Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Oc1c(Br)cc(Br)cc1I
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc3cc(Br)cc(Br)c3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 2,4-Dibromo-6-iodo-phenol [53872-06-3] (0.7 g, 1.8 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and CuI (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH and filtered to give 87 as a solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]([N+:33]([O-])=O)=[CH:22][N:21]=3)[CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:33][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][C:20]([O:19][C:15]2[CH:14]=[C:13]([S:10]([NH:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=2)=[N:21][CH:22]=1
Reactant: O=[N+]([O-])c1cnc(Oc2cccc(S(=O)(=O)NCCN3CCOCC3)c2)cc1Nc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(Oc2cccc(S(=O)(=O)NCCN3CCOCC3)c2)cc1Nc1ccccc1

Procedure:
The product of Step 3 (3.3 g, 6.6 mmol) was hydrogenated overnight with a balloon of hydrogen gas in MeOH (50 mL) in the presence of 5% Pd/C (300 mg). The reaction mixture was filtered through Celite and concentrated to give the title compound as a dark oil which was used directly in the next step (˜3.1 g, quant.).
Reaction SMILES: [C:1]([O:9][C@@:10]12[O:16][C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[C:1]([O:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@]12CCCC[C@H]1O2)c1ccccc1
Solvent: ClCCl
Product: O=C(O[C@H]1CCCCC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of (1R,2R)-2-benzoyloxy-1,2-epoxycyclohexane (0.030 g, 0.137 mmol, 93% ee) in anhydrous CH2Cl2 (0.4 mL) was added YbCl13 (0.0048 g, 0.0137 mmol). Upon stirring at room temperature for 30 min, the reaction mixture was quenched with saturated NaHCO3 solution, extracted with ether, dried over anhydrous Na2SO4, filtered, concentrated, and purified on buffered silica gel (0.5-1% Et3N) by flash column chromatography [EtOAc-CH2Cl2-hexane (3:7:40)] to afford (S)-2-benzoyloxy cyclohexanone (0.022 g, 73% yield, 88% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:13]=[C:12]([OH:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1.[C:25](Cl)(=[O:27])[CH3:26].N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:13]=[C:12]([O:24][C:25](=[O:27])[CH3:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(-n2nc(O)c3c(c2=O)Cc2ccc(Cl)cc2N3)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Product: CC(=O)Oc1nn(-c2ccc(C)cc2)c(=O)c2c1Nc1cc(Cl)ccc1C2
Temperature: 25 °C
Yield: 62 %

Procedure:
A suspension of the 7-chloro-4-hydroxy-2-(4′-methylphenyl)-5,10-dihydro-2H-pyridazino[4,5-b]quinoline-1-one (755 mg), acetyl chloride (0.205 mL) and 2,6-lutidine (0.337 mL) was refluxed in toluene (6 mL) for 2 hours. The resulting mixture was cooled to room temperature. The resulting paste was diluted with ether (15 mL) and filtered in vacuo. The solids were washed with ether and ethyl acetate. The crude solids were triturated in warm ethyl acetate, then cooled to room temperature and filtered in vacuo. After drying this afforded the title compound as a light yellow solid (528 mg, 62%). mp 238-240° C.; MS 382 (m+H); NMR 2.34(s,3H), 2.41(s,3H), 3.85(s, 2H), 6.98(dd,1H,J1=8.1,J2=1.9), 7.09(d,1H,J=1.9), 7.18(d,1H,J=8.1), 7.28(d,2H,J=8.3), 7.39(d,2H,J=8.3), 9.06(s,1H); Analysis C20H16ClN3O3. 0.03M H2O expected/theoretical C 62.09/62.04H 4.24/2.27 N 10.62/10.85.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[S:16][C:17]([C:20]2([CH3:26])[S:25][CH2:24][CH2:23][CH2:22][S:21]2)=[N:18][N:19]=1>C1(C)C=CC=CC=1.CCCCC>[CH3:26][C:20]1([C:17]2[S:16][C:15]([NH:14][C:5](=[O:6])[C:4]3[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=3[O:12][CH3:13])=[N:19][N:18]=2)[S:21][CH2:22][CH2:23][CH2:24][S:25]1
Reactant: CC1(c2nnc(N)s2)SCCCS1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: COc1cccc(OC)c1C(=O)Nc1nnc(C2(C)SCCCS2)s1
Temperature: 25 °C

