Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[N:7]=[C:6]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=2[CH3:9])[CH:14]=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(C=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccnc(Cl)n1
Product: Cc1ccc(C=O)cc1-c1ccnc(Cl)n1
Yield: 80 %

Procedure:
2,4 dichloropyrimidine and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was coupled following procedure A. The yield was 80%. LC-MS showed the product was >95% pure and had the expected M+H+ of 233. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 10.0 (s, 1H) 8.7 (s, 1H) 7.9 (d, 2H) 7.5 (d, 2H), 2.5 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1.[Cl:50][C:51]1[CH:52]=[C:53]([OH:57])[CH:54]=[CH:55][CH:56]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.O>[Cl:50][C:51]1[CH:52]=[C:53]([CH:54]=[CH:55][CH:56]=1)[O:57][C:7]1[N:6]=[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)[N:10]2[N:11]=[CH:12][C:13](/[CH:14]=[C:15]3/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/3)=[C:9]2[N:8]=1
Reactant: Oc1cccc(Cl)c1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(Oc4cccc(Cl)c4)nc23)N1
Temperature: 90 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (1.0 eq, 25 mg, 0.0704 mmol) was combined in a vial with 3-chlorophenol (5.0 eq, 45 mg, 0.35 mmol) and K2CO3 (5.0 eq, 48 mg, 0.347 mmol) in NMP (0.2 ml). The mixture was stirred at 90° C. for 1 hour. Water was added and the resulting solid was filtered and dried. Trituration in a mixture of ethyl acetate and hexanes followed by filtration provided (Z)-5-((2-(3-chlorophenoxy)-4-(cyclopropylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione as a tan solid (20 mg, 69%). LCMS (ES):>95% pure, m/z 412 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:51]=[C:50]([N:52]1[CH2:53][CH2:54][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:66])[F:67])[CH:60]=2)[CH2:56][CH2:57]1)[CH2:49][NH:48][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:16])=[CH:25][CH:24]=1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1ccc(C(=O)N2CCCC2)cc1
Reaction time: 0.03 h
Yield: 75.9 %

Procedure:
DIPEA (200 mg, 1.5 mmol) was added to a stirred solution of 4-(pyrrolidine-1-carbonyl)-benzoic acid (75 g, 0.34 mmol) in DMF (5 mL) followed by HOBt (50 mg, 0.37 mmol) and EDCI (164 mg, 0.85 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (127 mg, 0.37 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with cold water, the precipitate was collected to afford 130 mg (75.58% Yield) of N-{2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-4-(pyrrolidine-1-carbonyl)-benzamide. LC/MS [M+H]+: 504, 94.9%. 1H NMR (300 MHz, DMSO-d6): δ 7.2 (t, 1H), 7.96 (d, 2H), 7.64-7.48 (m, 3H), 7.36 (t, 3H), 4.9 (b, 1H), 4.2 (d, 2H), 4.0 (d, 2H), 3.5 (t, 2H), 3.4 (t, 2H), 2.1-1.8 (m, 6H), 1.7 (m, 3H).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH:2]12.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=3)[C:22]=2[OH:23])=[C:14]([CH3:33])[CH:13]=1)#[N:11].C(O)=O>>[OH:23][C:22]1[N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([N:6]3[CH2:5][CH2:4][N:3]4[CH2:7][CH2:8][CH2:9][CH:2]4[CH2:1]3)=[O:29])=[CH:26][N:25]=2)[N:20]=[CH:19][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][C:14]=1[CH3:33]
Reactant: C1CC2CNCCN2C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN4CCCC4C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using octahydropyrrolo[1,2-a]pyrazine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (47 mg, 0.099 mmol, 79%) as a white solid. MS: 429 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.52 (m, 1 H) 1.72 (br. s., 3H) 2.09 (br. s., 1 H) 2.21 (d, J=8.8 Hz, 2 H) 2.43 (s, 3 H) 2.54-2.61 (m, 1 H) 2.87-3.15 (m, 3 H) 3.50-3.88 (m, 1 H) 4.30-4.68 (m, 1 H) 7.63 (d, J=8.1 Hz, 1 H) 7.69 (s, 1 H) 7.88 (d, J=8.1 Hz, 1 H) 8.03 (dd, J=8.6, 2.0 Hz, 1 H) 8.09 (s, 1 H) 8.42 (d, J=8.3 Hz, 1 H) 8.52 (d, J=2.0 Hz, 1 H) 12.77 (br. s., 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][NH:11][CH3:12].Cl>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 5° C. 4-bromobenzylbromide (100 g, 402 mmol) in 100 mL DMF is added to a mixture of dimethylamine (40% in water, 150 mL, 1.33 mol). After 0.5 h stirring at RT, 6 M aqueous HCl is added and the reaction mixture is extracted with diethyl ether. The combined organic phases are washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue is purified by vacuum distillation (bp 58° C. at 2 mbar). Yield: 77.6 g.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:5]([CH2:6][NH:7][C:8]2[C:9]3[N:10]([C:15](C(O)=O)=[C:16]([CH3:18])[N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[C:4]([CH3:25])[CH:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1.[Cl-]>C(OCC)C>[CH3:18][C:16]1[N:17]=[C:9]2[C:8]([NH:7][CH2:6][C:5]3[C:4]([CH3:25])=[CH:3][C:2]([F:1])=[CH:23][C:22]=3[CH3:24])=[CH:13][C:12]([CH3:14])=[CH:11][N:10]2[CH:15]=1
Reactant: Cc1cc(NCc2c(C)cc(F)cc2C)c2nc(C)c(C(=O)O)n2c1
Agent: [Cl-]
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(NCc2c(C)cc(F)cc2C)c2nc(C)cn2c1
Yield: 55.5 %

