Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]1([P:21](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][O:12][P:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1ccc(C2CCCCC2)cc1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=P(OCc1ccc(C2CCCCC2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To a stirred solution of 4-cyclohexylbenzyl alcohol (1 g, 5.26 mmol) in 45 ml of dry dichloromethane, 5 ml of triethylamine and 41 mg of dimethylaminopyridine was added 1.05 ml (1.25 g) of diphenylphosphinic chloride. The mixture was stirred at room temperature for 3 h after which it was concentrated to approximately 10 ml. The mixture was diluted with dichloromethane, washed with cold 10% sodium bicarbonate, water, dried (sodium sulfate), filtered and concentrated to approximately 10 ml. The resulting solution was chromatographed on silica gel, eluting with ethyl acetate/heptane to provide 1.92 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH3:31])[CH2:11]C1)C1C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:11]([C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][C:13]=2[CH3:31])[CH2:1][O:8]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(Cc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.3 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 79, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution) and stirred overnight at room temperature. Work-up afforded 48.0 mg (76%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26]C)=[O:25])[CH2:19][CH2:18]4)[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[Li+].O>O1CCCC1.CO>[F:1][C:2]1[C:3]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:18]4)[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)CC1CCC(N2CC=C(c3cc4c(-c5cc(F)ccc5OC)c(F)cnc4[nH]3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCN(C4CCC(CC(=O)O)CC4)CC3)cc12
Reaction time: 0.25 h

Procedure:
A mixture of Example 298A (0.115 g, 0.232 mmol) and lithium hydroxide (0.011 g, 0.464 mmol) in tetrahydrofuran (3 mL), methanol (1.2 mL), and water (0.9 mL) was stirred overnight and concentrated. The residue was dissolved in 4 mL water and treated with 2M aqueous hydrogen chloride. The suspension was diluted with water, stirred for 15 minutes, filtered, washed with water, and vacuum oven-dried to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, Methanol-d4) δ 1.13-1.28 (m, 1H), 1.55-1.95 (m, 4H), 1.95-2.07 (m, 2H), 2.17-2.27 (m, 3H), 2.43 (d, J=7.6 Hz, 1H), 2.87-2.95 (m, 2H), 3.30-3.38 (m, 2H), 3.77 (s, 4H), 4.00-4.08 (m, 2H), 6.33 (s, 1H), 6.41 (bs, 1H), 7.08-7.26 (m, 3H), 8.15 (d, J=2.8 Hz, 1H). MS (ESI+) m/z 482.0 (M+H)+.
Reaction SMILES: C1(N[N:8]=[C:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10]2)C=CC=CC=1.P(=O)(O)(O)O.S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>[Cl-].[Zn+2].[Cl-]>[C:14]([N:11]1[CH2:12][C:13]2[C:30]3[CH:29]=[CH:12][CH:13]=[CH:9][C:10]=3[NH:8][C:9]=2[CH2:10]1)([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCO
Reactant: CCOC(=O)N1CCC(=NNc2ccccc2)C1
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Product: CCOC(=O)N1Cc2[nH]c3ccccc3c2C1

Procedure:
When N-carbethoxy-3-pyrrolidinone phenylhydrazone was reacted in refluxing ethanol in the presence of various strong acid catalysts such as 85% phosphoric acid, concentrated sulfuric acid and anhydrous zinc chloride, the best yield of 2-carbethoxy- 1,2,3,4-tetrahydropyrrolo[3,4-b]indole obtained was 10% of theory. The above phenylhydrazone (M.P. 138° C.) was obtained by reacting equimolar amounts of phenylhydrazine hydrochloride and N-carbethoxypyrrolidinone in refluxing ethanol. The phenylhydrazone is isolated by neutralizing the cooled reaction mixture with potassium carbonate, diluting with water, filtering and drying.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[NH:20][C:21]3[CH:22]=[N:23][N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=4)[CH:25]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([O:36]CC)=[O:35].[OH-].[Na+].Cl>O1CCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:33])[NH:20][C:21]3[CH:22]=[N:23][N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=4)[CH:25]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([OH:36])=[O:35]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cnn(-c5cccc(Cl)c5)c4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1cnn(-c2cccc(Cl)c2)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 3 h
Yield: 103 %

