Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+].Br[C:36]1[CH:37]=[CH:38][C:39]2[O:48][CH2:47][C:42]3([O:46][CH2:45][CH2:44][O:43]3)[CH2:41][C:40]=2[CH:49]=1>O1CCOCC1.[Cu]I.CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:36]3[CH:37]=[CH:38][C:39]4[O:48][CH2:47][C:42]5([O:43][CH2:44][CH2:45][O:46]5)[CH2:41][C:40]=4[CH:49]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: Brc1ccc2c(c1)CC1(CO2)OCCO1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)CC3(CO4)OCCO3)n2)ccc1Cl
Temperature: 100 °C
Yield: 18 %

Procedure:
To a solution of methyl N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]-methyl]carbamate (i.e. the product of Example 8, Step B) (400 mg, 1.50 mmol) in dioxane (16 mL) was added trans-N,N′-dimethylcyclohexane-1,2-diamine (0.30 mmol, 43 mg) under a nitrogen atmosphere. Copper (I) iodide (57 mg, 0.30 mmol) and potassium carbonate (1.24 g, 9.05 mmol) were added to the reaction mixture. 6-Bromospiro[2H-1-benzopyran-3(4H),2′-[1,3]dioxolane] (614 mg, 2.26 mmol) was added last and the reaction mixture was heated at 100° C. under a nitrogen atmosphere overnight. After TLC analysis (10% MeOH/CHCl3) shows 80% conversion of starting material, the reaction mixture was concentrated under vacuum. The resultant crude residue was purified on a silica gel column with 1% MeOH/CHCl3 as eluent to give the title compound, a compound of the present invention, (120 mg, 18% yield) as a solid.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:12])([CH2:9][CH2:10][CH3:11])[S:4]1)[OH:2].[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:13][NH:14][C:15]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:12])([CH2:9][CH2:10][CH3:11])[S:4]1)=[O:16]
Reactant: CN=C=O
Reactant: CCCC1(C)SC(=NO)N=C1C
Product: CCCC1(C)SC(=NOC(=O)NC)N=C1C

Procedure:
2-oxo-4,5-dimethyl-5-propyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4,5-dimethyl-5-propyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 66°-69° C. The 2-oxo-4,5-dimethyl-5-propyl-3-thiazoline-oxime starting material melts at 94°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Br:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:22]2[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=2)[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a solution of trans-1-(Boc)-4-hydroxy-L-proline methyl ester (0.5 g) (2 mmol), 4-bromophenol (0.52 g) (1.5 eq.) and Ph3P (0.78 g) (1.5 eq.) in 10 mL of dry THF at 0° C. was added DEAD (0.47 mL) in a minimal volume of THF. The reaction mixture was warmed to RT overnight. The solvent was removed in vacuo and the resulting residue suspended in ether. The solids were removed by filtration and the solvent evaporated under reduced pressure to afford after SiO2 chromatography (eluent: cyclohexane/EtOAc-9/1), cis-1-(Boc)-4-(4-bromo-phenoxy)-L-proline methyl ester as a colorless oil (0.54 g). NMR (CDCl3, 200 MHz): 7.37 (2H, d), 6.70 (2H, d), 4.85 (1H, m), 4.37-4.6 (1H, m), 3.6-3.85 (5H, m), 2.35-2.50 (2H, m), 1.4-1.5(9H). To a solution cis-1-(Boc)-4-(4-bromo-phenoxy)-L-proline methyl ester (0.54 g) in 8 mL of DCM at 0° C. was added 2.5 mL of TFA. The reaction mixture was stirred at 0° C. for 1 h and warmed to RT for an additional hour. The solvents were evaporated in vacuo. The resulting residue was dissolved in water and the aqueous layer basified with aqueous NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with water, dried over MgSO4, and the solvent was evaporated under reduced pressure to afford the titled compound as a colorless oil which solidified upon standing (0.39 g). NMR (CDCl3, 200 MHz): 7.35 (2H, d), 6.70 (2H, d), 4.8 (1H, m), 3.92 (1H, dd), 3.72 (3H, s), 3.35 (1H, d), 3.1 (1H, dd) 2.25-2.55 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.O1CCN([C:18]2[CH2:22][CH2:21][CH2:20][CH:19]=2)CC1>C(Cl)(Cl)Cl.S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:18]3[CH2:22][CH2:21][CH2:20][C:19]=3[C:10](=[O:11])[NH:9][C:5]=2[CH:4]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: C1=C(N2CCOCC2)CCC1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2c3c(c(=O)[nH]c2c1)CCC3

