Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:13]2=[N:14][C:15](Br)=[CH:16][CH:17]=[C:12]2[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(N(CC)CC)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.[Cu]I>[CH3:19][Si:20]([C:23]#[C:24][C:15]1[N:14]=[C:13]2[N:9]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=[CH:11][C:12]2=[CH:17][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O=C(c1ccccc1)n1ccc2ccc(Br)nc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2ccn(C(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.1 %

Procedure:
The synthesis was performed with reference to the known literature (Bulletin of the Chemical Society of Japan, Vol. 65, p. 2992, 1992). A solution of 1-benzoyl-6-bromo-1H-pyrrolo[2,3-b]pyridine (0.30 g, 1.0 mmol) in triethylamine (25 mL) was added with dichlorobis(triphenylphosphine)palladium(II) (0.036 g, 0.050 mmol), and copper(I) iodide (0.016 g, 0.085 mmol) under an argon atmosphere. Then, the mixture was slowly added with trimethylsilylacetylene (0.20 g, 2.0 mmol), and then the mixture was stirred at room temperature for 24 hours. Triethylamine was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (100:0→90:10)) to obtain 6-[(trimethylsilyl)ethynyl]-1-benzoyl-1H-pyrrolo[2,3-b]pyridine (0.045 g, 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][N:22]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:25]\[C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:28][CH:27]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(C(F)(F)F)nc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 5 ml was added 6-(trifluoromethyl) nicotinaldehyde 69 (70.8 mg, 0.404 mmol). PTSA (154 mg, 0.808 mmol) was added, and the reaction mixture stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound (E)-6-methoxy-5-morpholino-2-((6-(trifluoromethyl)pyridin-3-yl)methylene)-2,3-dihydro-1H-inden-1-one 70. The crude 70 was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 32% ethyl acetate in hexane to afford yellow coloured solid 70.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([N:11]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: O=C1CCNCCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCNC(=O)CC1
Yield: 58 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 1,4-diazepan-5-one gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-5-one as a yellow oil (173 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 6.35 (s, 1H), 3.82 (s, 3H), 3.53-3.47 (m, 2H), 3.38-3.31 (m, 4H), 2.83-2.78 (m, 2H)
Reaction SMILES: CO.Cl.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:24]=[C:23]2[C:14]([N:15]3[C:20]([CH2:21][O:22]2)=[N:19][NH:18][C:17](=[O:25])[C@H:16]3[CH3:26])=[CH:13][C:12]=1[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C=O.[BH3-][C:36]#N.[Na+]>C(O)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:24]=[C:23]2[C:14]([N:15]3[C:20]([CH2:21][O:22]2)=[N:19][NH:18][C:17](=[O:25])[C@H:16]3[CH3:26])=[CH:13][C:12]=1[CH:27]1[CH2:32][CH2:31][N:30]([CH3:36])[CH2:29][CH2:28]1
Reactant: [BH3-]C#N
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4CCNCC4)cc3N21
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4CCN(C)CC4)cc3N21
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
To a solution of MeOH (10 mL) and acetic acid (1 mL) was added (R)-7-(2-fluoro-phenyl)-4-methyl-6-piperidin-4-yl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (0.300, 0.761 mmol) and paraformaldehyde (0.228 g, 7.61 mmol) and the reaction mixture was stirred at rt for 4 h. Then NaCNBH3 (0.096 g, 1.52 mmol) was added and the reaction mixture was stirred for 30 min. The solvent was removed in vacuo and the residue was purified by prep-TLC (eluting with 10% MeOH in DCM) to give (R)-7-(2-fluoro-phenyl)-4-methyl-6-(1-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.160 g, 51%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.50-7.41 (m, 1H), 7.32-7.26 (m, 2H), 7.25-7.19 (m, 1H), 7.09 (s, 1H), 6.86 (s, 1H), 5.02-4.93 (m, 1H), 4.70-4.59 (m, 2H), 3.63-3.46 (m, 2H), 3.04-2.89 (m, 2H), 2.84 (s, 3H), 2.76 (m, 1H), 2.28-2.01 (m, 3H), 1.96-1.83 (m, 1H), 1.52 (d, J=6.4 Hz, 3H). LCMS (Table 1, Method 4) Rt=1.617 min; MS m/z: 409 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11]O)[C:6]=2[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:33]I.N1C=CN=C1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][I:33])[C:6]=2[CH:13]=1
Reactant: OCCc1csc2ccc(Cl)cc12
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc2scc(CCI)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(5-chloro-1-benzothiophene-3-yl)ethanol (1060 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was extracted with chloroform, washed well with 5% Na2S2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 2-(5-chloro-1-benzothiophene-3-yl)ethyl iodide, was obtained as brown liquid; Yield: 1.1 g (69%); 319 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:15])[N:5]([CH2:13][CH3:14])[C:6](=[S:12])[N:7]([CH2:10][CH3:11])[C:8]=1[NH2:9].C(=O)([O-])[O-].[Na+].[Na+].[CH:22]1([C:25](Cl)=O)[CH2:24][CH2:23]1>N1C=CC=CC=1.CCOCC>[CH2:13]([N:5]1[C:4](=[O:15])[C:3]2[NH:2][C:25]([CH:22]3[CH2:24][CH2:23]3)=[N:9][C:8]=2[N:7]([CH2:10][CH3:11])[C:6]1=[S:12])[CH3:14]
Reactant: O=C(Cl)C1CC1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCn1c(=O)c2[nH]c(C3CC3)nc2n(CC)c1=S