Procedure:
Ethyl 6-chloro-7-(4-(1-(3-chlorophenyl)-1H-pyrazol-4-ylcarbamoyl)phenoxy)chroman-4-carboxylate (280 mg, 0.5 mmol) was dissolved in 2:1 tetrahydrofuran/ethanol (3 mL) and treated with sodium hydroxide (2 ml of a 1 N solution, 2.0 mmol) at ambient temperature. After 3 hours, the reaction was diluted with water (20 mL), acidified with 2N HCl (2 mL) and extracted with ethyl acetate. The combined organic phases were dried (sodium sulfate), filtered and the solvent removed under vacuum to provide the title compound (270 mg, 102%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].[CH3:43][N:44](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:45].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CNC>CN(C=O)C.C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([N:44]([CH3:45])[CH3:43])=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and dimethylamine (41.3 uL, 0.0825 mmol, 2M soln in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (11.5 mg, 35%). LC-MS m/z 601 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Brc1ccccn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccccn2)C1
Temperature: 80 °C

Procedure:
A stirred solution comprising (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.0 g, 10.7 mmol), 2-bromopyridine (1.7 g, 10.7 mmol) and TEA (1.1 g, 10.7 mmol) in DMF (40 ml) is heated to 80° C. for 50 hours. The solvent is removed in vacuo the purification of the crude residue by chromatography on silica eluting with ethyl acetate:hexane (1:9 increasing to 1:4) yields the titled compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][C:12]([CH3:18])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CN(C)C=O>[Br:25][C:26]1[N:27]=[C:28]([CH2:32][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([CH3:18])[N:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc2c(=O)c(C(=O)c3ccc(C)c(C)c3)c[nH]c2n1
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)c(C(=O)c3ccc(C)c(C)c3)cn(Cc3cccc(Br)n3)c2n1
Yield: 18.7 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 0.100 g (0.342 mmol) of 3-(3,4-Dimethyl-benzoyl)-7-methyl-1H-[1,8]naphthyridin-4-one, 16.4 mg (0.410 mmol, 60% dispersion in oil) of sodium hydride, 0.103 g (0.410 mmol) of 2-bromo-6-bromomethyl-pyridine and 3.5 mL of N,N dimethylformamide. The crude brown solid was purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 29.5 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-7-methyl-1H-[1,8]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C24H20BrN3O2 [M+H]: 463.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.7 min
Reaction SMILES: [CH3:1][CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>[NH4+].[OH-].C(OCC)(=O)C>[CH3:1][CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][N:3]1[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2[nH]c3c(c2c1)CCNC3C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3C
Reaction time: 0.33 h

Procedure:
To a solution of 700 mg (3.24 mmol) 1-methyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline, and 5 drops NH4OH in ethyl acetate was added 0.4 mL (3.88 mmol) acetic anhydride under N2 gas. The reaction was stirred for 20 min. and then washed with water. The organic layer collected was dried over MgSO4, filtered, and concentrated in vacuo to a dark oil. The oil was dissolved in methanol and chromatographed on reverse phase C-18 using methanol and water. The product was collected and concentrated to a white solid, which showed characteristic peaks: NMR (CDCl3) δ: 1.45 ppm (d, 3H), 2.25 ppm (s, 3H), 3.85 ppm (s, 3H).
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[C:13]([CH3:25])=[N:12][C:11]=2[NH:10][NH:9]1)C1C=CC=CC=1.C(O)(=O)C>[OH-].[OH-].[Pd+2].C(O)C>[CH3:25][C:13]1[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:15](=[O:17])[C:16]2[N:8]=[N:9][NH:10][C:11]=2[N:12]=1
Reactant: Cc1ccccc1-n1c(C)nc2c(c1=O)N(Cc1ccccc1)NN2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccccc1-n1c(C)nc2[nH]nnc2c1=O
Reaction time: 48 h
Yield: 16.8 %

Procedure:
A mixture of 1-benzyl-5-methyl-6-o-tolyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (4.0 g, 12.07 mmol), acetic acid (150 mL), ethanol (25 mL), and palladium hydroxide on carbon (4.0 g) was hydrogenated on a Parr apparatus. After 5 hours the catalyst was filtered off and replaced with fresh palladium hydroxide on carbon (4.0 g). The hydrogenation was continued 48 hours longer. The reaction was filtered and the filtrate was concentrated to afford 5-methyl-6-o-tolyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (0.488 g, 17%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O>FC(F)(F)C(O)=O>[CH3:13][O:12][C:9]1[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:2]([OH:1])=[CH:11][CH:10]=1
Reactant: COc1ccc(O)c2c1C(=O)CCC2
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(O)c2c1CCCC2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101.5 %