Procedure:
A solution of 1.0 g of 2,6-dimethoxybenzoyl chloride in 50 ml of toluene containing 1.0 g of 2-amino-5-(2-methyl-1,3-dithian-2-yl)-1,3,4-thiadiazole was heated at reflux for fifteen hours. The reaction mixture was then cooled to room temperature and diluted with pentane, whereupon a white precipitate formed. The precipitate was collected by filtration and identified as N-[5-(2-methyl-1,3-dithian-2-yl)-1,3,4-thiadiazol-2-yl]-2,6-dimethoxybenzamide.
Reaction SMILES: C([NH:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C.[O:16]([CH2:23][CH2:24]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N[C@H](C(O)=O)CC1C=CC=CC=1.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:4][CH:5]([CH:23]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:24])[C:6]([OH:8])=[O:7]
Reactant: ClCCOc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(Oc1ccccc1)C(N)C(=O)O

Procedure:
(±)-2-Amino-3-phenoxybutyric acid was prepared from diethyl acetamidomalonate and 2-phenoxyethyl chloride by the procedures described in Example 5 and 6. MS (FAB) m/e 802 (M+H)+. Amino Acid Analysis: Cha (0.95), Gly (0.94), Leu (1.03), Arg (1.03).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][C:35](O)=[O:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][C:35]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: COc1ccc(CC(=O)O)cc1OC
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)Cc1ccc(OC)c(OC)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (3,4-dimethoxy-phenyl)-acetic acid to yield (3aR,4S,7aR)-methyl 4-(2-(3,4-dimethoxyphenyl)acetoxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H] 296 (ester elimination ion); RT=7.486 min LCMS Method III
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[N:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]3=[N:12][C:11]=2/[CH:25]=[CH:26]/[C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[CH:6][CH:5]=1)([O-])=O.O.[OH-].[Na+]>C(O)(=O)C.[Fe]>[O:22]1[CH2:21][CH2:20][N:19]([C:18]2[C:13]3[N:14]([C:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)=[C:11](/[CH:25]=[CH:26]/[C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:12]=3)[N:15]=[CH:16][CH:17]=2)[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of compound 10a (0.85 g, 1.8 mmol) in acetic acid (20 mL) was added iron powder (0.50 g, 8.9 mmol). The reaction mixture was stirred at 80° C. for 2 h, and allowed to cool to rt. The reaction mixture was treated with water, and the pH of the solution was adjusted to ca. pH 7 using 3 N NaOH solution. The mixture was extracted with DCM (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain compound 10b as a dark red solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H24N6O: 449.2 (M+H). found: 449.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=[C:13]([Br:12])[CH:14]=1)=[O:9]
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc(Br)cc(C(F)(F)F)c1)c1cc(Br)ccc1O
Yield: 73.3 %

Procedure:
Using 5-bromosalicylic acid and 3-bromo-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[Cl:23][C:24]1[C:25]([NH:39][C:40](=O)[CH2:41][O:42][CH3:43])=[C:26]2[C:31](=[CH:32][C:33]=1[Cl:34])[N:30]=[C:29]([O:35][CH3:36])[C:28]([O:37][CH3:38])=[N:27]2>O1CCCC1>[Cl:23][C:24]1[C:25]([NH:39][C:40](=[S:10])[CH2:41][O:42][CH3:43])=[C:26]2[C:31](=[CH:32][C:33]=1[Cl:34])[N:30]=[C:29]([O:35][CH3:36])[C:28]([O:37][CH3:38])=[N:27]2
Reactant: COCC(=O)Nc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COCC(=S)Nc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 166.7 %

Procedure:
2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (19.5 g, 48.2 mmol) was added to a solution of 6,7-dichloro-2,3-dimethoxy-5-methoxyacetamidoquinoxaline (27 g, 78 mmol) in tetrahydrofuran (480 ml) and the mixture was stirred for 18 hours at room temperature, then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel by gradient elution using hexane:dichloromethane (1:1 changing to 1:4, by volume) as the eluent to give 6,7-dichloro-2,3-dimethoxy-5-methoxythioacetamidoquinoxaline (29.1 g, >100%) as a white solid, mp 198-200° C., containing a minor impurity.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.C(OC([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=O)CCC.[ClH:23].[CH2:24]([OH:26])C>>[ClH:23].[CH3:24][O:26][C:9]1[C:4]2[C:3]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:2][S:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2sncc2c1
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CCO
Agent: Cl
Product: COc1cccc2snc(N3CCNCC3)c12
Reaction time: 0.5 h
Yield: 62 %

Procedure:
The butyloxycarbonylpiperazine benzisothiazole (0.012 mole) was taken up in warm absolute ethanol and acidified with ethanolic HCl (5 mole equiv.). The solution was stirred 30 minutes at 90°. The mixture was cooled and the solvent removed in vacuo. The crude solid was recrystallized from absolute EtOH affording 4-methoxy-1,2-benzisothiazol-3-yl-piperazine hydrochloride in 62% yield.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2O[CH:19]=[N:20][N:21]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.FC(F)(F)C(O)=O>C(O)CCC>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:26]([CH:23]3[CH2:25][CH2:24]3)[CH:19]=[N:20][N:21]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: O=C(Nc1cccc(-c2nnco2)c1)OCc1ccccc1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)OCc1ccccc1
Temperature: 110 °C
Yield: 30.8 %