Procedure:
25.1 g (100 mM) of 5,6-diamino 1,3-diethyl-2-thiouracil HCl were dissolved in 400 ml of pyridine, 12.72 g (120 mM) of sodium carbonate added, and under cooling a solution of 10.77 ml (120 mM) of cyclopropane carbonyl chloride in 50 ml of dried ether added within 10 minutes. After 20 min the solvents were evaporated in vacuo. The residue was treated with 200 ml of water and about 50 ml were removed again in vacuo. The suspension was diluted with 100 ml of 2N aqueous sodium hydroxide (NaOH) and heated under reflux for 30 minutes. A further 80 ml was distilled off during this time. After cooling the solution was acidified with 5N aqueous hydrochloric acid (HCl) to pH 5.5; 200 ml of water was added and the resulting suspension filtered. The solid was collected and washed, redissolved in 200 ml of 1N NaOH, treated twice with 0.4 g of charcoal, filtered and acidified again to pH 4.5. The solid was collected again, washed and dried to give 25.5 g of a solid which was suspended in 400 ml of hot methanol. The solid was collected again, washed and dried to give 23.5 g (89.0%) of 2-thioxanthine with mp subl. 265-7° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[CH2:31]([NH2:36])[CH2:32][CH2:33][CH2:34][NH2:35]>C(O)CCC>[NH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:36][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: NCCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(N(C)c2nc(NCCCCN)nc3ccccc23)cc1
Temperature: 105 °C
Yield: 39.3 %

Procedure:
To a suspension of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (300 mg, 1.0 mmol) in n-butanol (3 mL) and diisopropylethylamine (323 mg, 2.5 mmol) was added 1,4-butanediamine (132 mg, 1.5 mmol). The reaction was heated to 105° C. for 18 h, cooled to room temperature and concentrated. The crude product was purified by chromatography (amine column, i-PrOH/CHCl3, 0-100%) to give 138 mg (39%) of the title compound. 1H NMR (CDCl3) δ 7.5 (d, 1H), 7.4 (t, 1H), 7.15 (d, 2H), 6.95 (d, 2H), 6.7 (m, 2H), 3.8 (s, 3H), 3.6 (s, 3H), 3.55 (t, 2H), 2.8 (t, 2H), 2.1 (s, 3H), 1.75 (pentet, 2H), 1.63 (pentet, 2H); LC-MS (ESI+; 352 ([M+H]+)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Mg]Cl)(C)C.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[N:20]=[C:21]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)=[O:32])[S:22][C:23]=1[C:24](=[O:29])N(OC)C.[Cl-].[NH4+]>C1COCC1>[Br:8][C:4]1[N:3]=[C:2]([C:24]([C:23]2[S:22][C:21]([NH:30][C:31]([C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)=[O:32])=[N:20][C:19]=2[C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)=[O:29])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2cccc(Br)n2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
A THF solution (10 mL) of 2,6-dibromopyridine (4.97 g, 21.0 mmol) was added to a 2.0 mol/L solution of isopropylmagnesium chloride in THF (9.56 mL, 10.1 mmol) at 0° C., followed by stirring for 3 hours at room temperature. A THF solution (5 mL) of Compound 98 (1.37 g, 3.82 mmol) was added dropwise to the reaction mixture, followed by stirring for 3 hours at room temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=9:1) to afford the entitled Compound 300 (520 mg, 31%).
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:40]=[CH:41][CH:42]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:40]=[CH:41][CH:42]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:39]2[CH:40]=[CH:41][CH:42]=[C:37]([O:36][CH3:35])[CH:38]=2)=[S:47])=[C:29]([F:34])[CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: COc1cccc(C(=O)Cl)c1
Agent: COc1cccc(C(=O)N=C=S)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 90%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:16])=[O:15])=[N:7][N:8]2[CH:11](C)C)=[CH:4][CH:3]=1.[CH3:17]OC(C1C2C(=CC=CC=2)NN=1)=O.CI.C(I)(C)C>>[CH3:17][O:16][C:14]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[N:8]([CH3:11])[N:7]=1)=[O:15]
Reactant: CC(C)n1nc(C(=O)O)c2ccc(Br)cc21
Reactant: COC(=O)c1n[nH]c2ccccc12
Solvent: CI
Solvent: CC(C)I
Product: COC(=O)c1nn(C)c2cc(Br)ccc12

