Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([NH:11][C:12]([NH2:14])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[CH:16]([C:22]([C:24]([F:27])([F:26])[F:25])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[C:1]12([NH:11][C:12]3[O:13][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:22]([C:24]([F:25])([F:27])[F:26])[N:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: NC(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Product: CCOC(=O)c1oc(NC23CC4CC(CC(C4)C2)C3)nc1C(F)(F)F
Yield: 39.1 %

Procedure:
By the procedure of Example 4, 11.6 g (60 mmol) of adamantyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 24 hours. The product was separated and then recrystallized from methylcyclohexane to yield 7.0 g of a white solid product (m.p.=109°-111° C.) identified in Table I.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][CH2:1][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cccc(CNc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 101.9 %

Procedure:
To a stirred solution of methyl 3-formylbenzoate (0.5 g, 3.046 mmol) in anhydrous DCM (15 mL) was added 4-fluoroaniline (0.303 mL, 3.198 mmol) followed by glacial acetic acid (0.174 mL, 3.046 mmol). The reaction was stirred at room temperature for 64 hours. Sodium triacetoxyborohydride (1.614 g, 7.615 mmol) was added, and the reaction was stirred at room temperature for 2 hours. Water was added to quench the reaction and the mixture was diluted with DCM. The organic layer was washed with brine, passed through a hydrophobic fit and the solvent was removed in vacuo to afford the title compound as a red oil (0.805 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]([S:17]([N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])=[C:4]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH:3]=1.Br[C:35]1[C:40]([C:41]#[N:42])=[CH:39][C:38]([C:43]([F:46])([F:45])[F:44])=[N:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:35]2[CH:36]=[N:37][C:38]([C:43]([F:45])([F:46])[F:44])=[CH:39][C:40]=2[C:41]#[N:42])=[CH:6][C:5]([S:17]([N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])=[C:4]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH:3]=1
Reactant: CN(c1ccccn1)S(=O)(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1OCCCCO
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(c1ccccn1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCCO
Temperature: 90 °C
Yield: 37.5 %

Procedure:
A mixture of 4-chloro-2-(4-hydroxy-butoxy)-N-methyl-N-pyridin-2-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (150 mg, 0.34 mmol), 5-bromo-2-trifluoromethyl-isonicotinonitrile (111 mg, 0.44 mmol), Pd(Ph3P)4 (40 mg, 0.034 mmol) and Na2CO3 (217 mg, 2.1 mmol) in dioxane (2 mL) and water (0.2 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and then heated at 90° C. for 16 hrs. The mixture was absorbed onto silica gel and purified by chromatography on silica gel eluting with 20-25% acetone in hexanes to give 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-hydroxy-butoxy)-N-methyl-N-pyridin-2-yl-benzenesulfonamide as an oil (69 mg). A small sample was also purified by prep. LCMS. MS: 541.1 (M+H)+; tR=7.59 min (method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[C:9]#[N:10].C(=O)([O-])[O-:21].[K+].[K+].CS(C)=O.OO.Cl>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[C:9]([NH2:10])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: N#CC(c1ccccc1Cl)N1CCc2sccc2C1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 35 °C

