Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([C:22]4[C:23]5[CH:37]=[CH:36][NH:35][C:24]=5[N:25]=[C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30](C)[N:29]=5)[N:27]=4)[CH:21]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.BrC1C=C(C2C3C=CNC=3N=C(C3C=CC=CN=3)N=2)C=NC=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([C:22]4[C:23]5[CH:37]=[CH:36][NH:35][C:24]=5[N:25]=[C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[N:27]=4)[CH:21]=3)=[CH:14][CH:15]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1cccc(-c2nc(-c3cncc(-c4ccc(C(=O)N5CCN(C)CC5)cc4)c3)c3cc[nH]c3n2)n1
Agent: Brc1cncc(-c2nc(-c3ccccn3)nc3[nH]ccc23)c1
Product: CN1CCN(C(=O)c2ccc(-c3cncc(-c4nc(-c5ccccn5)nc5[nH]ccc45)c3)cc2)CC1

Procedure:
(4-Methyl-piperazin-1-yl)-{4-[5-(2-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyridin-3-yl]-phenyl}-methanone is prepared by an analogous method to that for (4-methyl-piperazin-1-yl)-(4-{5-[2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyridin-3-yl}-phenyl)-methanone (Example 9) by replacing 4-(5-bromo-pyridin-3-yl)-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Example 16) with 4-(5-bromo-pyridin-3-yl)-2-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine (Example 44).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[F:14][CH:15]([F:21])[C:16](OCC)=[O:17].[NH4+].[Cl-]>C1COCC1>[F:14][CH:15]([F:21])[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8])=[O:17]
Reactant: CCOC(=O)C(F)F
Reactant: Fc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1F)C(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (10.00 g, 57.14 mmol) in THF (200 mL) was added n-butyllithium (2.5 M, 24.00 mL) drop-wise at −78° C. over a period of 15 minutes under N2. The mixture was stirred at −78° C. for 30 min. Ethyl 2,2-difluoroacetate (10.64 g, 85.71 mmol) was added dropwise at −78° C. and stirred for 2 hours at −78° C. TLC showed no starting material remained. Saturated aqueous NH4Cl (15 mL) was added dropwise at −78° C. The reaction mixture was warmed to 25° C., extracted with ethyl acetate (100 mL, three times). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=95:5) to afford 2,2-difluoro-1-(2-fluorophenyl)ethan-1-one (5.60 g, 47.8% yield, 85% purity). 1H NMR (CDCl3, 400 MHz): δ 7.99-7.95 (m, 1H), 7.70-7.64 (m, 1H), 7.33 (t, J=7.6 Hz 2H), 7.24 (dd, J=10.8, 8.4 Hz, 1H), 6.59-6.32 (m, 1H).
Reaction SMILES: [Cl:1][C:2]#[C:3][CH2:4][CH2:5][Cl:6].[Cl:7][SiH:8]([Cl:10])[Cl:9]>C(O)(C)C>[Cl:1][CH2:2][C:3]([Si:8]([Cl:10])([Cl:9])[Cl:7])=[CH:4][CH2:5][Cl:6]
Reactant: ClC#CCCCl
Reactant: Cl[SiH](Cl)Cl
Solvent: CC(C)O
Product: ClCC=C(CCl)[Si](Cl)(Cl)Cl
Yield: 93.6 %

Procedure:
To a mixed solution of 15 ml (0.153 mol) of 1,4-dichloro-1-butyne [IV]and 13.6 ml (0.16 mol) of trichlorosilane (bp: 31°-32° C.) [V], were added 0.15 ml (10 mmol) of H2PtCl6 . 6H2O in an isopropyl alcohol solution (0.05 g/ml), which were heated for 8 hours. Then, it was directly distillated to obtain 37 g of 1,4-dichloro-2-(trichloro)silyl-2-butene [VI](yield: 94 %, bp: 70° C./1 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].CS(O)(=O)=O.[CH3:26][OH:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:27][CH3:26])=[O:10]
Reactant: CO
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Agent: CS(=O)(=O)O
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 85 °C