Procedure:
A mixture of 8-(4-fluoro-2,6-dimethylbenzylamino)-2-methyl-6-methylimidazo[1,2-a]pyridine 3-carboxylic acid (0.35 g, 1.03 mmol) and diphenyl ether and refluxed for 10 min. Petroleum ether 40-60 was added at room temperature followed by hydrogene chloride in diethyl ether. The petroleum ether diphenlether layer was removed from the formed precipitate. The precipitate was washed with petroleum ether thereafter dissolved in methylene chloride and basified with sodium hydroxide (2M). The layers were separated and the organic layer was washed with water. The solvent was evaporated and the residue was chromatographed (hexane:ethyl acetate, 2:1) giving 0.17 g (50%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:32][O:33][NH:34][CH3:35].C(N(CC)CC)C>C1COCC1.CN(C=O)C>[CH3:32][O:33][N:34]([CH3:35])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-(tert-Butoxycarbonyl)-4-piperidine carboxylic acid (2.29 g, 10 mmol) and 4-methyl morpholine (1.2 mL, 11 mmol) in THF (60 mL) cooled to −15° C. was added isobutyl chloroformate (1.36 mL, 10.5 mmol). To this solution was added N-methoxy-N-methyl amine (1.07 g, 11 mmol) in DMF (20 mL) followed by triethyl amine (1.53 mL, 11 mmol). The resulting reaction was warmed to room temperature. The reaction was quenched after 1 hour by adding a solution of saturated NaHCO3 (400 mL). The resulting mixture was extracted with EtOAc (3×). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified on the Biotage flash 40 M column using 1:1 ethyl acetate-hexanes as the solvent to give the title compound a colorless oil. 1H NMR (CDCl3, 500 M): δ 4.16(bm, 2H), 3.73(s, 31), 3.21(s, 3H), 2.79(m, 3H), 1.7(m, 4H), 1.48(s, 9H). LC-MS: 1.75 min; (M-56)=217.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].O>C(O)C>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: OCCCCCCCCCCCBr
Reactant: Oc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCCCCCCCCCSc1ccc(O)cc1
Temperature: 25 °C

Procedure:
1.45 g of 85% potassium hydroxide was dissolved in 100 ml of ethanol at room temperature. 2.78 g of 4-mercaptophenol was then added to the above-prepared solution, and dissolved therein. To the above prepared reaction mixture, 5.0 g of 11-bromo-1-undecanol was added, and the reaction mixture was allowed to react for 3 hours under the condition that the ethanol was refluxed. The thus obtained reaction mixture was cooled to room temperature, and concentrated by use of a rotary evaporator. The concentrated reaction mixture was poured into 500 ml of water, followed by vigorous stirring. Thus, a white solid separated out. The resultant white solid was recrystallized from a mixed solvent of ethyl acetate and hexane, so that 4.5 g of 4-(11-hydroxyundecylmercapto) phenol was obtained.
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH3:20])(=O)C.[Br:21]C#CCCCCCCBr>>[Br:21][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: BrC#CCCCCCCBr
Reactant: CCCCC=CCCC=CCCCCCCOC(C)=O
Product: CCCCC=CCCC#CCCCCCCBr