Procedure:
(±)-2-(2-Chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetonitrile (713 g; 2.46 mol) was added to methanol (3.505 l) at 23-28° C. with stirring. To this slurry, potassium carbonate (170 g; 1.23 mol) was added followed by dimethyl sulfoxide (263 ml; 3.7 mol). The contents were heated between 30-40° C. and 30.0% aqueous hydrogen peroxide solution (382 ml; 3.70 mol) was added between 40-50° C. slowly over a period of 3 hours. After the addition was over, the reaction mixture was maintained at this temperature for a further 2 hours, after which the reaction was brought to 20-30° C. 35% Hydrochloric acid (213.0 ml) in water (10.7 l) was added slowly to the reaction mixture over a period of 1 hour 15 minutes. After stirring for 1 hour, the solid formed was filtered and washed with a 1:1 methanol: water mixture (3.565 l). The isolated solid was dried in a vacuum oven at 75-80° C. for a period of 12 hours. Yield: 716 g (94.72%). mp: 124-126° C. The product was identified by IR spectrum, 1H and 13C NMR investigation.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([N:27]4[CH2:37][C@@H:36]([CH3:38])[CH2:35][C@H:28]4[C:29]([NH:31][CH2:32][C:33]#[N:34])=[O:30])[CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:19][CH:18]=2)=[CH:21][C:22]=1[N:27]1[CH2:37][C@@H:36]([CH3:38])[CH2:35][C@H:28]1[C:29]([NH:31][CH2:32][C:33]#[N:34])=[O:30]
Reactant: C[C@H]1C[C@@H](C(=O)NCC#N)N(c2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ccc2Cl)C1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@H]1C[C@@H](C(=O)NCC#N)N(c2cc(-c3ccc(N4CCNCC4)cc3)ccc2Cl)C1
Reaction time: 8 h

Procedure:
To (4S)-1-{4′-[4-(tert-butoxycarbonyl)piperazin-1-yl]-4-chloro-1,1′-biphenyl-3-yl}-N-(cyanomethyl)-4-methyl-L-prolinamide (66 mg, 0.123 mmol) in dry TBF (0.25 mL) under dry nitrogen was gradually added a total of 3 equivalents of MeSO3H (30 mL, 0.39 mmol) over a period of 1 hour in portions of 1–2 equivalents at a time and the reaction mixture was stirred overnight. Aqueous sat. NaHCO3 was added carefully and the product was extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (HOH/MeOH/CH2Cl2, 1/9/90) to afford (4S)-1-(4-chloro-4′-piperazin-1-yl-1,1′-biphenyl-3-yl)-N-(cyanomethyl)-4-methyl-L-prolinamide. MS (-APCI): 436.2 [M−1]−.
Reaction SMILES: [Mg].[C:2]1([C:14]2[C:15](=[O:29])[NH:16][C:17](=[O:28])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH2:7][CH2:6][CH2:5][N:4]3[CH:3]=1.C(OCC)(=O)C>CO>[C:2]1([C@H:14]2[C@H:18]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[C:17](=[O:28])[NH:16][C:15]2=[O:29])[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH2:7][CH2:6][CH2:5][N:4]3[CH:3]=1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 89.3 %

Procedure:
Magnesium turnings (3.05 g, 0.125 mol) were added to a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrole-2,5-dione (2.56 g, 6.97 mmol) in anhydrous methanol (100 ml) and heated to reflux under an atmosphere of nitrogen for 40 minutes. After cooling to room temperature the mixture was poured into ethyl acetate (300 ml), washed with 1M hydrochloric acid (300 ml) and water (500 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was then purified by silica gel chromatography using 40-50% ethyl acetate in hexanes to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione as a pale pink solid (2.3 g). 1H NMR (DMSO-d6) 400 MHz δ: 11.54 (s, 1H), 11.03 (s, 1H), 7.32-7.4 (m, 4H), 7.17 (d, 1H, J=7.2 Hz), 7.07 (t, 1H, J=7.6 Hz), 6.96 (t, 1H, J=7.6 Hz), 6.82-6.89 (m, 2H), 4.5 (dd, 2H, J=7.2 and 20 Hz), 4.07 (t, 2H, J=5.2 Hz), 2.87 (t, 2H, J=6 Hz), 2.08 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>[N+](C)([O-])=O>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:34][CH:33]=3)[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2O1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46.2 %

