Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=[C:5]2[CH:6]=1
Reactant: C1COCCN1
Reactant: Brc1ccn2nc(Br)nc2c1
Product: Brc1ccn2nc(N3CCOCC3)nc2c1
Yield: 35.9 %

Procedure:
A mixture of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (1 g, 3.61 mmol) and morpholine (10.0 g, 10 ml, 115 mmol) was refluxed for 4 hours under argon atmosphere, the formerly green mixture turning to yellow. The reaction mixture is concentrated to dryness, applied on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 10-100% as eluent affording 4-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)morpholine (367 mg, 35.9%) as a white solid. mp.: 178-9° C. MS: m/z=285.0, 283.0 (M+H+).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl>ClC1C=CC=CC=1Cl>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: ClCCNCCCl
Reactant: Nc1ccccc1C1=CCCCCC1
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: C1=C(c2ccccc2N2CCNCC2)CCCCC1
Temperature: 200 °C
Reaction time: 5 h
Yield: 45.9 %

Procedure:
To a solution of 2-cyclohept-1-enylphenylamine (617 mg, 3.29 mmol) in 1,2-dichlorobenzene (8 mL) was added bis(2-chloroethyl)amine hydrochloride (705 mg, 3.95 mmol), and the mixture was stirred at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was blown into the reactor to remove the hydrogen chloride gas in the reactor. This procedure was repeated several times. After 5 hours, the reaction mixture was air-cooled to room temperature, and then aqueous solution of potassium carbonate, ethyl acetate and methanol were added to the reaction mixture and extraction was performed three times with ethyl acetate. The obtained organic layers were dried over anhydrous sodium sulfate, and then the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 387 mg of the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17]1>>[CH2:21]([N:18]1[CH2:19][CH2:20][CH:16]([NH:15][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([NH:13][CH3:14])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Reactant: NC1CCN(Cc2ccccc2)C1
Product: CNc1cc(OC)c(C(=O)NC2CCN(Cc3ccccc3)C2)cc1Cl

Procedure:
Following the procedure set forth in general method A supra using 1.08 g. of 5-chloro-2-methoxy-4-methylaminobenzoic acid and 0.97 g. of 3-amino-1-benzylpyrrolidine, 1.07 g. of N-(1-benzyl-3-pyrrolidinyl)-5-chloro-2-methoxy-4-methylaminobenzamide was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.C(Cl)(=O)C(Cl)=O.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1.CN1CCOCC1>ClCCl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:20](=[O:22])[CH2:19][N:3]2[CH2:4][CH2:5][C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]2=[O:1])=[N:34][CH:35]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)Nc1ccc(Cl)cn1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) in dichloromethane (0.5 mL) at room temperature was added a solution of oxalyl chloride in dichloromethane (2.0 M, 0.102 mL, 0.203 mmol). The reaction was stirred for 1 hour and then concentrated under a stream of nitrogen. The resulting acid chloride was dissolved in dichloroethane (0.5 mL), and 5-chloropyridin-2-amine (0.024 g, 0.186 mmol) was added followed by N-methyl morpholine (0.028 mL, 0.254 mmol). The reaction was heated to 70° C. After stirring for 3 hours, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the product was eluted using a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes over 25 minutes (flow=30 mL/minute). The product was contaminated with aminopyridine starting material. A second silica gel column chromatography (SF15-24, Analogix®) eluting with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes over 30 minutes (flow=30 mL/minute) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.44-8.46 (br s, 1H), 8.22 (dd, J=2.5, 0.7 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.65 (ddd, J=8.8, 2.6, 0.5 Hz, 1H), 7.21-7.39 (m, 10H), 4.19 (s, 2H), 3.54 (t, J=6.5 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H); MS (ESI+) m/z 406 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][S-:13].[Na+].O>CN(C=O)C>[CH3:12][S:13][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: C[S-]
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.3 %

Procedure:
Methyl 6-chloronicotinate (100 mg, 0.583 mmol) in N,N′-dimethylformamide (1.5 mL) was added with sodium thiomethoxide (41 mg) under ice-cold conditions, and then stirred at room temperature for 3 hours. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and methyl 6-(methylthio)nicotinate (120 mg, yield >100%) was obtained as a yellow oil.
Reaction SMILES: [ClH:1].[NH:2](C(OC(C)(C)C)=O)[C@H:3]([C:19]([NH:21][C@H:22]([C:27]([NH:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(OCC)(=O)C>[NH2:2][C@H:3]([C:19]([NH:21][C@H:22]([C:27]([NH:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[O:28])[CH2:23][CH:24]([CH3:25])[CH3:26])=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10].[ClH:1]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: -13.5 °C
Yield: 92.4 %

