Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1>[OH-].[Na+]>[O:14]([C:7]1[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(Oc2ccccc2)c(S(N)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)ccc1Oc1ccccc1

Procedure:
6.2 g of 3-N-(3-azabicyclo-[3.2.0]-heptano)-4-phenoxy-5-sulphamylbenzoic acid methyl ester are suspended in 60 ml of 1 N NaOH and the suspension is heated on the waterbath until a clear solution is formed. The acid is then precipitated with 2 N HCl, while stirring well, and is recrystallised from glacial acetic acid.
Reaction SMILES: [Na].COS([O-])(=O)=O.CN(C)[C:10]1[CH2:14][CH2:13][CH2:12][N+:11]=1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:23]([O:25][C:26](=[O:38])[CH2:27][C:28]1[CH:37]=[CH:36][C:33]([O:34][CH3:35])=[C:30]([O:31][CH3:32])[CH:29]=1)[CH3:24].O>C(O)C.C(OCC)C>[CH2:15]([N:11]1[CH2:12][CH2:13][CH2:14][C:10]1=[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:38])[C:28]1[CH:37]=[CH:36][C:33]([O:34][CH3:35])=[C:30]([O:31][CH3:32])[CH:29]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(OC)c1
Reactant: CN(C)C1=[N+](Cc2ccccc2)CCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=C1CCCN1Cc1ccccc1)c1ccc(OC)c(OC)c1

Procedure:
Add (dropwise at 90°, with stirring, in a stream of nitrogen) a solution of 2.6 g of sodium in 50 ml of ethanol to 34.5 g of 2-dimethylamino-1-benzyl-1-pyrroliniummethylsulfate and 19.7 g of homoveratric acid ethyl ester. Keep the resulting reaction mixture at this temperature for a further 30 minutes and then distribute it between water and diethyl ether. Dry the ether solution over sodium sulfate and then concentrate it to obtain a yield [32.2 g (96% of theory)] of title compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]=[O:9].C[Si]([C:14]#[N:15])(C)C>[I-].[Zn+2].[I-].CCOCC>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]([OH:9])[C:14]#[N:15]
Reactant: C[Si](C)(C)C#N
Reactant: CC1=C(C=O)CCCC1
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CC1=C(C(O)C#N)CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methyl-1-cyclohexene-1-carbaldehyde (3.7 g., 29.8 mmole), trimethylsilyl cyanide (4.7 ml., 1.25 equivalents) and 50 mg. of zinc iodide were stirred in 50 ml. of ether for 1.5 hours at room temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate concentrated in vacuo. The residual trimethylsilyl ether was taken up in 50 ml. acetone and acidified with 5 ml. 6N HCl. The mixture was stirred for 3 hours at room temperature, diluted with 500 ml. of ether, and the aqueous layer separated and discarded. The organic layer was washed 1×50 ml. saturated NaHCO3, dried over Na2SO4 and concentrated to an oil (3.2 g.). The oil was chromatographed on 100 ml. silica gel initially with 9:1, then 4:1, then 2:1 hexane:ethyl acetate and finally ethyl acetate as eluant. Product fractions were combined and evaporated to yield title product as an oil, 800 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[O:18]=[C:19]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21](=[O:32])[N:20]1[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH:25]=[CH:26][CH:27]=2>>[O:18]=[C:19]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21](=[O:32])[N:20]1[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:25]=[CH:26][CH:27]=2
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1C(=O)c2cccc3cccc(c23)C1=O
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)c2cccc3cccc(c23)C1=O