Procedure:
200 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of nitromethane and the solution was cooled to 0° C. under a nitrogen atmosphere. 240 mg of finely powdered aluminum chloride were added and, after stirring at 0° C. for 5 minutes, 388 mg of 4-nitrobenzoyl chloride were added. After 16 hours at room temperature 120 mg of aluminum chloride were added and the mixture was stirred at 100° C. for 45 minutes. After dilution with diethyl ether and washing with sodium hydroxide solution the organic phase was dried over sodium sulphate and evaporated. The residue crystallized and was triturated with diethyl ether to give 150 mg of 3,4-dihydro- 2,2-dimethyl-6-(4-nitrobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran.
Reaction SMILES: [OH:1][P:2]([CH2:5][N:6]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:15][P:16]([OH:19])([OH:18])=[O:17])[CH2:8][CH2:7]1)([OH:4])=[O:3].Cl[CH2:21][C:22]([OH:24])=[O:23].[OH-].[Na+].Cl>O>[C:22]([CH2:21][N:12]1[CH2:13][CH2:14][N:6]([CH2:5][P:2]([OH:4])([OH:1])=[O:3])[CH2:7][CH2:8][N:9]([CH2:15][P:16]([OH:18])([OH:19])=[O:17])[CH2:10][CH2:11]1)([OH:24])=[O:23]
Reactant: O=P(O)(O)CN1CCNCCN(CP(=O)(O)O)CC1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CCN(CP(=O)(O)O)CCN(CP(=O)(O)O)CC1
Temperature: 80 °C

Procedure:
To a solution of 0.25 millimoles of N,N'-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane in water were added 0.3 millimoles of chloroacetic acid, and the pH was adjusted to 9.0 by dropwise, addition of NaOH. The mixture was then heated to 80° C. and held at that temperature overnight. Hydrochloric acid was then added to a pH of 1.5, and the water was evaporated. The solids were then triturated with ether followed by ethanol to remove contaminants, and the remaining solid product was identified by proton NMR as N-carboxymethyl-N',N"-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:13]=[CH:14][C:15]=1[CH3:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[C:18](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:19]>>[CH3:17][C:3]1[C:2]([N:1]=[C:18]=[S:19])=[C:15]([CH3:16])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1N
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1N=C=S
Yield: 65 %

Procedure:
The title compound is prepared from N-(3-amino-2,4-dimethyl-benzyl)-2,2-dimethyl-propionamide, 1,1′-thiocarbonyldi-2-pyridone in analogy to step Af.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:19][S:20]([NH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:31])[CH2:29]Br)=[CH:26][CH:25]=1)(=[O:22])=[O:21].C(N(CC)CC)C.CO>ClCCl>[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:29][C:28]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:33][CH:32]=3)=[O:31])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Nc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)CN2CCN(c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(4-Methanesulphonamidophenyl)piperazine hydrochloride (1.18 g), 4-methanesulphonamidophenacyl bromide (1.16 g), [see J. Med. Chem, 9, 88 (1966)], triethylamine (0.82 g), methanol (10 ml) and dichloromethane (10 ml) were warmed briefly to attain homogeneity, then stirred at ambient temperature for 4 hours, evaporated to dryness, the residue triturated and washed with water, and then crystallized from methanol/acetone. The yield of the title compound was 0.88 g, m.p. 222°-5° (dec.).
Reaction SMILES: C1(O)C=CC=CC=1.C(O)C=CCCCCCCC.CCOC(/N=N/C(OCC)=O)=O.[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CCCCCCCC)=[CH:36][CH:35]=1>CCOCC>[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41]/[CH:42]=[CH:43]/[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCCCCCC=CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: CCCCCCC/C=C/COc1ccc(C(=O)OC)cc1
Yield: 65 %

Procedure:
Phenol 34 (486 mg, 3.2 mmol), 2-decenol 26 g (500 mg, 3.2 mmol), TPP (965 mg, 3.68 mmol), and DEAD (641 mg, 3.68 mmol) in 32 ml ether were reacted according to the procedure for compound 35a. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5-90/10 (v/v, Hex/EtOAc). Evaporation of solvent yielded 603 mg (65%) of colorless needles.
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(O)O.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.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>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ccccn2)cc1
Yield: 90.9 %