Procedure:
In particular, 7,11-hexadecadienyl acetate expressed by the formula CH3 (CH2)3CH=CH(CH2)2CH=CH(CH2)6OCOCH3 is prepared by first reacting a Grignard reagent of 1-halo-3-octene and 1,8-dibromo-1-octyne to form 1-bromohexadeca-11-en-7-yne which is then acetylated and partially hydrogenated in the presence of a Lindlar catalyst.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[OH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:27])[CH:33]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1-c1cccc(O)c1
Temperature: 130 °C

Procedure:
To a solution of {1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (2087 μmol) and 3-hydroxyphenylboronic acid (1.55 eq) in a mixture of DME/EtOH: 1/1 (8 ml) were added Na2CO3 (4 eq) and Pd tetrakis (0.05 eq.). The reaction mixture was flushed with Ar and was heated in the microwave at 130° C. for 1.5 hours. The reaction mixture was cooled to RT, diluted with 1N NaHCO3 and extracted with EtOAc. The organic layer was extracted with 1N NaHCO3 and the combined aqueous layers were acidified with citric acid and 1N HCl. The aqueous layer was extracted with EtOAc, the organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The compound was purified by recrystallization from EtOAc.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)[CH:3]=1>CO.[C].[Pd]>[C:22]1([C:20]([N:17]2[CH2:18][CH2:19][N:14]([C:4]3[CH:3]=[CH:2][N:7]=[N:6][C:5]=3[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:15][CH2:16]2)=[O:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)N1CCN(c2cc(Cl)nnc2-c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1ccccc1)N1CCN(c2ccnnc2-c2ccccc2)CC1
Reaction time: 3 h

Procedure:
To (4-(6-chloro-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone (1 g) dissolved in methanol (40 ml), and palladium carbon (10 mol %) was added very slowly under nitrogen atmosphere and the reaction mixture was stirred under hydrogen atmosphere (1 kg pressure) for 3 hrs. The progress of reaction was monitored by TLC. After consumption of starting material, the reaction mixture was filtered through celite, washed with methanol and the filterate was concentrated under reduced pressure to get phenyl(4-(3-phenylpyridazin-4-yl)piperazin-1-yl)methanone as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][N:15]3[CH:19]=[N:18][C:17]([C:20](OC)=[O:21])=[N:16]3)[CH:11]=[N:10][C:9]=2[O:24][CH3:25])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][N:15]3[CH:19]=[N:18][C:17]([CH2:20][OH:21])=[N:16]3)[CH:11]=[N:10][C:9]=2[O:24][CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ncn(Cc2cnc(OC)c(-c3cccc(Cl)c3)n2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(Cn2cnc(CO)n2)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
To a solution of methyl 1-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (Example 127, 77.00 mg, 0.21 mmol), in THF (1 mL) was added lithium borohydride (4.66 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 hr. The mixture was diluted with water and extracted into DCM. The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification (FCC, SiO2, 0-5% DCM/MeOH) afforded the title compound (50 mg; 70%). 1H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 8.21 (s, 1H), 8.02 (td, J=1.1, 2.1 Hz, 1H), 8.00-7.92 (m, 1H), 7.45-7.38 (m, 2H), 5.53 (s, 2H), 4.59 (s, 2H), 4.06 (s, 3H). [M+H]=332.15.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[Cl-].[Li+].C([Sn](CCCC)(CCCC)/[CH:20]=[CH:21]\[O:22][CH2:23][CH3:24])CCC.[NH4+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8](/[CH:20]=[CH:21]\[O:22][CH2:23][CH3:24])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Cl)nc1N
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCO/C=C\c1cnc(C(=O)OC)c(N)n1
Temperature: 80 °C
Yield: 82.4 %

