Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2)#[N:2].[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]([CH3:31])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2)#[N:2]
Reactant: N#Cc1ccc2c(c1)CCC(NC(=O)c1ccc(-c3ccc(F)cc3)cc1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccc(-c2ccc(F)cc2)cc1)C1CCc2cc(C#N)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4′-Fluoro-biphenyl-4-carboxylic acid (6-cyano-1,2,3,4-tetrahydro-naphthalen-2-yl)-amide, 3, (0.200 g, 0.541 mmol) in anhydrous DMF (4 mL) is added 60% NaH dispersed in mineral oil (32 mg, 1.5 eq.) and the resulting solution is stirred at room temperature for 30 min. Methyl iodide (0.101 mL, 3 eq.) is added to the solution and the reaction solution is stirred for another 30 min. A minimal amount of water is added to quench the reaction and the mixture is dried over anhydrous MgSO4 then concentrated in vacuo to afford 0.201 g of the desired product which is used without further purification. LRMS: 385.22 (M+H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[CH:16]=2)[O:8][CH:7](O)[C@H:6]1[O:33][C:34](=[O:36])[CH3:35])(=[O:3])[CH3:2].Cl.[NH2:38][OH:39].C1CCN2C(=NCCC2)CC1.ClN1C(=O)CCC1=O>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[CH:16]=2)[O:8]/[C:7](=[N:38]\[OH:39])/[C@H:6]1[O:33][C:34](=[O:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2cc([C@@H]3O/C(=N\O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 6 h
Yield: 66.7 %

Procedure:
Compound from step A (142 mg, 0.27 mmol) and hydroxylamine hydrochloride (57 mg, 0.82 mmol) were dissolved in pyridine (1.4 ml). The reaction was stirred for 6 hours, diluted with EtOAc, washed with 1 M aq. NaHSO4, H2O, sat. aq. NaHCO3, and brine (with back extraction), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in CH2Cl2, cooled to −78° C., and treated with DBU (49 μL, 0.33 mmol) followed by N-chlorosuccinimide (44 mg, 0.33 mmol). The reaction was stirred for 20 minutes at −78° C., then allowed to warm to room temperature over 15 minutes The reaction was diluted with EtOAc, washed with H2O and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (12 g SiO2, 0-50% EtOAc:Hex.) to give acetic acid (3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-[(Z)-hydroxyimino]-tetrahydro-pyran-3-yl ester (97 mg, 0.18 mmol, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.C1C(=O)N([Br:25])C(=O)C1>CO.C(Cl)Cl.[Pd]>[Br:25][C:5]1[CH:6]=[C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(CCN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
To a solution 4-[2-(4-nitro-phenyl)-ethyl]-morpholine (0.70 g, 2.97 mmol) (as prepared in the previous step) in 15 mL of MeOH was added 10% Pd/C (30 mg) and the mixture hydrogenated under 20 psi of H2 for 2 h. The mixture was filtered though Celite and concentrated. The residue was dissolved in DCM (20 mL) and NBS (0.53 g, 2.97 mmol) was added and the reaction stirred for 20 min at RT. The reaction was diluted with DCM (20 mL) and washed with NaHCO3 (2×40 mL) and the organic layer dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE with 100% EtOAc to give 0.49 g (58%) of a light yellow oil. Mass spectrum (ESI, m/z): Calcd. for C12H17BrN2O, 285.0 (M+H). found 285.0.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](I)[CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCI
Reactant: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: CCCCn1c(=Nc2ccc(C)cc2)sc2ncccc2c1=O
Yield: 52 %

Procedure:
The reaction procedure of Example 11 was followed except that 909 mg (3.38 mmol) of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 27 mg of lithium hydride and 621 mg of butyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 571 mg of 3-butyl-2,3-dihydro-2-[(4-methylphenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (52%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 157 mg of 2-[N-butyl-N-(4-methylphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ether) as a high polarity substance.
Reaction SMILES: [C:1]1([Sb:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([CH3:31])[CH:25]=[CH:24][C:23]([S:26]([O:29]C)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:20]1([CH3:31])[CH:21]=[CH:22][C:23]([S:26]([O-:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[CH3:20][Sb+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: c1ccc([Sb](c2ccccc2)c2ccccc2)cc1
Product: C[Sb+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A mixture of 17.65 g (0.05 mol) of triphenylstibine and 9.31 g (0.05 mol) of methyl p-toluenesulfonate was heated in a 130° C. bath with nitrogen bubbling through the melt for 18 hr. The resulting syrup was cooled to an amorphous glass which was crystallized by treatment with ether. The resultant crystals were collected and dried.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[Si:10]([CH3:13])([CH3:12])[CH3:11]>C[Si](C)(C)N[Si](C)(C)C>[I:1][C:2]1[CH:3]=[N:4][C:5]([O:8][Si:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: O=c1ncc(I)c[nH]1
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)Oc1ncc(I)cn1