Procedure:
To a solution of 4-boronobenzoic acid (1.66 g, 10 mmol) and 2-bromopyridine (1.72 g, 11 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) were added. The mixture was degassed and purged withed nitrogen. The mixture was stirred under reflux for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=4 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.81 g of white solid of 4-(pyridin-2-yl)benzoic acid. Yield: 91%. LC-MS (ESI) m/z: 200 (M+1)+.
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+:14]>>[Na+:14].[NH2:1][C@H:2]([C:10]([O-:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](Cc1ccccc1)C(=O)[O-]

Procedure:
A solution of N-(2-chloro-6-methylbenzoyl)-4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine (0.15 g) in 1.0 N NaOH (0.3 mL) was applied to a 2×20 cm open column of C-18 reversed phase silica gel (40-63 μM, RP Silica Gel60, as supplied by EM Separations, Cat. 10167) eluting with water, then with 40-50% methanol in water to give N-(2-chloro-6-methylbenzoyl)-4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine sodium salt (147 mg) as an amorphous white solid after lyophilization.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>[Pt]=O.C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc([N+](=O)[O-])nc2)C1
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(N)nc2)C1
Reaction time: 20 h
Yield: 111.7 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with platinum oxide (200 mg), 251a (2.00 g, 6.78 mmol), ethyl acetate (30 mL) and ethanol (30 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 20 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (10.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with methanol (2×50 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 100% yield (2.01 g) of 251b as a white solid: mp 83-84° C.; 1H NMR (500 MHz, DMSO-d6) d 7.53 (d, 1H, J=3.0 Hz), 7.04 (dd, 1H, J=9.0, 3.0 Hz), 6.41 (d, 1H, J=9.0 Hz), 5.32 (br s, 2H), 4.21 (t, 2H, J=6.5 Hz), 3.75 (t, 2H, J=6.5 Hz), 3.25 (m, 1H), 1.37 (s, 9H); MS (ESI+) m/z 266.2 (M+H).
Reaction SMILES: [SH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[O:6][C:7]=1[C:8](OCC)=[O:9]>O1CCCC1>[SH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[O:6][C:7]=1[CH:8]=[O:9]
Reactant: CCOC(=O)c1oc(C)nc1CS
Solvent: C1CCOC1
Product: Cc1nc(CS)c(C=O)o1
Reaction time: 4 h

Procedure:
10 mmol of ethyl 4-(mercaptomethyl)-2-methyl-1,3-oxazole-5-carboxylate was dissolved in 100 ml of dried tetrahydrofuran, then 42 ml of the 0.5M SDBBA solution was gradually added with keeping the temperature at −30 to −20° C. After the adding, reaction was carried out for 4 hours at −20° C. Then 20 ml of wafer was added into the reaction system to stop the reaction and then an organic layer was separated. To the remaining water phase, sodium hydrogen carbonate was added until the pH of the water phase reached 8 to 9. The product was extracted and separated into an organic layer using ethyl acetate. This organic layer and the previously obtained organic layer were combined together and dried under sodium sulfate. The solvent was evaporated out and then the product was purified using a column separation with solvents of ethyl acetate and hexane, obtaining 4-(mercaptomethyl)-2-methyl-1,3-oxazole-5-carbaldehyde.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][C:3](=O)[CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCC(CC2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C1CN2CCC(CC2)N1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a stirred solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (1.0 g, 7.2 mmol) in 1,4-dioxane (7.2 mL) at room temperature was added lithium aluminum hydride [2.0M/THF] (4.1 mL, 8.2 mmol). The reaction mixture was then heated at reflux for 6 hours before cooling to room temperature. The reaction was quenched by the stepwise addition of 200 L of H2O, 200 L of 15% aqueous NaOH, and 600 L of H2O. The mixture was filtered through Celite which was subsequently washed with EtOAc. The combined filtrate was concentrated in vacuo to afford the product (0.82 g, 90%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.28-3.25 (m, 1H), 2.99-2.95 (m, 8H), 1.86-1.80 (m, 3H), 1.69-1.64 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([C:11]4=[O:18])[CH2:9]2)[CH2:15]3)[CH:7]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([C:11]3=[O:18])[CH2:9]1)[CH2:15]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C2CC3CC1CC(c1cc(Br)ccc1O)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C2CC3CC1CC(c1cc(Br)ccc1OCc1ccccc1)(C3)C2
Yield: 93.8 %