Procedure:
A mixture of (3-[1,3,4]Oxadiazol-2-yl-phenyl)-carbamic acid benzyl ester (200 mg, 0.68 mmol), cyclopropylamine (0.5 mL, 7.2 mmol), trifluoroacetic acid (0.05 mL, 0.65 mmol) in anhydrous 1-butanol mL) was heated at 110° C. overnight in a sealed tube. The reaction mixture was cooled to room temperature and the solvent was removed. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. Solvent was removed after drying with sodium sulfate and purified by silica gel chromatography (rf=0.26 in 20:1 ethyl acetate/methanol) to obtain [3-(4-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-phenyl]-carbamic acid benzyl ester as a white powder (70 mg, 31%). M+1=335.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]3[CH2:14][NH:13][CH2:12][C@H:11]([CH3:15])[N:8]3[C:9]=2[CH:10]=1.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[CH2:14][NH:13][CH2:12][C@H:11]([CH3:15])[N:8]3[C:9]=2[CH:10]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@@H:7]3[CH2:14][NH:13][CH2:12][C@H:11]([CH3:15])[N:8]3[C:9]=2[CH:10]=1
Reactant: C[C@H]1CNCc2cc3ccc(Cl)cc3n21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C[C@H]1CNC[C@@H]2Cc3ccc(Cl)cc3N21
Product: C[C@H]1CNC[C@H]2Cc3ccc(Cl)cc3N21
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %
Yield: 8 %

Procedure:
(4S)-7-Chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole (0.152 g; 0.689 mmol) is dissolved in a tetrahydrofurane/trifluoroacetic acid mixture (1:2; 7.5 ml) and cooled to 0° C. Sodium borohydride (52 mg; 1.38 mmol) is added and the solution was stirred for 2 h. The reaction mixture was poured in an aqueous NaOH solution (pH was put to 14) and extracted twice with ethyl-acetate. Organic phases were pooled, dried with MgSO4 and the solvent was evaporated. Chromatography on silica gel (dichloromethane/methanol 9:1) gave (4S,10aS)-7-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (113 mg, 74%) and (4S,10aR)-7-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (12 mg, 8%).
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[C:37]1([C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCCCCC=C(c1ccccc1)c1ccccc1
Yield: 70.5 %

Procedure:
The reaction was carried out as in Example 87 using the following reagents: sodium hydride (56% dispersion in oil; 8.36 g); dimethylsulfoxide (100 mL), (6-carboxyhexyl)triphenylphosphonium bromide (37.7 g), benzophenone (17.5 g); and tetrahydrofuran (100 mL). The crude product, isolated in the usual way, was recrystallized from hexane (200 mL) to yield 16.6 g of 8,8-diphenyl-7-octenoic acid, mp 88°-89° C. Anal. Calculated for C20H22O2 : C, 81.60; H, 7.53. Found: C, 81.34; H, 7.25.
Reaction SMILES: [CH2:1]([C:8]1[NH:12][N:11]=[C:10]([C:13]2[S:17][C:16]([C:18]([OH:20])=O)=[C:15]([CH3:21])[CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:53][CH2:54][C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:8]1[NH:12][N:11]=[C:10]([C:13]2[S:17][C:16]([C:18]([NH:53][CH2:54][C:55]3[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=3)=[O:20])=[C:15]([CH3:21])[CH:14]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(-c2n[nH]c(Cc3ccccc3)n2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2n[nH]c(Cc3ccccc3)n2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
To a stirred mixture of 5-(5-benzyl-1H-1,2,4-triazol-3-yl)-3-methylthiophene-2-carboxylic acid (0.13 g, 0.43 mmol), 1-hydroxybenzotriazole (0.088 g, 0.65 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g, 0.65 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.23 mL, 1.30 mmol), followed by the addition of 3-(aminomethyl)pyridine (0.044 mL, 0.44 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h, and diluted with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (3×35 mL) and water (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 10% methanol in dichloromethane to afford the title compound as a colorless foam (0.11 g, 67%): mp 82° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 8.66 (t, J=5.6 Hz, 1H), 8.55 (s, 1H), 8.46 (s, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.42-7.20 (m, 8H), 4.44 (d, J=5.6 Hz, 2H), 4.10 (s, 2H), 2.43 (s, 3H); MS (ES+) m/z 390.3 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12].[OH-].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([NH:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][C:11]([OH:13])=[O:12])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NCc1ccccc1CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCc2ccccc2CC(=O)O)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of o-aminomethylphenylacetic acid hydrochloride (7.50 g., 37 m.mol.) and sodium hydroxide (4.74 g., 118 m.mol.) in water (100 ml.) was added p-toluenesulfonyl chloride (7.64 g., 40 m.mol.) in portions at 60° C. The mixture was stirred for 1 hour at the same temperature and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate (4 × 50 ml.). The combined extracts were washed with water, treated with a small amount of carbon and dried. The solvent was evaporated under reduced pressure and the residue crystallized from ethyl acetate to afford 2 as colorless prisms. Yield, 9.84 g. (84%). M.p. 155°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH2:27][CH3:28].C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH2:27][CH3:28])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: CCc1cnccc1N
Reactant: O=c1[nH]c(-c2cc(Cl)ccc2F)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: CCc1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-chloro-2-fluorophenyl)-pteridin-4-one with 4-amino-3-ethylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])=[CH:6][C:5]=1[F:21])=[N+:2]=[N-:3].[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[C:26]#[CH:27])[CH3:23]>C1C=CC=CC=1>[F:21][C:5]1[CH:6]=[C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:8]=[CH:9][C:4]=1[N:1]1[CH:27]=[C:26]([CH:25]([O:28][CH2:29][CH3:30])[O:24][CH2:22][CH3:23])[N:3]=[N:2]1
Reactant: C#CC(OCC)OCC
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N=[N+]=[N-])c(F)c2)C(=O)O1
Solvent: c1ccccc1
Product: CCOC(OCC)c1cn(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)nn1
Yield: 81.8 %