Procedure:
A solution of 3-methoxyphenylisocyanate (25.0 g, 168 mmol) in chloroform (110 ml) is mixed with 1-morpholino-1-cyclopentene (25.3 ml, 168 mmol) and refluxed for 15 minutes. The batch is concentrated by evaporation and purified by column chromatography (SiO2) with ethyl acetate-hexane: 34.8 g (87%) of cyclopentanone-2-carboxylic acid-(3-methoxyphenyl)amide: 1H-NMR (CDCl3): δ=1.80-2.55 (m, 6H), 3.18 (t, 1H), 3.81 (s, 3H), 6.68 (dd, 1H), 7.04 (ddd, 1H), 7.22 (t, 1H), 7.33 (t, 1H), 8.76 (br. s, 1H). The amide (11.6 g, 50 mmol) is stirred in concentrated sulfuric acid (40 ml) for 30 minutes at 100° C. The batch is poured onto ice water, diluted with water and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum: 2.43 g (23%) of product.
Reaction SMILES: [NH:1]1CC[CH2:6][CH:2]1[C:3](O)=O.C(=O)([O-])[O-].[K+].[K+].I[C:16]1[CH:17]=[C:18]([C:22]2[N:23]=[C:24]3[C:30]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][NH:28][C:25]3=[N:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1.C(N)(C)C>[Cu](I)I.CS(C)=O>[CH:2]([NH:1][C:16]1[CH:17]=[C:18]([C:22]2[N:23]=[C:24]3[C:30]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][NH:28][C:25]3=[N:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1)([CH3:6])[CH3:3]
Reactant: O=C(O)C1CCCN1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(I)c3)nc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)N
Solvent: CS(C)=O
Product: CC(C)Nc1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 16.5 %

Procedure:
DMSO (1.5 mL) was added to a mixture of copper iodide (10.6 mg; 0.056 mmol), d,l-proline (12.8 mg; 0.11 mmol), potassium carbonate (113 mg; 0.81 mmol), and 1-[2-(3-Iodo-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (150 mg; 0.37 mmol). Isopropyl amine (0.315 mL; 0.219 g, 3.7 mmol) was added and the resulting mixture was stirred at 110° C. (oil bath) for 24 hrs. The reaction mixture was quenched with water and extracted 3 times with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give a yellow oil. Preparative HPLC afforded 6.1 mg (5% yield) of 1-[2-(3-Isopropylamino-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow solid
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]=O)[CH2:2][CH2:3][CH3:4].Cl.[NH2:26][OH:27].C([O-])(=O)C.[NH4+]>CO.O>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]=[N:26][OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCCCNc1cc(C=NO)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzaldehyde (10 g; prepared as in Example 93) in hot methanol (100 ml) a solution of hydroxylamine hydrochloride (10 g) and ammonium acetate (10 g) in water (25 ml) is added, and the mixture is left for 3 days. Water (500 ml) is then added, and the resulting precipitate is collected by filtration, washed with water and dried in air. After recrystallization from a mixture of ethanol and 2-methoxyethanol, 3-n-butylamino-4-phenoxy-5-sulfamylbenzaldoxime is obtained with a melting point of 226°-228° C.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][CH:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:19][CH:20]=1
Reactant: CC(NC(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(NC(=O)c1ccc(N)cc1)c1ccccc1

Procedure:
A solution of 5 g (0.018 mole) of 4-nitro-N(alpha-methylbenzyl)-benzamide (#3) in 200-ml of absolute ethanol was added to a Paar hydrogenation bottle. To the solution was added a 0.4 g sample of 5% palladium on charcoal and the bottle placed on a Paar low-pressure hydrogenation apparatus. The mixture was shaken at room temperature in the presence of 45 p.s.i. of hydrogen for 2.5 hours. The catalyst was then removed by filtration through celite and the ethanol evaporated to yield the desired compound, 4-amino-N-(alpha-methylbenzyl)-benzamide (#4). Recrystallization from benzene produced the compound in pure form.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:10][C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>C(OCC)(=O)C>[F:1][C:2]1[C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:5]2[N:6]([CH2:10][C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: Cc1nc(Cn2c(=O)sc3cc(F)ccc32)no1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1nc(Cn2c(=O)sc3cc(F)c([N+](=O)[O-])cc32)no1
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
A compound of 6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (11.5 g) was added portionwise to concentrated sulfuric acid (200 g) which had been cooled to a temperature of 5° to 10° C. The reaction mixture was stirred at a temperature of 0° to 5° C. for 10 minutes. To the reaction mixture was dropwise added a 98% nitric acid (3 g). The reaction mixture was stirred at a temperature of 0° to 5° C. for 2 hours, and then poured onto ice. Ethyl acetate (1 liter) was added to the mixture, and the whole was stirred. The ethyl acetate layer was separated, washed with water, with a saturated aqueous sodium bicarbonate solution, and then with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol, so that the aimed product, i.e. 6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-5 -nitro-2(3H)-benzothiazolone (13.0 g) was obtained. m.p. 192°-193° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH2:20][OH:21])[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH:20]=[O:21])[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CO)nc12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(C=O)nc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.3 g of 6-benzyl-7-cyclopentyl-4-ethyl-2-hydroxymethyl-imidazo[4,5-e]-s-triazolo[1,5-a]pyrimidin-5-one (for preparation see Synthesis Example I) are dissolved in 1.1 ml of dichloromethane and 0.45 g of pyridinium dichromate are added. The brown suspension obtained is stirred for about 24 hours at ambient temperature. The solvent is distilled off and the residue remaining is stirred with an ethyl acetate/cyclohexane mixture (2:1.5 ml). The clear, light yellow supernatant solution is filtered through silica gel. After the solvent has been distilled off, 0.15 g of the title compound are left in the form of a colourless resin.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([NH2:11])=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O1CCOCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>N1C=CC=CC=1>[F:1][C:2]1[C:3]([C:9]#[N:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NC(=O)c1ncc(Cl)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ncc(Cl)cc1F
Yield: 91.5 %