Procedure:
Batch size: 6.1 g (41.0 mmol) 3-(3-pyridyl)-acrylic acid, 14.2 g (111.8 mmol) oxalyl chloride and 10.0 g (37.3 mmol) 4-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-butylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11](=[O:24])[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[C:31]1(=O)[O:36][C:34](=[O:35])[CH2:33][CH2:32]1>CN(C)C=O>[CH2:17]([N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([N:1]4[C:34](=[O:35])[CH2:33][CH2:32][C:31]4=[O:36])=[CH:30][CH:29]=3)=[N:8][C:9]=2[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:11]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(N4C(=O)CCC4=O)cc3)nc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
To a solution of 8-(4-amino-benzyl)-1-benzyl-3-butyl-3,7-dihydro-purine-2,6-dione (60 mg) (prepared as described in example 64) in N,N-dimethylformamide (2 mL) was added succinic anhydride (Aldrich) (20 mg) and the mixture stirred at RT under argon for 48 h. The reaction mixture was concentrated in vacuo and acetyl chloride (Aldrich) (2 mL) added to the residue. After stirring at RT for an additional 70 h saturated aqueous sodium bicarbonate (5 mL) was added cautiously to the reaction mixture. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purified by crystallization from methanol/water to give the desired product as a pale yellow solid (36%). Mp=208–212° C. MS, m/z(M+)=485.2064.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][N:9]=1
Reactant: COc1ccc2c(COc3ccccc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(COc3ccccc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-phenoxymethyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH3:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[I:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([N:21]3[CH:22]=[C:18]([I:17])[N:19]=[CH:20]3)[N:7]=2)=[CH:9][C:10]=1[CH3:15]
Reactant: Ic1c[nH]cn1
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidine (example A.47) (3.5 g, 13.8 mmol) and commercially available 4-iodo-imidazole (2.95 g, 15.2 mmol) according to the general procedure IVa. Obtained as an off-white solid (2.67 g, 92%). MS (ISP) 485.1 [(M+H)+]; mp 223° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19]>CCCCCC>[O:17]([CH2:21][CH2:22][NH:23][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([CH3:1])[CH:3]=1)[N+:18]([O-:20])=[O:19]
Reactant: Cc1cccc(OCC(=O)O)c1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CCCCCC
Product: Cc1cccc(OCC(=O)NCCO[N+](=O)[O-])c1
Yield: 55.4 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 3-methylphenoxyacetic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.50 g of the title compound was obtained as colorless powdery crystals (solvent for recrystallization; hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[C:19]([C:21](Cl)=[O:22])[CH:20]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].N1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH:34][C:21]([C:19]2[CH:20]=[C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]3[N:18]=2)=[O:22])[CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: O=C(Cl)c1cc2nc(-c3ccc(Cl)cc3)cc(C(F)(F)F)n2n1
Reactant: CS(=O)(=O)c1cccc(N)c1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(NC(=O)c2cc3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carbonyl chloride (0.100 g, 0.277 mmol) (prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid using standard procedures, e.g.; thionyl chloride) was added to a solution of 3-methanesulfonyl-phenylamine (0.052 mL, 0.304 mmol) in acetonitrile (10 mL) containing pyridine (0.067 mL, 0.831 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate (25 mL) and washed with 1M hydrochloric acid (50 mL). The organic layer was collected, concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel to give 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (3-methanesulfonyl-phenyl)-amide (0.128 g, 93%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([OH:9])=O)[C:2]=1[C:10]([OH:12])=O.C(OC(=O)C)(=O)C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[C:10](=[O:12])[C:2]3[C:3](=[N:4][CH:5]=[CH:6][N:1]=3)[C:7]2=[O:9])=[N:22][CH:23]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)c1nccnc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1c2nccnc2C(=O)N1c1ccc(Cl)cn1

Procedure:
In Indian Published Patent Application No. 645/MUM/2004 discloses the reaction of pyrazine-2,3-dicarboxylic acid with acetic anhydride and concomitant reaction with 2-amino-5-chloro pyridine at a temperature of 120-130° C. in a mole ratio 1.23:1 to obtain 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine, which is selectively reduced with sodium borohydride in the presence of organic solvent-water system. The product, 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine (V) is reacted with 1-chlorocarbonyl-4-methyl piperazine in pyridine and methylene chloride system to yield 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4-b]pyrazin-5-yl-4-methyl piperazine-1-carboxylate (zopiclone).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH2:19]([C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1)[CH3:20]>>[CH2:19]([C:21]1[CH:22]=[C:23]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:24]=[CH:25][CH:26]=1)[CH3:20]
Reactant: CCc1cccc(N)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: CCc1cccc(Nc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-ethyl-phenylamine give N1-(3-ethyl-phenyl)-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 344(MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=O)[CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:3][CH2:2]1>C1COCC1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)N2CCOCC2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCCN2CCOCC2)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
Tert-butyl 4-(2-morpholino-2-oxoethoxy)piperidine-1-carboxylate (75) (8.84 g, 26.92 mmol) was dissolved in dry THF (50 mL), to this was added borane-methyl sulfide complex (20.19 mL, 40.38 mmol) and the reaction was stirred at 40° C. for 3 hours then at ambient temperature overnight. The gummy mixture was evaporated and was quenched with 2.0 N sodium carbonate (50 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford The desired material as a colourless liquid (6.50 g, 77% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.45 (9H, s), 1.54-1.45 (2H, m), 1.84-1.79 (2H, m), 2.90-2.84 (2H, m), 3.16-3.03 (6H, m), 3.79-3.67 (5H, m), 3.97 (2H, t), 4.15-4.10 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([Cl:26])[CH:17]=3)[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[N+:31]([O-])([OH:33])=[O:32].S(=O)(=O)(O)O.CCCCCC>O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:31]([O-:33])=[O:32])=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[C:18]([Cl:26])[CH:17]=3)[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:27]([F:30])([F:28])[F:29]
Reactant: FC(F)(F)c1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)c(Cl)c3)c2)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1Oc1ccc(C(F)(F)F)c(Cl)c1