Procedure:
To a solution of 5-(5′-bromo-2′-hydroxyphenyl)-2-adamantanone (4.57 g, 14.20 mmol) in acetone (42 mL) was added benzyl bromide (2.67 g, 15.6 mmol) followed by K2CO3 (2.65 g, 19.2 mmol). The mixture was stirred at reflux for 25.7 h under argon. Acetone was removed, and 2 N HCl (60 mL) was added. The resultant mixture was extracted with EtOAc (250 mL), and the organic layer was washed with brine and dried. After removal of solvent at reduced pressure, the residue was purified on silica gel (14% to 20% EtOAc/hexane) to give 5.48 g (94%) of 5-(2′-benzyloxy-5′-bromophenyl)-2-adamantanone as a white solid, mp 163-165° C. 1H NMR (DMSO-d6) δ 1.79-2.42 (m, 13H, AdCH and AdCH2), 5.12 (s, 2H, C6H5CH2), 7.03 (d, J=8.5 Hz, 1H, 3′-ArH), 7.21 (d, J=2.4 Hz, 1H, 4′-ArH), 7.29-7.44 ppm (m, 6H, 6′-ArH, C6H5).
Reaction SMILES: C1(N2CCN3C(CC4(C5C=CC=CC=5)CCCC4)=NC(=O)C(O)=C3C2=O)CC1.C([O:36][C:37]1[C:42](=[O:43])[N:41]=[C:40]([CH2:44][C:45]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:49][CH2:48][CH2:47][CH2:46]2)[N:39]2[CH2:56][CH2:57][N:58]([CH2:61][CH:62]3[CH2:64][CH2:63]3)[C:59](=[O:60])[C:38]=12)C1C=CC=CC=1>>[CH:62]1([CH2:61][N:58]2[CH2:57][CH2:56][N:39]3[C:40]([CH2:44][C:45]4([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:46][CH2:47][CH2:48][CH2:49]4)=[N:41][C:42](=[O:43])[C:37]([OH:36])=[C:38]3[C:59]2=[O:60])[CH2:64][CH2:63]1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1CC1CC1
Agent: O=C1c2c(O)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(O)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1CC1CC1
Yield: 15.9 %

Procedure:
This compound was prepared following the same method as described for 2-cyclopropyl-9-hydroxy-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (287) from 9-benzyloxy-2-cyclopropylmethyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (306) (130 mg, 0.32 mmol). The product was obtained as a white solid (20 mg, 16%).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[CH:9][C:8](=[O:23])[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4].[Cl-].[NH4+:34]>CO.O.[Zn]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]2[NH:34][C:9]3[C:8](=[O:23])[N:7]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[C:6](=[O:32])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10]=3[N:11]=2)=[CH:15][CH:16]=1
Reactant: [NH4+]
Reactant: CCCCn1c(NCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(Cc2ccccc2F)c1=O
Agent: [Cl-]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
1-Butyl-3-(2-fluorobenzyl)-6-[2-(4-nitro-phenyl)-ethylamino]-1H-pyrimidine-2,4-dione (2.0 g, 4.46 mmol) was dissolved in methanol (100 mL) and treated with zinc dust (<10 μm, Aldrich; 2.91 g) followed by the addition of a solution of ammonium chloride (5.96 g, 112 mmol) in water (50 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered through a pad of celite. The filtrate was concentrated to remove methanol and the residual aquous solution was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford 8-(4-amino-benzyl)-3-butyl-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione as a pale yellow solid (1.64 g, 87%). LCMS, m/z(M+H)=422.18.