Procedure:
A solution of 1.70 g (5.8 mmol) of the azide of example 17 in 50 mL benzene was treated with 4.46 g (34.8 mmol) of 1,1-diethoxy-2-propyne followed by warming at reflux for 18 h. The solution was treated with 1.0 g (7.80 mmol) of 1,1-diethoxy-2-propyne followed by warming at reflux for an additional 3 h. The solution was cooled and concentrated in vacuo to afford an oil which was chromatographed over 200 g of 230-400 mesh silica gel, eluting with 2-3% (v/v) methanol in dichloromethane to afford 2.0 g (80%) of (S)-N-[[3-[3-Fluoro-4-(4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)phenyl]-2-oxo-5-oxazoldinyl]methyl]acetamide and (S)-N-[[3-[3-Fluoro-4-(5-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)phenyl]-2-oxo-5-oxazoldinyl]methyl]acetamide as an inseparable mixture of isomers. Of this material, 410 mg (0.973 mmol) was dissolved in 10 mL THF and treated with 1 mL of 1N HCl solution followed by stirring at ambient temperature for 48 h, and then warming at reflux for 1 h. The mixture was dissolved in ethyl acetate and extracted with water. Drying (Na2SO4) and concentration in vacuo afforded an oil which was subjected to radial chromatography on a 2 mm chromatotron plate eluting with 7% (v/v) methanol in dichloromethane. The less polar fraction [110 mg (33%)] from the chromatography proved to be the title compound, isolated as a white solid. 1H NMR (CDCl3) δ 8.60, 7.99, 7.85, 7.36, 6.1, 4.86, 4.12, 3.89, 3.72, 2.04.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:23]=[C:24](Br)[CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2].[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C(#N)C.CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:23]=[C:24]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:25]=[CH:26][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1)c1cc(Br)ccc1-2
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1)c1cc(C#C[Si](C)(C)C)ccc1-2
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of ester 112 (3.0 g, 7.07 mmol) and bis(triphenylphosphine)palladium(II) acetate (0.42 g, 0.57 mmol) was dissolved in a mixed solvent system of acetonitrile (80 mL) and TEA (120 mL). The mixture was degassed under vacuum and argon gas was added, after which trimethylsilylacetylene (2 mL, 14.14 mmol) was added into the mixture. The mixture was degassed again under vacuum (argon) and heated to reflux. The mixture was heated at reflux until analysis by TLC (EtOAc) indicated that all of the starting material 112 had been consumed. The mixture was cooled to rt and the precipitate which formed was removed by filtration through celite. The filtrate was concentrated under reduced pressure and partitioned between H2O and EtOAc. The combined layers of EtOAc were washed with brine and dried (Na2SO4), after which the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, EtOAc:hexane 1:1). Conditions for TLC were EtOAc. A white solid 113 (2.60 g, 83.3%) was obtained. mp 160-162° C.; IR (KBr, cm−1) 3365, 2925, 1706, 1616, 1553, 1498; 1H NMR (CDCl3) δ 7.89 (s, 1H), 7.73 (dd, J=1.73 Hz, 1H), 7.51-7.36 (m, 7H), 6.66 (q, J=7.30, 1H), 4.45-4.30(m, 2H), 1.40 (t, J=7.11, 3H), 1.25 (d, J=7.38 Hz, 3H), 0.15 (s, 9H). MS (EI) m/e (relative intensity) 441 (M+, 15), 369 (25), 323 (55), 295 (100), 267 (15).