Procedure:
A solution of HCl (28 g, 770 mmol) in ethyl acetate (100 g) at −10° C. was rapidly added to Boc-Lys(Z)-Leu-Leu-OMe (35.0 g, 55.74 mmol) under N2 at −15 to −12° C. The mixture was stirred and maintained at −15 to −12° C. for 60 to 70 min and allowed to crystallize for 1 h at −10 to −5° C. The solid was filtered while excluding moisture, washed with several portions of t-butyl methyl ether and dried in vacuo to give H-Lys(Z)-Leu-Leu-OMe.HCl (28.7 g, 91.4%).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[CH:23]=[CH:24][C:25]2[N:26]([N:28]=[CH:29][N:30]=2)[N:27]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:22]3[CH:23]=[CH:24][C:25]4[N:26]([N:28]=[CH:29][N:30]=4)[N:27]=3)[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc(C(OC2CCN(c3ccc4ncnn4n3)CC2)c2ccccc2)cc1
Yield: 54.4 %

Procedure:
4-(Diphenylmethoxy)piperidine (1.12 g) and 6-chloro[1,2,4]triazolo[1,5-b]pyridazine (558 mg) were dissolved in 1-butanol (25 ml), followed by addition of N-ethyldiisopropylamine (700 mg). The mixture was refluxed under heating for 17 hours. After being cooled, the mixture was concentrated under reduced pressure. Ice-water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of hexane and ethyl acetate (1:3). Fractions containing the objective compound were collected and recrystallized from ethanol to yield the title compound (757 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nccc2ccccc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1nccc2c([N+](=O)[O-])cccc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution 1-methylisoquinoline (D91) (1 g, 7 mmol) in sulfuric acid (2.5 ml) was cooled (<4° C.) and concentrated nitric acid (1 ml) was added over 10 mins. The reaction was stirred for 30 mins and then heated at 60° C. for 2 h. After cooling, the reaction mixture was poured into ice water slurry (100 ml) and basified using solid potassium carbonate followed by extraction with DCM. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo to afford the product as a white solid (1.05 g). 1H NMR (400 MHz, DMSO) δ (ppm): 8.69 (d, 1H), 8.59 (m, 2H), 8.11 (d, 1H), 7.88 (t, 1H), 2.99 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:7]([O:6][C:4](=[O:5])[C:3]1[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:2]=1[F:1])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(N)cc1F
Temperature: 95 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Tert-butyl 2-fluoro-4-nitrobenzoate (24.2 g, 0.100 mol) was added to a warm (95° C.) solution of ammonium chloride (53.5 g, 1.00 mol), dissolved in ethanol (300 ml) and water (150 ml). Iron powder (325 mesh, 16.8 g, 0.300 mol) was added with stirring in small portions over ca. 1 h. The reaction mixture was stirred and heated at 95° C. for another 30 minutes and then filtered while still warm. The filter cake was washed thoroughly with excess ethanol. The filtrate and washings were diluted with water (1 L) and extracted with ether (3×150 ml). Combined ether extracts were washed with water and brine, dried (MgSO4), and evaporated to give the product as an off-white solid (21.1 g, 98%); mp 100-101° C. 1H NMR.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][N:12]([CH2:42][C:43]([OH:45])=[O:44])[CH:13]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=1)[CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH:17]([CH3:27])[N:18]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C:20]([OH:22])=[O:21])([OH:10])=[O:9].[H][H]>[Pd].O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][N:12]([CH2:42][C:43]([OH:45])=[O:44])[CH:13]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH:17]([CH3:27])[N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH2:23][C:24]([OH:26])=[O:25])([OH:10])=[O:9]
Reactant: CC(CN(CC(=O)O)CC(Cc1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(CN(CC(=O)O)CC(Cc1ccc(N)cc1)N(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O
Yield: 125.5 %