Procedure:
A suspension of 15.06 g (67.83 mmol) of 5-iodo-2(1H)-pyrimidinone was refluxed in 40 ml of hexamethyldisilazane and 2 ml of chlorotrimethylsilane for 1 hour. The excess reagent was removed in vacuo to yield a yellow oil 5-iodo-2-trimethylsilyloxypyrimidine, which was dissolved with 30 ml of dry degassed triethylamine. To this solution was added 11.5 ml (81.37 mmol) of trimethylsilylacetylene, 0.32 g (2.5 mol %) of CuI and 0.48 g (1 mol %) of (φ3P)2PdCl2. The reaction mixture was stirred under nitrogen, at room temperature, for 3 days and diluted with 100 ml of dry THF. The mixture was filtered under dry nitrogen; the precipitate washed several times with dry THF and the filtrate was concentrated to a residue. The latter was treated with methanol to give a white crystalline, chromatographically homogeneous material 5-(2-Trimethylsilyl)ethynyl-2(1H)-pyrimidinone (9.99 g, 76.6%). Analytically pure material could be obtained by recrystallization from methanol; mp 203°-206° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][O:14][CH2:15][CH2:16][C:17](O)=[O:18].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O[Li].O>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[CH2:16][CH2:15][O:14][CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: COCCC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li]O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCCC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.9 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 3-methoxypropanoic acid (204.2 μL, 2.174 mmol) and triethylamine (605.9 μL, 4.347 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP—Cl (202.7 mg, 2.174 mmol). The mixture was stirred at room temperature for 24 hours. 2M LiOH.H2O in water (3 mL) was then added and stirred for 30 minutes. The precipitate formed was filtered, washed with CH2Cl2 (3×2 mL), and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide (115 mg, 42% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.05 (br s, 1H), 9.55 (s, 1H), 8.34 (d, 1H), 7.63 (s, 1H), 3.63 (t, 2H), 3.26 (s, 3H), 2.58 (t, 2H); LCMS (APCI+) m/z 317.9 (M+H)+, Retention time=2.57 minutes (Method 2).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CCN(CC)CC.Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27].O>C(Cl)Cl>[CH:25]([S:26]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:4]2[CH2:8]1)(=[O:28])=[O:27])=[CH2:24]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
To a stirred mixture of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.0 g, 4.71 mmol) in DCM (20 mL) at 0° C., Et3N (1.43 g, 14.1 mmol) was added. The mixture was stirred at 0° C. for 5 min, and then a solution of 2-chloroethanesulfonyl chloride (0.77 g, 4.71 mmol) in DCM (5 mL) was added dropwise. The resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (30 mL×3). The combined organic layer was washed with brine (15 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-50% ethyl acetate/petroleum ether) to afford the desired product (0.5 g, 35% yield) as a solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][NH:6][NH2:7].[C:8]([CH:11]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[C:12](=S)[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])(=O)[CH3:9]>C(O)C.C(OCC)(=O)C>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:11]1[C:8]([CH3:9])=[N:7][N:6]([CH3:5])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: CC(=O)C(C(=S)Nc1ccc(F)cc1F)c1ccc(Cl)cc1Cl
Reactant: CNN
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nn(C)c(Nc2ccc(F)cc2F)c1-c1ccc(Cl)cc1Cl