Procedure:
2 g (0.00652 mol) (±)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide and 2 mL (0.0308 mol) methane sulfonic acid and 20 mL methanol were mixed and the solution was refluxed at 85° C. for 12 hrs. The excess of solvent was removed under reduced pressure. The pH was adjusted to about 9 with aq. solution of sodium bicarbonate at 0° C., and the product was extracted with 70 mL ethyl acetate. The combined organic extracts were dried over anhy. Na2SO4 and concentrated. The residue obtained was purified by column chromatography using hexane:ethyl acetate as eluent. The product thus obtained was concentrated, was stored under nitrogen atmosphere, and kept in refrigerator before converting into salt. The yield of titled product was 0.419 g (20%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[C:22]([NH:24][C:25]([NH:27][CH3:28])=[O:26])[S:23][C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[CH3:28][NH:27][C:25]([NH:24][C:22]1[S:23][C:17]2[CH2:16][NH:15][CH2:20][CH2:19][C:18]=2[N:21]=1)=[O:26]
Reactant: CNC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CNC(=O)Nc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
10% TFA in 60 ml chloroform was added to 2.3 g 2-(3-methyl-ureido)-6,7-dihydro-4H-thiazolo-[5,4-c]pyridine-5-carboxylic acid tert-butyl ester in 28 ml chloroform and stirred for 2 h at RT. The mixture was concentrated, the residue was diluted with chloroform and basified with 2.5 M aqueous potassium carbonate solution and extracted with chloroform. The organic layer was concentrated. The residue was washed with a mixture of 50% ethyl acetate and 50% hexane to yield 1.5 g of the desired product. (M+H)+: 213
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH2:5][S:4][CH2:3]1.[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:22][O:21][C:19]([C:17]1[N:16]([CH:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=3)[CH2:5][S:4][CH2:3]2)[CH:15]=[N:14][CH:18]=1)=[O:20]
Reactant: N#Cc1ccc2c(c1)CSCC2O
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1CSCc2cc(C#N)ccc21
Temperature: 0 °C

Procedure:
To a solution of 4-hydroxy-isothiochroman-7-carbonitrile (630 mg, 3.3 mmol) in THF (20 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 460 mg, 3.6 mmol), and triphenylphosphine (909 mg, 3.4 mmol). The reaction is cooled to 0° C. and diisopropyl azodicarboxylate (0.66 mL, 3.4 mmol) is added. The reaction is permitted to warm to room temperature and stirred until LC-MS analysis indicates complete consumption of 4-hydroxy-isothiochroman-7-carbonitrile. The reaction mixture is diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:1) to provide 3-(7-cyano-isothiochroman-4-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 300.1 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 3.08-3.23 (m, 1 H), 3.32 (dd, J=14.4, 4.0 Hz, 1 H), 3.73-4.07 (m, 2 H), 3.91 (s, 3 H), 6.46-6.61 (m, 1 H), 7.15 (d, J=8.1 Hz, 1 H), 7.46 (s, 1 H), 7.49-7.54 (m, 1 H), 7.56 (s, 1 H), 7.84 (s, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(7-cyano-isothiochroman-4-yl)-3H-imidazole-4-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:7]([O:9]C)=[O:8])=[O:3].[OH-].[Na+].Cl.O>CO>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:7]([OH:9])=[O:8])=[O:3]
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Temperature: 22.5 °C
Reaction time: 24 h

Procedure:
To a mixture of methyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate (XXII, PREPARATION 5, 0.197 g, 0.64 mmol) in methanol (5.0 mL) is added sodium hydroxide (1N, 3.0 mL). The mixture is stirred at 20-25 degrees C. for 24 hours. The mixture is acidified to about pH 5 with hydrochloric acid (10%). Water (50 mL) is added and the mixture is washed twice with ethyl acetate (2×50 mL). The organic extracts are combined and dried over anhydrous magnesium sulfate and concentrated to give the title compound, NMR (DMSO-d6) delta 0.66, 0.930, 1.48, 1.62, 3.12, 3.35, 7.54, 7.98, 8.22 and 8.51.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(OCC)(=O)C>[Cl:15][CH2:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:18]
Reactant: NCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCCCCCCNC(=O)CCl
Reaction time: 1 h
Yield: 96 %

Procedure:
11-Aminoundecanoic acid (10.7 grams; 0.05 mole) was added to 125 ml of ethyl acetate and refluxed with 5 ml of chloroacetyl chloride as above. After one hour no precipitate was noted and the excess chloroacetyl chloride and ethyl acetate was removed by vacuum distillation. 14 Grams (96% yield) of N-chloroacetylamino-11-undecanoic acid was obtained. This compound was confirmed by elemental analysis and infrared spectroscopy.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][OH:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc2c(Br)cccc2o1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1cc2c(Br)cccc2o1
Yield: 80.7 %