Procedure:
To a Parr flask was added 3.40 g (3.84 mmol) of N,N,N′,N″,N″-Pentakis(carboxymethyl)-2-[(4-nitrophenyl)methyl-]-6-methyldiethylenetriamine trifluoroacetic acid salt and 50 ml of water followed by the addition of 0.3 g of 5% palladium on carbon. The flask was pressurized to 30 psi hydrogen and vented twice. The vessel was then pressurized to 45 psi hydrogen and shaken. Once hydrogen uptake ceased, typically after 2 to 4 hours, the flask was vented and the mixture filtered through a pad of celite. The celite was washed with 20 ml of water. The filtrate was concentrated under reduced pressure to afford 3.02 g of product with a yield of 92.03%. The spectral data obtained for this product are consistent with those of a reference standard.
Reaction SMILES: C[O-].[Na+].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([O:12]C)=O.[CH3:14][C:15]([CH3:17])=[O:16]>O1CCCC1>[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH2:14][C:15](=[O:16])[CH3:17]
Reactant: CC(C)=O
Reactant: COC(=O)c1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1ccccn1
Temperature: 20 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A sodium methoxide solution (28% in methanol) was added dropwise to a mixture of 10 g (73 mmol) of methyl picolinate and 25 ml (124 mmol) of acetone in 150 ml of tetrahydrofuran. The mixture was stirred at 20° C. for 3 hours and the solvent was removed under reduced pressure. The residue was taken up in water, acidified with 2-molar aqueous hydrochloric acid and extracted with dichloromethane. Drying of the combined organic phases and removal of the solvent under reduced pressure gave 7.940 g of product (60% of theory).
Reaction SMILES: N[C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[Br-:12].[Na+].C(ON=O)(C)(C)C>CC#N.[Cu]Br>[Br:12][C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: COC(=O)c1nc(N)sc1C
Reactant: [Br-]
Agent: [Cu]Br
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1nc(Br)sc1C
Temperature: 80 °C
Yield: 57.1 %

Procedure:
To a stirred suspension of methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate (5 g, 29.03 mmol, 1 eq.) in 75 ml of MeCN, were added sodium bromide (5.97 g, 58.07 mmol, 2 eq.), Copper (I) bromide (6.08 g, 31.93 mmol, 1.1 eq.) and t-Butylnitrite (90%, 3.65 g, 31.93 mmol, 1.1 eq.). The reaction was slowly heated to 80° C. for 1 h and allowed to cool. MeCN was evaporated and 100 ml DCM were added to the residue. The crude was triturated, filtered through “celite” plug and washed with further 50 ml of EtOAc. The organic layers were combined, dried over MgSO4, and evaporated to give methyl 2-bromo-5-methyl-1,3-thiazole-4-carboxylate (3.91 g, 42% yield) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>CN(C=O)C>[N+:9]([C:7]1[CH:6]=[CH:5][C:3]([NH:4][S:15]([CH3:14])(=[O:17])=[O:16])=[C:2]([Br:1])[CH:8]=1)([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Commercially available 2-bromo-4-nitroaniline (10.0 g, 46.07 mmol) was dissolved in DMF (250 mL) and NaH (60% in oil dispersion; 3.7 g, 92.15 mmol) added portion wise at 0° C. After 15 minutes, methanesulfonyl chloride (10.7 mL, 138.23 mmol) was added and the reaction was stirred overnight at ambient temperature. The reaction was quenched with 1M citric acid (100 mL) and extracted with ethyl acetate (3x). The combined extracts were washed with brine (2x), dried (MgSO4), filtered and concentrated in vacuo to yield a red oil that was purified by flash chromatography (silica gel; 20% EtOAc/Hexane) to afford the title compound as a yellow solid which was recrystallyzed from ether/hexanes. mp 148°-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 3.24 (s, 3H), 7.70 (d; J=9 Hz; 1H), 8.23 (dd; J=9,3 Hz; 1H), 8.49 (d; J=3 Hz; 1H), 9.85 (br. s., 1H). MS (DCI-NH3) m/z 312 (M+NH4)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:25]([SH:28])[CH:26]=[CH2:27].F[C:30]1[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=1>C(#N)C>[CH2:25]([S:28][C:30]1[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=1)[CH:26]=[CH2:27]
Reactant: NS(=O)(=O)c1ncccc1F
Reactant: C=CCS
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCSc1cccnc1S(N)(=O)=O

Procedure:
33.2 g (0.24 tool) of potassium carbonate as well as 1.32 g (0.005 tool) of 18-crown-6 and 15.8 g (0.17 tool) of 80 % allylmercaptan in 50 ml of acetonitrile are added to a solution, cooled to +5° C., of 17.62 g (0.1 mol) of 3-fluoropyridin-2-ylsulfonamide in 400 ml of acetonitrile.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH:56](=O)[CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH2:56]([N:53]1[CH2:54][CH2:55][N:50]([C:41]2([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:40][CH:39]=3)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]2=[O:49])[CH2:51][CH2:52]1)[CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: CCCCCC=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCN1CCN(C2(c3ccc(OCc4cc(C)nc5ccccc45)cc3)C(=O)NC(=O)NC2=O)CC1
Yield: 63.2 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with hexanal (18.8 mg, 1.5 eq) to provide the title barbituric acid (70.0 mg, 63%). MS found: (M+H)+=544.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH:9]=[CH2:10]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N:4]1[CH:3]=[C:2]([C:9](=[CH2:10])[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]=[N:6][CH:5]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Brc1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC(C)(C)C)c1cncnc1
Temperature: 80 °C