Procedure:
Acetic acid (50 μL) and methylhydrazine (41 μL) were added to a stirred suspension of α-acetyl-2,4-dichloro-N-(2,4-difluorophenyl)benzeneethanethioamide (238 mg, 0.64 mmol) in ethanol (4 mL). The reaction mixture was heated at reflux for 2 h and allowed to cool. Then the reaction mixture was diluted with ethyl acetate (10 mL) and washed with 1 N aqueous NaOH (10 mL), water (10 mL) and brine (10 mL), dried over MgSO4, and concentrated to leave a solid residue. The residue was purified by column chromatography on 5 g of silica gel with a gradient of hexanes/ethyl acetate (2:1 to 1:1) to give the title compound as a solid (170 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(OC)cc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(COc2ccc(-c3c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c3N3CCC(C)(C)CC3)cc2)cc1
Yield: 84.7 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0348 g, 0.059 mmol) and LiOH (0.014 g, 0.591 mmol) in 9:1 EtOH/H2O (2 mL0 was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0279 g, 0.050 mmol, 84% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J=8.0 Hz, 2H), 7.16 (d, J=7.7 Hz, 1H), 7.03-7.08 (m, 3H), 6.96 (d, J=7.9 Hz, 2H), 5.97 (br. s., 1H), 5.04-5.11 (m, 2H), 3.85 (s, 3H), 3.59 (br. s., 1H), 2.91 (br. s., 1H), 2.63 (br. s., 3H), 2.24-2.30 (m, 1H), 2.22 (s, 3H), 2.02-2.14 (m, 1H), 1.24 (s, 9H), 0.87 (br.s., 3H), 0.67 (br. s., 3H). 4H of piperidine were not resolved. LCMS (M+H)=561.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]([CH3:31])[CH:16]2[CH2:30][CH:19]3[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:15]([CH3:31])[CH:16]2[CH2:30][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (217.4 mg, 0.48 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then the resulting mixture was extracted with DCM (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (100.3 mg, 59.4%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]#[C:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C1COCC1>[N:53]1([C:23]([C:22]2[CH:21]=[N:20][C:19]([C:18]#[C:17][Se:16][C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=4[CH:4]=3)=[CH:27][CH:26]=2)=[O:25])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1
Reactant: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)O)cn1)C(C)(C)CCC2(C)C
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)N3CCOCC3)cn1)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to that of Example 10, 300 mg (0.72 mmol) of 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinic acid are reacted with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 75.7 mg (0.87 mmol) of morpholine in 20 ml of THF. After purification on a column of silica (ethyl acetate 20/heptane 80), 60 mg (17%) of a colourless oil are obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[N:4]1)[CH3:2].[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20][NH:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:9])[CH:6]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: CCn1nc(C)cc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1cc(C)nn1CC)C(=O)OCC

Procedure:
12.5 g. of 1-Ethyl-3-methyl-5-aminopyrazole (0.1 mol.) and 21.6 g. of ethoxymethylene malonic acid diethyl ester (0.1 mol.) are heated to 120° (bath temperature) for 2 hours with stirring. The ethanol formed by this reaction is removed by means of a water aspirator. Vacuum distillation (b.p. 0.05 152°-153°) yields 24.0 g. (81.5%) of a quickly crystallizing oil, [[(1-ethyl-3-methyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester, m.p. 60°-67°. The product, recrystallized from ligroin (90°-100°), melts at 69°-70°.
Reaction SMILES: [CH3:1]N(C)C=O.[CH:6]([O:9][C:10](=[O:47])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]([CH:44]=[O:45])[CH3:43])[CH:37]=3)[NH:32][C:31]2=[O:46])=[CH:26][CH:25]=1)[NH:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>O.C(O)(=O)C>[CH:6]([O:9][C:10](=[O:47])[C@H:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]([CH:44]=[O:45])[CH3:43])[CH:37]=3)[N:32]([CH3:1])[C:31]2=[O:46])=[CH:28][CH:29]=1)[NH:12][C:13](=[O:22])[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20])([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)OC(=O)[C@H](Cc1ccc(-n2c(=O)[nH]c3ccc(CN(C)C=O)cc3c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)OC(=O)[C@H](Cc1ccc(-n2c(=O)c3cc(CN(C)C=O)ccc3n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 23 °C
Yield: 94 %