Procedure:
1.39 g of 3-fluoro-5-chloro-2-pyridinecarboxamide (Example H7) are initially introduced into 8 ml of absolute dioxane, and 1.3 ml of dry pyridine are added. 1.30 ml of trifluoroacetic anhydride are slowly added with a syringe, while stirring and cooling in an ice-bath, and the mixture is subsequently stirred for 30 minutes. The resulting reaction mixture is poured onto 1N hydrochloric acid at 25° C. and extracted with diethyl ether. The ether phase is washed with dilute hydrochloric acid, water, dilute sodium bicarbonate solution and water. After drying over sodium sulfate, the mixture is filtered and the filtrate is concentrated to dryness. 1.14 g of the desired compound are obtained as a slightly violet-coloured solid of melting point 72-73° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30](Br)=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[C:36]([N:38](C)C)=O>C(Cl)Cl.[C-]#N.[C-]#N.[Zn+2].[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([C:36]#[N:38])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(Br)n4cc3-c3ccccc3)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(C#N)n4cc3-c3ccccc3)cc2)CCC1
Temperature: 160 °C

Procedure:
A mixture of compound 4-3 (80 mg 0.154 mmol.), Zn(CN)2 (11 mg, 0.0906 mmol.), Zn (1 mg 0.015 mmol.) and Pd(dppf)Cl2 (10 mg) in DMA (2 mL) was heated at 160° C. in microwave system for 45 min. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HCl(aq) and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 60 mg of 4-9.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[C:6]([N:10]2[CH:14]=[C:13](I)[N:12]=[C:11]2[CH3:16])[CH:5]=[N:4]1)[CH3:2].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)#[CH:18]>>[CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[C:6]([N:10]2[CH:14]=[C:13]([C:18]#[C:17][C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)[N:12]=[C:11]2[CH3:16])[CH:5]=[N:4]1)[CH3:2]
Reactant: C#Cc1cccc(C)c1
Reactant: CCn1ncc(-n2cc(I)nc2C)cc1=O
Product: CCn1ncc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O