Procedure:
To a cooled (0° C.), stirred solution of 5-hydroxy-8-methoxy-3,4-dihydro-2H-naphthalen-1-one (1.7 g) in trifluoroacetic acid (20 mL) triethylsilane (4.2 mL) was added and the reaction warmed to RT and then stirred for 1.5 h). The reaction mixture was concentrated in vacuo, partitioned between ethyl acetate/water, the organic layer was washed with water, brine, and then dried over sodium sulfate and concentrated in vacuo. The resulting oil is flash chromatographed (10% ethyl acetate/hexanes) to afford the title compound as a colorless solid (1.6 g).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[O:8][C:9](=[O:20])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O-:19])=[O:18])[CH:11]=2.[Na+].[CH3:22]O>O>[CH3:6][C:7]1[O:8][C:9](=[O:20])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH3:22])=[O:18])[CH:11]=2
Reactant: CO
Reactant: Cc1cc2ccc(C(=O)[O-])cc2c(=O)o1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc2cc(C)oc(=O)c2c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Concentrated sulfuric acid (3 mL) was added to a mixture of sodium 3-methyl-1-oxo-1H-isochromene-7-carboxylate (1.69 g) and methanol (50 mL), and heated under stirring in an oil bath at 60° C. for 2 days. The reaction mixture was returned to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain methyl 3-methyl-1-oxo-1H-isochromene-7-carboxylate (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C([O-])(=O)C.[Na+].[Br:18]Br>CCCCCC>[Br:18][CH2:11][C:10]([C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[C:7]([Cl:8])[C:2]=1[Cl:1])=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Product: O=C(CBr)c1ccc(Cl)c(Cl)c1Cl

Procedure:
A mixture of 2',3',4'-trichloroacetophenone (21.4 g, 0.0958 mole), anhydrous sodium acetate (8.0 g), and n-hexane (50 ml) was heated under reflux while treated with a solution of bromine (15.3 g, 0.096 mole) in 25 ml of n-hexane in five portions, decolorizing before each new addition. The mixture was then filtered while hot and the insoluble residue was triturated twice with 50 ml of boiling n-hexane. Enough additional n-hexane was added to the combined filtrates to avoid oiling out of product at 40°. The solution was then seeded and cooled at -10° for 18 hours. Product was collected and air dried to give 17.9 g (62%), mp 44°-46°.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16](Br)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].[Br-].[CH:28]1([Zn+])[CH2:30][CH2:29]1>C1COCC1>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([CH:28]2[CH2:30][CH2:29]2)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: Cc1nc(C(C)(C)NC(=O)c2cnc(Br)c(-c3cccc(Cl)c3)n2)no1
Reactant: [Zn+]C1CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(C(C)(C)NC(=O)c2cnc(C3CC3)c(-c3cccc(Cl)c3)n2)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.3 %

Procedure:
5-Bromo-6-(3-chloro-phenyl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (0.100 g, 229 μmol), and tetrakis-(triphenyl-phosphine)palladium (13.2 mg, 11.4 μmol) were dissolved in THF (2.5 mL). Cyclopropylzinc(II)bromide (0.5M in THF, 1800 μl, 900 μmol) was added drop by drop at 0° C. and the reaction mixture was stirred at room temperature for 1.5 hours and at reflux temperature overnight. The mixture was partitioned between water and ethyl acetate and the organic phase was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 5% to 40% ethyl acetate in n-heptane) to give the desired product (24 mg, 26%) as white solid; MS (EI): 398.2 (M+H). As side product 11 mg of 6-(3-chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid (cyano-dimethyl-methyl)-amide (Example 2) was isolated.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.Br[C:13]1[N:18]=[C:17]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:4]2[CH:5]=[N:1][N:2]([C:13]3[N:18]=[C:17]([C:19]4[N:20]=[CH:21][CH:22]=[CH:23][N:24]=4)[CH:16]=[CH:15][CH:14]=3)[CH:3]=2)[CH:7]=1
Reactant: Brc1cccc(-c2ncccn2)n1
Reactant: c1cncc(-c2cn[nH]c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(-c2cccc(-n3cc(-c4cccnc4)cn3)n2)nc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
DMF was added to 0.8 g (5.5 mmol) of 3-(1H-pyrazol-4-yl)pyridine (Angew. Chemie, 2006, 118 (8) 1304), 1.3 g (5.5 mmol) of 2-(6-bromopyridin-2-yl)pyrimidine (WO 2010/006713), 0.29 g (0.82 mmol) of copper-8-hydroxyquinoline complex (cf. Tetrahedron Lett, 2006, 149) and 2.28 g (16.5 mmol) of potassium carbonate, and the mixture was stirred at 120° C. under argon for 16 hours. The entire reaction mixture was then concentrated under reduced pressure. The residue was admixed with aqueous citric acid, aqueous sodium chloride, ethyl acetate and diluted aqueous sodium hydroxide solution until the mixture gave an alkaline reaction (pH=9), the mixture was extracted four times with ethyl acetate and the combined organic phases were dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: cyclohexane/acetone). This gave 0.56 g (32% of theory) of 2-{6-[4-(pyridin-3-yl)-1H-pyrazol-1-yl]pyridin-2-yl}pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12].ClC1C=CC=CC=1N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: N#CC(C#N)=NNc1ccccc1Cl
Reactant: NN
Solvent: Nc1ccccc1Cl
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccccc1Cl
Yield: 29 %