Procedure:
A mixture of 30 g 5-bromopyrimidine, 1.2 g palladium acetate, 25 mL triethylamine and 250 ml t-butyl acrylate was heated at 80° C. for 5 days. The resulting mixture was concentrated to a waxy solid in vacuo. The residue was taken up in ethyl acetate and filtered. The filtrate was kept in the cold (-20° C., hexane added), and 10.5 g of tan needles deposited: 1H NMR (300 MHz) (d6-DMSO) δ 1.45 (s, 9H), 6.1 (d, 1H, J=12.3 Hz), 6.8 (d, H, J=12.3 Hz), 8.85 (s, 1H), 9.15 (s, 1H); MS (FAB) m/e (MH+): 206.2
Reaction SMILES: FC1C=CC([C:8]2([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9]2)=CC=1.F[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[N:16]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:21][C:17]1[N:16]=[C:15]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:20]=[CH:19][CH:18]=1
Reactant: NCC1(c2ccc(F)cc2)CCC1
Reactant: Fc1cccc(F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC1(c2cccc(F)n2)CCC1
Yield: 64 %

Procedure:
Following the same procedure as described for 2-(3-fluoropyridin-2-yl)acetonitrile (Example 18), 2,6-difluoropyridine (5.0 g, 43 mmol, 1.0 equiv), cyclobutylcarbonitrile (3.5 g, 43 mmol, 1.0 equiv) and NaHMDS (2.0 M in THF, 24 mL, 47 mmol, 1.1 equiv) in toluene (100 mL) gave the desired product (4.9 g, 64%) as a colorless oil following purification over silica gel using 25% EtOAc/hexanes as eluent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=O)=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]2[NH:15][C:11]3=[N:10][C:9]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[F:1])[CH:13]=[C:12]3[N:14]=2)=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Solvent: c1ccncc1
Product: Fc1ccc(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 140 °C
Reaction time: 48 h
Yield: 65.3 %

Procedure:
3″-Fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1,158 mg, 0.56 mmol), 4-fluorobenzoyl chloride (73.0 μL, 0.62 mmol) and pyridine (ca. 4 mL) were placed in a sealed tube. The solution was initially heated at 140° C. for 48 h and afterwards, at 160° C. for another 48 h. Then, the reaction mixture was cooled to room temperature, the pyridine was removed in vacuo, and the crude oil was purified by flash column chromatography (CH2Cl2/EtOH, 95:5) affording the title compound as a white solid (141 mg, 65%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:5]1([CH2:4][O:3][C:1](=[O:2])[NH:11][C@@H:12]([CH3:13])[C:14](=[O:16])[NH:17][N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nn1cccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nn1cccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.3 %

Procedure:
To a stirred solution of carbobenzyloxy-L-alanine (10.0 g) and N-aminopyrrole (3.68 g) in dry DCM (224 ml) was added DCC (9.71 g) at 0° C. under nitrogen. The cooling bath was removed after ten minutes and the reaction mixture was allowed to stir at room temperature for 17 hours. The mixture was filtered and the solid DCU filter cake was washed with hot ethyl acetate. Concentration of the combined filtrate gave the crude product. Recrystallization from ethyl acetate/hexane afforded 10.46 g of the product as a solid, m.p. 169°-171° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[C:5]([CH3:28])[CH:4]=1.Cl.[OH:30][CH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][C@@H:32]4[CH2:31][OH:30])=[CH:4][C:5]=3[CH3:28])=[O:27])[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: OC[C@H]1CCCCN1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(Br)cn2)cc1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCCC[C@@H]2CO)ccc1C(=O)Cn1ccc(OCc2ccc(Br)cn2)cc1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 4b, 100 mg, 0.20 mmol) in DMF (2 mL) is added (R)-2-hydroxymethylpiperidine hydrochloride (75 mg, 0.50 mmol) and K2CO3 (55 mg, 0.40 mmol). The reaction mixture is stirred 2 h at 80° C. The mixture is purified via reverse phase HPLC chromatography (Phenomenex Gemini-C18 10 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).