Procedure:
A mixture of 4-bromo-2-hydroxymethylbenzofuran (0.3 g) and manganese dioxide (0.75 g) in ethyl acetate (3 ml) was heated to reflux for 4 hours. Manganese dioxide was removed by filtration and washed with ethyl acetate. Ethyl acetate was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1) to give 4-bromo-2-formylbenzofuran (0.24 g).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:59][O:60][C:61]1[CH:62]=[C:63]([C:67]2[C:79]3[C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[NH:72][C:71]=3[CH:70]=[CH:69][CH:68]=2)[CH:64]=[N:65][CH:66]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:10][C:4]1[CH:3]=[C:2]([N:72]2[C:71]3[CH:70]=[CH:69][CH:68]=[C:67]([C:63]4[CH:64]=[N:65][CH:66]=[C:61]([O:60][CH3:59])[CH:62]=4)[C:79]=3[C:78]3[C:73]2=[CH:74][CH:75]=[CH:76][CH:77]=3)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COc1cncc(-c2cccc3[nH]c4ccccc4c23)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cncc(-c2cccc3c2c2ccccc2n3-c2ccc(C#N)c(F)c2)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
0.74 g of 4-bromo-2-fluorobenzonitrile, 3.07 g of caesium carbonate, 0.172 g of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and 0.055 g of palladium acetate are successively added, under argon, to a solution of 0.68 g of 4-(5-methoxypyridin-3-yl)-9H-carbazole in 30 ml of dioxane. The reaction mixture is refluxed for 2 and a half hours, cooled to ambient temperature, filtered through celite and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (80/20 by volume), so as to give 0.78 g of 2-fluoro-4-[4-(5-methoxypyridin-3-yl)-9H-carbazol-9-yl]benzonitrile in the form of a colourless oil, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([S:13](Cl)(=[O:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[CH3:18][NH:19][CH3:20]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([S:13]([N:19]([CH3:20])[CH3:18])(=[O:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccc(Cl)cc21
Product: CN(C)S(=O)(=O)c1cn(C)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride (7.3 g) and dimethylamine (33% w/w solution in industrial methylated spirit; 150 ml) was stirred at room temperature for 72 hours. The precipitate and residue from evaporation of the filtrate were combined and crystallised from industrial methylated spirit. The product was ground under water, collected and dried to give the novel compound 7-chloro-1,N,N-trimethyl-4-oxo-1,4-dihydroquinoline-3-sulphonamide, m.p. 207°-209°.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][C@H:40]([CH2:43][CH3:44])[CH2:41][OH:42]>>[OH:42][CH2:41][C@H:40]([NH:39][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:28])=[O:29])=[CH:38][CH:37]=1)[CH2:43][CH3:44]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: CC[C@@H](N)CO
Product: CC[C@H](CO)NC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 58.2 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg, 0.50 mmol, 1.0M in DMF) were combined to give 35 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 602 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH3:36])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[CH2:32][CH:33](O)[CH3:34]>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([O:15][CH:33]([CH3:34])[CH2:32][C:25]2[C:26]([CH3:31])=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=2[CH3:36])=[O:14])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(CC(C)O)c(C)c1
Reactant: CC(C)(C)N1C(=O)C(NCC(=O)O)=C(c2ccccc2)S1(=O)=O
Product: Cc1cc(C)c(CC(C)OC(=O)CNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c(C)c1

Procedure:
The title compound was prepared from [(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]acetic acid and 1-mesitylpropan-2-ol. Mass Spectrum: [M+H]+ 499.15, [M−H]− 497.98.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][CH:28]=2)=[O:26])=[CH:19][CH:18]=1>N1CCCCC1.C(O)C>[N:17]1[CH:18]=[CH:19][C:20]([CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[CH:4]4[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]4)[NH:11][C:10]3=[O:16])[NH:29][CH:28]=2)=[O:26])=[CH:21][CH:22]=1
Reactant: Cc1c(C(=O)NCc2ccncc2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)NCc2ccncc2)c[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (54 mg, 0.25 mmol), 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (pyridin-4-ylmethyl)-amide (64 mg, 0.2625 mmol) and piperidine (2 drops) in ethanol (0.5 mL) was stirred at room temperature for 7 days. The precipitate which formed was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12](=[O:16])[NH:13][C:14]=1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C)C=O>[C:1]([C:9]1[CH:10]=[CH:11][C:12](=[O:16])[NH:13][C:14]=1[CH:15]=[CH:19][N:20]([CH3:22])[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(=O)ccc1C(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1[nH]c(=O)ccc1C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture containing 26.5 g of 5benzoyl-6-methyl-2(1H)-pyridinone, 100 ml of dimethylformamide and 21 ml of dimethylformamide dimethyl acetal was heated on a steam bath with stirring for 8 hours and then concentrated on a rotary evaporator to yield a solid residue. The residue was recrystallized from methanol and dried in a vacuum oven at 80°-85° C., to yield 15.8 g of 5-benzoyl-6-[2-(dimethylamino)ethenyl]-2(1H)-pyridinone, m.p. 202°-204° C.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]2[N:21]=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]=1.[Br:25]N1C(=O)CCC1=O>C1C=CC=CC=1.COC(C)(C)CC(C)C#N>[Br:25][CH2:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]2[N:21]=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]=1
Reactant: Cc1nc2cccnc2n(-c2cccc(-c3ccccc3)c2)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)C#N
Solvent: c1ccccc1
Product: O=c1c(CBr)nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Yield: 23.5 %