Procedure:
There was added, to 21.26 L of N,N-dimethylformamide (DMF), 5.445 kg of Nα-(2,6-dichlorobenzoyl)-4-{6-(N-formyl-N-methylamino-methyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester, the resulting mixture was stirred at 23° C. and in a nitrogen gas stream to dissolve the isopropyl ester compound. Then 2.46 kg of potassium carbonate and 2.491 kg of methyl p-toluene-sulfonate were added to the resulting solution and the mixture was stirred with heating at 55 to 65° C. After the confirmation of the progress of the N-methylation reaction by HPLC, 2.14 kg of acetic acid was added to the mixture and subsequently the mixture was stirred with heating at 50° C. for one hour. To the reaction solution, there was dropwise added 10.9 L of water, followed by the addition of 6 g of seed crystals and stirring of the mixture at 50° C. for 2 hours. To the resulting slurry, there was further added 10.9 L of water, the mixture was cooled to 25° C. and stirred overnight. The precipitates thus obtained were recovered by the filtration using a centrifuge and the resulting cake was washed with 21.8 kg of water. The resulting wet crystals were dried under reduced pressure at 60° C. to thus give 5.235 kg of the title compound as a white crystalline solid (yield: 94%).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[S:5][C:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)(O)[O-].[Na+]>CC(C)C(O)=O.O>[CH3:4][CH:8]([CH3:9])[CH2:7][NH:3][C:4]1[S:5][C:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc(Cc2ccccc2)sc1N
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)C(=O)O
Product: CCOC(=O)c1cc(Cc2ccccc2)sc1NCC(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium borohydride (3.0 g) was added in 6 portions over 3 hours to a stirred solution of ethyl 2-amino-5-(phenylmethyl)thiophene-3-carboxylate in 2-methylpropanoic acid under nitrogen. The mixture was stirred at room temperature for 20 hours and was then diluted with water, neutralized with sodium bicarbonate and extracted with ethyl acetate four times. The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography, eluting with diethyl ether:isohexane (1:19) to give the subtitle compound (2.80 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[N+:10]([C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:13](=[O:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4]2)([O-:12])=[O:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ccc([N+](=O)[O-])cc1C=O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O

Procedure:
A solution of 10.0 g (46 mmol) of 1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, ethyl ester [J. Chem. Soc., 2518 (1962)] and 50 ml of sulfuric acid is stirred in an ice bath and a cold mixture of 9.75 ml of 70% nitric acid and 9.75 ml of sulfuric acid is added dropwise over 10 minutes. The reaction solution is stirred with ice bath cooling for 1 hour and then is poured into ice and water with stirring. The resulting solid is collected by filtration and washed with water and ethanol. After drying, 10.7 g of the requisite ester is obtained, mp>310°. The structure is assigned by an unequivocal synthesis from the condensation of 2-amino-5-nitrobenzaldehyde and diethyl malonate to give the same 1,2-dihydro-6-nitro-2-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: [I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1.CO.O1CCOCC1.[Cl-].[NH4+]>O.[Fe]>[I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(I)c2occc2c1
Temperature: 100 °C
Yield: 99.7 %

Procedure:
7-Iodo-5-nitro-1-benzofuran (2.5 g, 8.6 mmol) and iron (2.51 g, 45.0 mmol) were added to a round bottom flask. Methanol (25 mL), 1,4-dioxane (25 mL) and ammonium chloride (2.5 g, 46.7 mmol), dissolved in water (50 mL), were added and the mixture was heated at 100° C. for 16 h. The reaction mixture was filtered through Celite and volatiles were evaporated off. The residue was dissolved in a mixture of methanol (10 mL) and DCM (90 mL). This mixture was filtered through a silica plug and the solvent was evaporated yielding 2.22 g (99%) of the title compound as a brown oil. HPLC purity 70%, RT=1.26 min (System A; 10-97% MeCN over 3 min). MS (ESI+) for C8H6INO m/z is 260 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[N:6][CH:7]=1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Br)cnc1-n1cccn1
Temperature: 120 °C
Reaction time: 26.5 h

Procedure:
To a mixture of 5-bromo-2-chloro-3-nitropyridine (10 g, 42 mmol) in 1,4-dioxane (100 ml) was added pyrazole (5.8 g, 85 mmol). The resulting mixture was stirred at 120° C. for 26.5 h., and then evaporated after cooling to r.t. The crude material was purified by flash chromatography (0 to 5% EtOAc/Hexanes) to give the desired product 5-Bromo-3-nitro-2-pyrazol-1-yl-pyridine. 1H NMR: (CD3OD) δ 8.77 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 7.73 (s, 1H), 6.57 (s, 1H); LC/MS: (ES+) m/z (M+H)+=269, 271, HPLC Rt=1.223.