Procedure:
1,3-Bis(2-chloro-α,α,α-trifluoro-p-tolyloxy)benzene (12 g. 0.0255 mole) is added to a mixture of concentrated nitric acid (12 g.) and sulfuric acid (15 g.) at 5° C. The temperatures is then allowed to rise to 25°-30° C. with manual stirring and mild ice bath cooling and after 10-20 minutes, the oil solidifies. The mixture is taken up in water/benzene (400 ml)/hexane (400 ml) and the organic phase is washed with water, dried, filtered through activated silica gel (~20 g.), and the solvents removed. The residue is recrystallized from isopropanol to give 1,3-bis(2-chloro- α,α,α-trifluoro-p-tolyloxy)-4-nitrobenzene, (7.4 g. 56%) m.p. 110°-111.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:15]=2[N+:21]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N#N.[C:26]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>[Pd].CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:21]=[C:34]([C:33]4[CH:36]=[CH:37][C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:31][CH:32]=4)[O:20][C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: N#N
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3oc(-c4ccc(C(C)(C)C)cc4)nc23)CC1
Temperature: 80 °C
Yield: 81 %

Procedure:
4-(3-hydroxy-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 3.09 mmol) was charged to a 250 mL round bottom flask containing 10% Pd/C, stir bar and septum. Under a positive stream of N2, 2-propanol (80 mL) was added via syringe. The flask was evacuated and fitted with a balloon containing H2 and stirred, under H2, at room temperature for 18 h. LC-MS indicated only aniline present. 4-tert-Butyl-benzaldehyde (800 μL, 4.64 mmol) was added, the balloon was replaced with an air condenser and the stirring solution was heated to 80° C. for 48 h. The reaction was cooled to room temperature and filtered through celite to remove the catalyst and the solvent removed in vacuo to give a brown oil. This oil was adsorbed onto silica and purified by column chromatography, eluting with 11% ethyl acetate in hexane to afford the product as a clear waxy material (1.09 g, 81%). Mass Spectrum (+ESI): 436 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([N:13]2[CH2:27][CH2:26][C:16]3([O:21][CH2:20][C:19](=[O:22])[N:18]([CH:23]4[CH2:25][CH2:24]4)[CH2:17]3)[CH2:15][CH2:14]2)[C:10]([NH2:12])=[O:11])=[C:4]([F:28])[CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[CH:42][CH:43]=[N:44]3)=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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(Cl)Cl>[CH:23]1([N:18]2[CH2:17][C:16]3([CH2:26][CH2:27][N:13]([CH:9]([C:5]4[C:6]([F:8])=[CH:7][C:2]([C:37]5[CH:46]=[C:45]6[C:40]([CH:41]=[CH:42][CH:43]=[N:44]6)=[CH:39][CH:38]=5)=[CH:3][C:4]=4[F:28])[C:10]([NH2:12])=[O:11])[CH2:14][CH2:15]3)[O:21][CH2:20][C:19]2=[O:22])[CH2:25][CH2:24]1
Reactant: NC(=O)C(c1c(F)cc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)C(c1c(F)cc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Yield: 22 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (246 mg, 0.54 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (137 mg, 0.54 mmol) and 2M aq K2CO3 (0.59 mL, 1.18 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (21.9 mg, 0.03 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in the microwave at 110° C. for 25 min, at which point the reaction had proceeded to completion. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 5 mL of 1M aq HCl. The organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered through a pad of celite, and concentrated in vacuo. Purification of the residue with reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) followed by chiral HPLC (Lux Cell 4, methanol) afforded the title product in 99.9% ee (61 mg, 22% yield). αD=+30 deg (c=0.1, methanol); MS(ES)+ m/e 507 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.58-0.71 (m, 2 H) 0.76-0.87 (m, 2 H) 1.65 (dd, J=11.12, 4.29 Hz, 1 H) 1.71-1.81 (m, 1 H) 1.95 (s, 1 H) 1.92 (s, 1 H) 2.29-2.38 (m, 1 H) 2.64-2.75 (m, 2 H) 2.75-2.84 (m, 1 H) 2.84-2.96 (m, 1 H) 3.14 (s, 2 H) 3.98 (s, 2 H) 4.78 (s, 1 H) 5.68 (br. s., 1 H) 7.40-7.47 (m, 3 H) 7.49 (dd, J=8.21, 4.17 Hz, 1 H) 7.85 (dd, J=8.59, 2.02 Hz, 1 H) 8.00 (d, J=8.59 Hz, 1 H) 8.27 (d, J=8.34 Hz, 1 H) 8.36 (s, 1 H) 8.99 (dd, J=4.29, 1.77 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13](N(CC)CC)[CH3:14].C=C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C)C=O>[CH:13]([C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])=[CH2:14]
Reactant: CCN(CC)CC
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: C=Cc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 100 °C
Yield: 53.6 %

