 ml N-Methylmorpholine were added. The reaction was stirred and cooled down to 5° C. Then, 43.8 g TBTU were added and the mixture was allowed to stir for another 1.5 hours. Finally the solvent was removed and the residue dissolved in 400 ml dichloromethane. This organic phase was washed two times with 500 ml NaHCO3 solution. The dichloromethane phase was dried then the solvent was evaporated. Purity of the product was judged by gas chromatography.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[CH2:8][CH2:9][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CCC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1C=C(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 9.7 g of 1-phenyl-1,4-pentanedione (0.055 mole), 500 ml of water, 15 g of sodium hydroxide and 1000 ml of ethanol was heated under reflux for 4 hours. The mixture was allowed to cool to room temperature and was then neutralized with acid. Ethanol was evaporated. The 3-phenylcyclopent-2-en-1-one formed was recovered by extraction and crystallization.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: C1=Cc2ccccc2C1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.98 g (20 mmole) of para-nitro iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline yellow precipitate was isolated, recrystallized from ethanol, washed with cold ethanol and dried under vacuum to obtain 1.94 g (41%) of 2-(4-nitro-phenyl)-indene.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]([CH3:20])[CH3:19])[C:4]=2[N:5]=[CH:6][N:7]=1.F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:18]([N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])=[CH:15][CH:16]=2)=[CH:9]1)([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)n1cc(-c2ccc(O)cc2)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2ccc(Oc3ccccc3[N+](=O)[O-])cc2)c2c(N)ncnc21
Temperature: 120 °C

Procedure:
A mixture of 4-amino-5-(4-hydroxyphenyl)-7-isopropylpyrrolo[2,3-d]-pyrimidine (0.29 g), 2-fluoronitrobenzene (0.15 g), potassium carbonate (0.149 g) and N,N-dimethylformamide (4.0 ml) was shaken and heated at 120° C. for 5 hours. The mixture was evaporated to dryness under reduced pressure and the residue was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was separated, washed with water, and then with dilute sodium hydroxide solution, and then with brine, then dried, filtered and evaporated to give a solid which was triturated with ether to give 7-isopropyl-5-[4-(2-nitrophenoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. The structure was confirmed by 1H nmr.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8]C(C#N)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.OS(O)(=O)=O.[CH3:18][C:19]([OH:21])=[O:20]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:18]([C:19]([OH:21])=[O:20])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 87 %

Procedure:
A suspension of 4-methyl-2-nitrobenzonitrile (5.00 g, 30.8 mmol) and 50% H2SO4 (25 mL) in HOAc (25 mL) was heated to reflux for 22 h. The reaction mixture was poured into ice-water (150 g) under stirring and stirred at 5° C. for 30 minutes. The deposited crystals were collected by filtration, washed with H2O and n-hexane, and dried at 40° C. in vacuum to give the title compound as pale brown crystal (4.85 g, 87%).
Reaction SMILES: Cl.[C:2]1([C:8]2[S:12][C:11]([CH2:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C@H:20]4[CH2:24][CH2:23][CH2:22][NH:21]4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32]>>[C:2]1([C:8]2[S:12][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:18][CH2:19][C@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:25][CH:26]=3)=[CH:10][CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(-c2ccc(Cc3ccc(OC[C@H]4CCCN4)cc3)s2)cc1
Reactant: COC(=O)CCCBr
Agent: Cl
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ccccc3)s2)cc1
Yield: 35.3 %

Procedure:
The title compound (60 mg, 36%) was prepared from the product of Example 159 (0.15 g, 0.39 mmol) and methyl 4-bromobutyrate (84 mg, 0.47 mmol) using the procedure of Example 147; 1HNMR (400 MHz, CD3OD) δ 7.50 (d, J=8.8 Hz, 2H), 7.32 (t, J=6 Hz, 2H), 7.24 (m, 3H), 7.18 (d, J=3.6 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.77 (d, J=3.6 Hz, 1H), 4.36 (dd, J=7.2, 3.6 Hz, 1H), 4.18 (m, 1H), 4.10 (s, 2H), 4.00 (m, 1H), 3.71 (m, 1H), 3.55 (m, 1H), 3.25 (m, 2H), 2.50-2.30 (m, 4H), 2.19-1.98 (m, 4H), LC/MS (ESI+) m/z: 90%; 437 (M+1, 100).
Reaction SMILES: [C:1]1(=[N:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:17]([N:20]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:22][CH2:23]Cl)([CH3:19])[CH3:18].C(O)(=O)/C=C/C([O-])=O>>[CH:17]([N:20]([CH2:21][CH2:22][CH2:23][O:14][N:13]=[C:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:25]([CH3:27])[CH3:26])([CH3:19])[CH3:18]
Reactant: CC(C)N(CCCCl)C(C)C
Reactant: ON=C1CCCCCCCCCCC1
Agent: O=C([O-])/C=C/C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)N(CCCON=C1CCCCCCCCCCC1)C(C)C

Procedure:
Starting from 19.7 g. (0.1 moles) of cyclododecanone oxime, 2.4 g. (0.1 moles) of sodium hydride and 19.55 g. (0.11 moles) of 1-diisopropylamino-3-chloropropane the title product is prepared as in Example 1. Yield: 24.2 g. (71.6%). Hydrogen fumarate, m.p.: 119°-121° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH3:13])[C:4]=2[S:5][CH:6]=1.C([Li])CCC.[CH3:19][S:20]SC.Cl>CCCCCC.CCOCC>[CH3:19][S:20][C:6]1[S:5][C:4]2[C:7]([CH2:11][NH:12][CH3:13])=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]=1[Br:1]
Reactant: CSSC
Reactant: CNCc1cccc2c(Br)csc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CNCc1cccc2c(Br)c(SC)sc12
Temperature: 25 °C

Procedure:
To a solution of 2.55 g of N-(3-bromo-7-benzo[b]thienylmethyl)methylamine in abs. ether are added dropwise under inert gas at -70° 13.8 ml (2 equivalents) of a 15% solution of n-butyllithium in n-hexane. 1.9 ml of dimethyldisulfide are then added slowly at -70° and the reaction mixture gradually warmed to room temperature. It is then poured into ice-cooled 2N HCl, shaken and the acid phase separated, made alkaline with NaOH and extracted with ether. The ether phase is dried, concentrated under vacuum and the oil thus obtained directly further reacted.