Procedure:
The title compound is prepared essentially as described in the synthesis of 6-bromo-1-isopropyl-1H-indazole-3-carboxylic acid substituting 6-bromo-1H-indazole-3-carboxylic acid methyl ester for 1H-indazole-3-carboxylic acid methyl ester and methyl iodide for isopropyl iodide ES/MS m/e 268.0 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=12>CN(C=O)C.CCOCC>[N:1]1[NH:2][N:3]=[N:17][C:16]=1[C:13]1[CH:14]=[CH:15][N:10]2[CH:9]=[CH:8][N:7]=[C:11]2[CH:12]=1
Reactant: N#Cc1ccn2ccnc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1cn2ccc(-c3nn[nH]n3)cc2n1
Temperature: 80 °C
Yield: 330 %

Procedure:
Sodium azide (97 mg, 1.45 mmol) was added to a stirred mixture of NH4Cl (82 mg, 1.53 mmol) and imidazo[1,2-a]pyridine-7-carbonitrile (200 mg, 1.4 mmol) in dry DMF (5 ml) at RT under N2. The reaction was stirred and heated at 80° C. in a sealed vial for 10 hours. [3 identical reactions were run in parallel] After cooling to RT the reaction mixtures were combined and diluted with Et2O. The solid was collected by filtration and dried to give the title compound (860 mg) as a light brown solid. [presumably contains NaCl] 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, dd), 8.02 (1H, s), 7.94 (1H, s), 7.57 (1H, d), 7.54 (1H, dd).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][C@H:28]([CH:33]=O)[CH2:27]2)#[N:23]>>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C@@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][CH2:33][C@@H:28]4[CH2:27][C:26]5[C:30](=[CH:31][CH:32]=[C:24]([C:22]#[N:23])[CH:25]=5)[CH2:29]4)[CH2:7][CH2:6]3)[C:9]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](N)CC1
Reactant: N#Cc1ccc2c(c1)C[C@@H](C=O)C2
Product: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NC[C@H]2Cc3ccc(C#N)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-2-[1-(4-amino-cyclohexyl)-5-chloro-1H-benzoimidazol-2-yl]-propan-2-ol and (S)-5-cyano-indan-2-carbaldehyde. LC-MS showed a single peak, C27H31ClN4O (m/e) calcd 462.2186, obsd 463.2 (M+H). 1H-NMR (CD3OD) □ 7.96 (d, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.49 (d, 1H), 7.38 (d, 1H), 7.18 (d, 1H), 5.38 (m, 1H), 3.22 (m, 2H), 2.75-2.97 (m, 8H), 2.01 (m, 2H), 1.72 (s, 6H), 1.68 (m, 4H).
Reaction SMILES: [NH:1]1[CH:8]=CC(N)=[N:4][C:2]1=[O:3].FS(O)(=O)=O.[F].[F:15][C:16](F)(F)[C:17]([OH:19])=O>O>[F:15][C:16]1[C:17](=[O:19])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cc[nH]c(=O)n1
Agent: O=S(=O)(O)F
Agent: [F]
Solvent: O
Product: O=c1[nH]cc(F)c(=O)[nH]1

Procedure:
Into a solution of cytosine (11.1 g) in a mixture of trifluoracetic acid (80 ml) and water (10 ml) kept at 10° C., fluorine fluorosulfonate was blown while stirring. The cytosine was completely consumed in 90 minutes, and the total amount of fluorine fluorosulfonate used was 18 mmol. The reaction mixture was heated under reflux for 4 hours and then treated as in Example 11 to give 5-fluorouracil (10.4 g). Yield, 80%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[CH2:32]([O:31][C:29](=[O:30])[C:28]([C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14])=[O:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccncc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3-tert-Butoxycarbonylamino-pyridin-4-yl)-oxo-acetic acid ethyl ester was prepared according to a procedure described by Estel, etc (J. Heterocycl. Chem., 1989, 26, 105-): To a solution of pyridin-3-yl-carbamic acid tert-butyl ester (8.50 g, 43.8 mmol) and TMEDA (16.5 mL, 109 mmol) in THF (200 mL) at −78° C. was cannulated tert.-BuLi (64.1 mL, 1.7 M in pentane) over 30 min under nitrogen. The mixture was then stirred for 2 hours between −10° C. and −20° C. After cooling to −60° C. diethyl oxalate (17.8 mL, 131 mmol) was added and the mixture allowed to warm to 0° C. After 3 hours the mixture was poured onto ice/1M HCl (120 mL) and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with water (100 mL), brine (75 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (gradient, hexane/ethyl acetate 5:2, 2:1), to give 3.04 g (24% yield) of compound 146 as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl>O>[C:15]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:17])[CH3:16]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)O