Procedure:
The title compound, light brown crystalline solid, MS: m/e=319.1 (M+), was prepared in accordance with the general method of example 21a from 2-ethyl-5-(4-iodo-2-methyl-imidazol-1-yl)-2H-pyridazin-3-one and 1-ethynyl-3-methyl-benzene.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:16][C:11]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9](=[O:17])[C:8]=2[CH:18]=1.Cl>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:16][C:11]3([CH2:12][CH2:13][CH2:14][CH2:15]3)[CH2:10][CH:9]([OH:17])[C:8]=2[CH:18]=1
Reactant: O=C1CC2(CCCC2)Oc2ccc(Br)cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CC2(CCCC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (4.65 g, 0.123 mol) was added to a stirred suspension of 6-bromo-3,4-dihydro-spiro[2H-1-benzopyran-2,1′-cyclopentan]-4-one (31.83 g, 0.1137 mol) in methanol (650 mL) at 0° C. and the mixture was maintained at this temperature for a further 30 minutes. After stirring for an additional 30 minutes at room temperature, concentrated hydrochloric acid was added until acid and the solvent was evaporated under reduced pressure. Water was added to the residue and the product was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The crude product was recrystallized from diethylether/petroleum ether 40-60° C. (⅓). The resulting precipitate was collected by filtration, washed with petroleum ether and dried (71%). mp: 123-123.5° C., IR (KBr): 3271 (O—H), 2963, 2873 (C—H aliphatic) cm−1, Anal. (C13H15O2Br) C, H.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1C
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][NH:23][CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:24]([N:23]([CH3:22])[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH3:26])[CH3:25]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CNC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N(C)C(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (170 mg, 0.50 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), N-methylpropan-2-amine (73 mg, 1.00 mmol, 2.00 equiv), and potassium carbonate (207 mg, 1.50 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water. The resulting solids were collected by filtration. This resulted in 109.8 mg (59%) of methyl 3-(isopropyl(methyl)amino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.S(O)(O)(=O)=O.[NH2:61][C:62]1[NH:63][CH:64]=[CH:65][N:66]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:61][C:62]2[NH:63][CH:64]=[CH:65][N:66]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Reactant: Nc1ncc[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc[nH]2)cc1Br
Yield: 58.9 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 148A, 100 mg, 0.266 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (187 mg, 0.42 mmol), triethylamine (115 μL, 1.064 mmol), and 2-aminoimidazole sulfate (56 mg, 0.42 mmol) in methylene chloride (10 mL) was stirred at 25° C. for 15 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution (1×10 mL) and water (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, ethyl acetate) afforded 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-imidazol-2-yl)-propionamide (69 mg, 53%) as a white solid: mp >210° C. (dec); EI-HRMS m/e calcd for C18H22BrN3O3S (M+) 439.0565, found 439.0566.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1>Cl.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:4][CH:3]=[O:2]
Reactant: COC(CC(c1ccccn1)c1ccccn1)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=CCC(c1ccccn1)c1ccccn1
Temperature: 0 °C
Yield: 75.2 %

Procedure:
A solution of 1.86 g of Compound 16A and 0.08 g of 1,4-dihydroquinone in 36 mL of 2 N HCl was stirred at 80° C. for 15 min, cooled to 0° C., diluted with 50 mL of dichloromethane and neutralized with 20% aq. sodium carbonate (pH=7-8). The organic layer was dried on sodium sulphate and evaporated to dryness affording 1.15 g of crude title compound as a grey glassy solid, which was used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[C:15]([CH3:18])=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1Cl>[Br:21][CH2:18][C:15]1[C:14]2[CH:19]=[CH:20][C:11]([O:10][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=3[C:7]#[N:8])=[CH:12][C:13]=2[O:17][N:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1noc2cc(Oc3ccc(F)cc3C#N)ccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: N#Cc1cc(F)ccc1Oc1ccc2c(CBr)noc2c1
Temperature: 150 °C
Yield: 26.1 %

Procedure:
5-fluoro-2-(3-methyl-benzo[d]isoxazol-6-yloxy)-benzonitrile (3v), (0.87 g, 3.2 mmol), N-bromosuccinimide (0.82 g, 4.6 mmol), benzoyl peroxide (0.12 g, 0.49 mmol) and o-dichlorobenzene (6 mL) were combined in a 15 mL pressure tube. The mixture was stirred and heated in a 150° C. bath. After 2.5 hours the reaction was cooled and the residue was purified directly by column chromatography (silica, 70% CH2Cl2/hexanes) to provide compound (4v) (0.29 g, 26% yield) plus recovered starting material (3v) (0.57 g, 65%). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=7.0 Hz, 1H), 7.45-7.43 (m, 1H), 7.35-7.31 (m, 1H), 7.16-7.13 (m, 2H), 7.08-7.05 (m, 1H), 4.72 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].C([O-])(=O)C.[NH4+].[OH-].[Na+]>C1C=CC=CC=1.O>[CH2:15]([O:14][C:12](=[O:13])[C:11](=[C:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:9]#[N:10])[CH3:16]
Reactant: CN1CCC(=O)CC1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(C#N)=C1CCN(C)CC1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
A mixture containing 1.05 g (9.27 mmoles) of 1-methyl-4-piperidone (commercially available: Aldrich Chemical Co., 1.00 mL (9.4 mmoles) of ethyl cyanoacetate, and 148 mg of ammonium acetate in 35 mL of benzene was heated at reflux for 3 hours with continuous azeotropic removal of water by means of a Dean-Stark trap. The product was isolated by cooling the mixture to room temperature, pouring it into 30 mL of 2:1 (v/v) 1M aqueous NaOH:saturated brine, and extraction with ether. The organic extracts were washed with 10% aqueous sodium chloride solution, then were dried over anhydrous sodium sulfate and subsequently filtered. Removal of the ether and benzene by evaporation at reduced pressure afforded 1.46 g (76% yield) of cyanoester 9.