Procedure:
The mixture of 2-methyl-4-(3-biphenylyl)-3-oxo-3,4-dihydropyrido[ 2,3-b]pyrazine (17 g), N-bromosuccinimide (10.6 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile (167 mg) in benzene (200 ml) was refluxed for 2 hours. The mixture was washed with water and evaporated. The crude products was purified by column chromatography to obtain 2-bromomethyl-4-(3-biphenylyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH:7]([OH:17])[C:8]1[N:13]=[C:12]([I:14])[C:11]([O:15][CH3:16])=[CH:10][CH:9]=1>[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][C:7]([C:8]1[N:13]=[C:12]([I:14])[C:11]([O:15][CH3:16])=[CH:10][CH:9]=1)=[O:17]
Reactant: COC(=O)CCCC(O)c1ccc(OC)c(I)n1
Agent: [Mn+4]
Agent: [O-2]
Product: COC(=O)CCCC(=O)c1ccc(OC)c(I)n1
Yield: 43.3 %

Procedure:
Under the conditions of example 16 E, 9.98 g of (5RS)-5-hydroxy-5-(2-iodo-3-methoxy-6-pyridyl)-pentanoic acid methyl ester is reacted with 43 g of manganese dioxide for 6 hours, worked up, and the crude product is chromatographed on silica gel with hexane/0-35% ethyl acetate. 4.3 g of 5-(2-iodo-3-methoxy-6-pyridyl)-5-oxopentanoic acid methyl ester of melting point 111° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:21](=[O:24])[CH2:22][CH3:23])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Product: CCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added propanoyl chloride (0.37 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.58 g (88. %) of product as an off-white solid: mp 221-223° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 5.16 (dd, J=5.2 and 12.6 Hz, 1H), 2.99-2.85 (m, 1H), 2.66-2.45 (m, 4H), 2.11-2.07 (m, 1H), 1.14 (t, J=7.5 Hz, 3H); 13C NMR (DMSO-d6) δ 172.69, 172.65, 169.71, 167.79, 166.62, 136.65, 136.09, 131.35, 125.93, 118.12, 116.66, 48.91, 30.91, 29.73, 21.97, 9.13; Anal. Calcd. For C16H15N3O5: C, 58.36; H, 4.59; N, 12.76. Found: C, 58.01; H, 4.45; N, 12.61.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH2:4][N:3]1[C@@H:8]([C@@H:16]([CH3:19])[CH2:17][CH3:18])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:27][CH:28]=[C:29]([CH2:31]O)[N:30]=2)[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[O:1]=[C:2]1[N:6]([CH2:31][C:29]2[N:30]=[C:26]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[S:27][CH:28]=2)[C:5](=[O:7])[CH2:4][N:3]1[C@@H:8]([C@@H:16]([CH3:19])[CH2:17][CH3:18])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: OCc1csc(-c2cccnc2)n1
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)NC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)N(Cc2csc(-c3cccnc3)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 36C (0.081 g, 0.30 mmol) in dichloromethane (2 mL) at 0° C. was treated with the product from Example 57A (0.063 g, 0.33 mmol), triphenylphosphine (0.103 g, 0.39 mmol), followed by diethyl azodicarboxylate (0.061 mL, 0.39 mmol), stirred at 25° C. for 16 hours. Water (3 mL) was added and the reaction was stirred for 2 hours at 25° C. The reaction mixture was partitioned between dichloromethane and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated, to give the crude product, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:20])[N:11]([CH2:18][OH:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[P:21](Cl)(=[O:38])([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[P:21]([O:19][CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:20])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:38]
Reactant: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Product: Cc1cc(C)c(/C=C2\C(=O)N(COP(=O)(OCc3ccccc3)OCc3ccccc3)c3ccccc32)[nH]1

Procedure:
The title compound was prepared from (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (1) and dibenzyl phosphorochloridate (modification of procedure used to prepare {3(Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl}methyl acetate (2)).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([Cl:27])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].B.O1CCCC1>>[OH:2][CH2:1][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([Cl:27])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(Cl)n3)C2)cc1
Agent: B
Solvent: C1CCOC1
Product: CC(Cc1ccc(OCCO)cc1)N1CCOC(c2csc(Cl)n2)C1

Procedure:
Prepared by analogy to Example 71 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-chloro-thiazol-4-yl)morpholine with borane/tetrahydrofuran complex (1 molar solution in tetrahydrofuran) for 60 hours.