Procedure:
To a 100 mL Parr reactor Model # 4768 was added 4.6 g, 20 mmol of 5bromo-2-nitrobenzaldehyde of example 1 with dimethylformamide (30 mL), triethylamine (9.1 g, 90 mmol), tri-o-tolyl phosphine (0.060 g, 0.2 mmol), and palladium acetate (0.022 mg, 0.1 mmol). The reactor was charged with ethylene gas (300 psi) and heated to 100° C. for 12 hours. The reactor was then cooled to room temperature and the excess ethylene released. The product, 5-vinyl-2-nitrobenzaldehyde, was recovered by dissolving the reaction mixture in water and washing the aqueous solution with ether (3×50 mL). The combined organic solutions were dried over magnesium sulfate before filtration, followed by removal of the solvent by vacuum. The 5-vinyl-2-nitrobenzaldehyde product was purified by column chromatography with silica gel as stationary phase and chloroform as eluent to give a light brown solid (1.9 g, 53% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:14]3[CH2:15][CH2:16][CH:10]2[CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)=[N:7][CH:8]=1)#[N:2].Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:26][NH:25][C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:10]3[CH2:16][CH2:15][CH:14]2[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]3)=[N:7][CH:8]=1)=[NH:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(C#N)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(C(=N)NO)cn1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
The product of step b) (7.6 g) is dissolved in 75 ml of ethanol, and a solution of 3.36 g of hydroxylamine hydrochloride dissolved in 38 ml of water is added, followed by addition of 5 g of sodium carbonate. The mixture is stirred at 90° C. for 4 hours. The resulting mixture is cooled and filtered. 8 g of the title compound are obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=2[N:3]=1.Cl.COC(=O)[C@H](C[SH:35])N.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(O)(=O)C>[SH:35][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=2[N:3]=1
Reactant: CC(C)=CCn1c(Br)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Reactant: COC(=O)[C@@H](N)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)=CCn1c(S)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
50 mg of 8-bromo-3-methyl-7-(3-methylbut-2-enyl)-1-(2-oxo-2-phenylethyl) -3,7-dihydropurine-2,6-dione were dissolved in 1 ml of dimethylformamide and, after addition of 24 mg of L-cysteine methyl ester hydrochloride and 37 mg of potassium carbonate, the mixture was heated with stirring at 90° C. for 1 hour. After cooling to room temperature, 10 ml of water were added, and the mixture was made weakly acidic with glacial acetic acid. A precipitate separated out on stirring and was filtered off and dried in a vacuum.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([O:19]CC)=O)=[C:15]([Cl:22])[N:14]=[C:13]3[CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35].[CH3:41][NH2:42]>>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([NH:42][CH3:41])=[O:19])=[C:15]([Cl:22])[N:14]=[C:13]3[CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][S:34]([C:37]([F:38])([F:40])[F:39])(=[O:35])=[O:36]
Reactant: CCCCc1nc(Cl)c(C(=O)OCC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Reactant: CN
Product: CCCCc1nc(Cl)c(C(=O)NC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1

Procedure:
A solution of the product of Example 65 (0.17 g) in methylamine (10 ml) was heated at 50° for 18 hours. The solvent was allowed to evaporate. The residue was dissolved in dichloromethane (50 ml) and washed with hydrochloric acid (2M:50 ml). The organic solution was purified by column chromatography eluting with dichloromethane/methanol (20:1) to give the title compound as a white foam (0.136 g) m.p. 89°-92° C.