Procedure:
A mixture of 3-amino-5-chloro-pyrazine-2-carboxylic acid methyl ester [28643-16-5] (2 g, 10.66 mmol), lithium chloride (1.582 g, 37.3 mmol), Pd(PPh3)2Cl2 (0.748 g, 1.066 mmol) and tributyl-((Z)-2-ethoxy-vinyl)-stannane (6.42 ml, 19.19 mmol) in DMF (104 ml) under argon was heated at 80° C. bath temperature for 1.5 h. A saturated. aq. NH4Cl was added and the mixture was extracted with MTBE, then once with EtOAc/THF 3/1. The combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:9) to provide the title compound as yellow oil (1.96 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][CH:4]([NH:8][C:9](=[O:27])[CH:10]([NH:18][C:19]([C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:45][NH:46][NH:47][CH3:48]>C1COCC1.[OH-].[Na+]>[CH2:11]([CH:10]([NH:18][C:19]([C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1)=[O:20])[C:9]([NH:8][CH:4]([C:5]([N:46]([CH3:45])[NH:47][CH3:48])=[O:7])[CH2:3][CH:2]([CH3:28])[CH3:1])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNNC
Reactant: CC(C)CC(NC(=O)C(Cc1ccccc1)NC(=O)c1cnccn1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CNN(C)C(=O)C(CC(C)C)NC(=O)C(Cc1ccccc1)NC(=O)c1cnccn1
Temperature: -10 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
4-Methyl-2-(3-phenyl-2-[(2-pyrazinylcarbonyl)amino]propanoylamino) pentanoic acid (200 mg, 0.52 mmol) was dissolved in THF (1.2 mL). N-Methylmorpholine (0.057 mL, 0.52 mmol) was added, and the resulting clear solution was cooled to −10° C. Isobutyl chloroformate (0.068 mL, 0.52 mmol) was added dropwise to cause N-Methylmorpholine HCl salt precipitation. N,N′-dimethylhydrazine hydrochloride salt (346 mg, 2.6 mmol) was dissolved in 3N NaOH (1.7 mL). The resulting mixture was added to the solution and stirred for 1 h. The solution was extracted by EtOAc, and washed with 5% NaHSO3, saturated sodium bicarbonate solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, 20/1: DCM/MeOH, Rf=0.3) afforded N2-[1-benzyl-2-(1-[(1,2-dimethylhydrazino) carbonyl]-3-methylbutylamino)-2-oxoethyl]-2-pyrazinecarboxamide as a pale yellow solid (197 mg, 89%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].B(Br)(Br)Br.C(OCC)(=O)C.O>ClCCl>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (26.2 g) in dichloromethane (100 mL) was added dropwise boron tribromide (1.0 M dichloromethane solution, 170 mL) at 0° C. After stirring for 18 hr, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (22.1 g, 87%) as a colorless solid.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O.CCOCC>[CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=2[CH2:2]1
Reactant: O=C1CCCc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Product: O=C1CCCc2c1cccc2[N+](=O)[O-]

Procedure:
10 ml (75 mmol) of α-tetralone was added dropwise to 7.6 g (75 mmol) of potassium nitrate dissolved in 75 ml of concentrated sulfuric acid (at -10° C). The resulting mixture was poured onto ice and the precipitate was suspended in ether. The precipitate (the 7 nitro isomer) was filtered off and the ether solution was evaporated. The residue was purified by column chromatography on silica gel. Yield: 4.7 g of the title compound, M.p. 94°-96° C.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:8](Cl)[C:9](Cl)=[O:10]>[Zn].C(O)(=O)C>[CH:2]12[CH2:8][C:9](=[O:10])[CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3]2
Reactant: C1=CCCC=C1
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CC2C=CCCC12

Procedure:
The starting material is prepared by the treatment of 1,3-cyclohexadiene with dichloroacetyl chloride, followed by dechlorination with zinc and acetic acid of the resulting adduct to give bicyclo[4,2,0]-oct-2-en-7-one. This compound is subjected to Baeyer-Villiger oxidation to give 7-oxabicyclo[4,3,0]non-2-en-8-one which is treated with thallium (III) nitrate under carefully controlled conditions to give 6-formyl-2-oxabicyclo[3,3,0]octane-3-one having properties identical with those reported by Corey and Ravindranathan, Tetrahedron Letters, 1971, 4753.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.Br.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.BrCC1CCCCO1>>[F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: BrCc1ccccn1
Reactant: COc1cc2c(cc1F)C1(CO2)C(=O)Nc2ccccc21
Agent: Br
Agent: BrCC1CCCCO1
Product: COc1cc2c(cc1F)C1(CO2)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2 (bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 5-fluoro-6-methoxy-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (77%) as a colorless solid: mp 142-144° C.; 1H NMR (300 MHz, CDCl3) δ 8.59-8.53 (m, 1H), 7.65 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.28-7.10 (m, 4H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.60 (d, J=6.8 Hz, 1H), 6.52 (d, J=10.1 Hz, 1H), 5.20 (d, J=15.8 Hz, 1H), 5.03-4.90 (m, 2H), 4.72 (d, J=9.0 Hz, 1H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.3, 157.2 (d), 155.4, 149.6, 149.3, 149.1, 149.0, 146.1, 142.1, 137.1, 131.8, 129.0, 123.8, 123.6, 122.8, 121.6, 119.0 (d), 110.7, 110.4, 109.6, 96.3, 80.5, 58.1, 56.4, 46.0; MS (ES+) m/z 377.2 (M+1).