Procedure:
This compound was prepared using 102 mg (0.5 mmol) of 2-[(2-chlorophenyl)-hydrazono]malononitrile, which was derived from 2-chloroaniline (105 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 34 mg (29%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Mg].[F:10][C:11]([F:16])([F:15])[C:12](O)=[O:13].Cl>CCOCC>[CH:4]1[C:5]([C:12]([C:11]([F:16])([F:15])[F:10])=[O:13])=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)C(F)(F)F
Reaction time: 0.25 h

Procedure:
In a three-neck flask, 52.5 g of 4-fluoro-1-bromobenzene are charged with 60 ml ether, then 7.3 g magnesium turnings. The walls of the flask are rinsed with a few ml ether. Small crystals of iodine are added thereto and the mixture is heated to reflux until all the magnesium has reacted with the same. The mixture is left to revert to room temperature, then a solution of 11.4 g trifluoro acetic acid in 15 ml ether is very slowly added in about 20 minutes. The inner temperature is kept at about 20°-30° by external cooling. The mixture is kept aside at room temperature for 15 minutes and then heated to reflux for three hours. The mixture is thereafter kept in a cool place for 12 hours. The cooled mixture is poured on a mixture of crushed ice and chlorhydric acid. The etherous phase is separated. The aqueous phase is extracted twice with 100 ml ether.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14]O)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:16]=[CH:17][CH:18]=[N:19][C:5]1=2.N1C=CC=CC=1.CS([Cl:30])(=O)=O.C(Cl)Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:30][CH2:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[N:16]=[CH:17][CH:18]=[N:19][C:5]=3[N:4]([CH2:3][O:2][CH3:1])[C:9]=2[CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCN1c2cc(CO)ccc2Sc2nccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCN1c2cc(CCl)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a solution of 19 g of 10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine-8-methanol and 13.9 ml of pyridine in N,N-dimethylformamide (150 ml) was added dropwise under a nitrogen atmosphere 13.3 ml of methanesulfonyl chloride at 0° C. Then the reaction mixture was stirred at room temperature for 1 hour and then poured into a pre-cooled aqueous solution of methylene chloride/sodium hydrogen carbonate. Then it was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with methylene chloride) to thereby give 13.6 g of the title compound as pale yellow crystals.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:10][C:11](=[O:15])[CH2:12][CH2:13]Cl)[CH3:9].C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:8]([O:10][C:11](=[O:15])[CH2:12][CH2:13][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: CCOC(=O)CCCl
Reactant: NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: CCOC(=O)CCNC1CCCCC1
Temperature: 80 °C
Yield: 72.3 %

Procedure:
Cyclohexylamine (0.86 g, 8.7 mmol) and 3-chloro-propionic acid ethyl ester (1.18 g, 8.67 mmol) were combined neat and K2CO3 (1.2 g, 8.7 mmol) and a catalytic amount of tetrabutylammonium iodide (ca. 5 mg) was added. The mixture was heated at 80° C. overnight. The resulting mixture was then partitioned between water and dichloromethane. The organic layer was dried (MgSO4) and concentrated to afford 1.25 g (72%) of the title compound.