Procedure:
To a stirred solution of 20.0 parts of D-phenylalanine in 121 parts of water, cooled to about 1° -2°, is added, portionwise, an aqueous 50% sodium hydroxide solution until pH 12 is reached. Then 37 parts of acetic anhydride is added, while continuously adding aqueous 50% sodium hydroxide to keep the pH at about 12 and cooling the solution to keep the temperature at between about 10° to 30°. After about 20 minutes the mixture is acidified to pH 1 with concentrated hydrochloric acid and filtered. The recovered solid is recrystallized from water to afford N-acetyl-D-phenylalanine, melting at about 170°-172°.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]1)(=[O:28])=[O:27])[CH:20]=[CH:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]1)(=[O:27])=[O:28])[CH:20]=[CH:19]2
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: [Li+]
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[ethoxycarbonyl]piperazine
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].[CH:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1.Cl>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[C:3]([O:22][CH2:21][CH:18]2[CH2:20][CH2:19]2)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: OCC1CC1
Reactant: O=C(O)c1cc(I)c(Cl)cn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Temperature: 80 °C
Reaction time: 25 h
Yield: 57.2 %

Procedure:
To a solution of 5-chloro-4-iodo-pyridine-2-carboxylic acid (CAN 120643-06-3, 600 mg, 2.12 mmol) in THF (20 mL) and DMF (2 mL) was added with stirring potassium tert-butoxide (1.0 g, 8.91 mmol) and cyclopropanemethanol (1.5 mL, 18.8 mmol). The resulting mixture was stirred at 80° C. for 25 h, cooled, acidified with hydrochloric acid (25 mL, 1 N) and partitioned into ethyl acetate. The organic portions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by prep. HPLC (Gemini NX, acetonitrile/water gradient) to give the title compound (276 mg, 57%) as light yellow solid. MS (ESI, m/z): 228.4 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])[C:5]([Cl:13])=[CH:4][N:3]=1.[OH:14]S(O)(=O)=O.[NH4+].[OH-]>O>[Cl:13][C:5]1[C:6]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:7][C:2](=[O:14])[NH:3][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)NCc1cc(Cl)ncc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NCc1cc(=O)[nH]cc1Cl
Temperature: 200 °C

Procedure:
Compound N-(2,5-dichloro-pyridin-4-ylmethyl)-acetamide (250 mg, 1.14 mmol) was added to 33% H2SO4 (3 mL) and the mixture heated in a CEM microwave reactor at 200° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and basified with excess concentrated NH4OH. The reaction mixture was then frozen using a dry ice/acetone bath and evaporated to dryness in vacuo overnight in a freeze-dry apparatus. The solids were purified by column chromatography using a 12 g ISCO combi-flash column and dry-loading cartridge (silica gel, 100:0 to 50:50 DCM:DCM/MeOH/NH4OH 6:3:1) to afford N-(5-chloro-2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-acetamide (246 mg, quant.) as an off-white solid. This material was directly in the next step.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.O>C1COCC1>[C:1]([N:8]1[CH2:15][C@H:14]([O:16][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: BrCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2cccc3ccccc23)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Commercially available Boc-4(R)-hydroxyproline (5.00 g, 21.6 mmol) was dissolved in THF (100 mL) and cooled to 0° C. Sodium hydride (60% dispersion in oil, 1.85 g, 45.4 mmol) was added portionwise over 10 minutes and the suspension was stirred at RT for 1 h. Then, 1-(bromomethyl)naphthalene (8.00 g, 36.2 mmol) (prepared as described in E. A. Dixon et al. Can. J. Chem., (1981), 59, 2629-2641) was added and the mixture was heated at reflux for 18 h. The mixture was poured into water (300 mL) and washed with hexane. The aqueous layer was acidified with 10% aqueous HCl and extracted twice with ethyl acetate. The organic layers were combined and washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (49:49:2 hexane: ethyl acetate: acetic acid) to give the title compound as a colorless oil (4.51 g, 56% yield). 1H NMR (DMSO-d6) indicated the presence of two rotamers: δ 8.05 (m, 1H), 7.94 (m, 1H), 7.29 (d, J=14 Hz, 1H), 7.55-7.45 (m, 4H), 4.96 (m, 2H), 4.26 (br. s, 1H), 4.12 (dd, J=J=8 Hz, 1H), 3.54-3.42 (m, 2H), 2.45-2.34 (m, 1H), 2.07-1.98 (m, 1H) 1.36 (s, (3/9) 9H), 1.34 (s, (6/9) 9H).