Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(C(C)C)CC)(C)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[C:38]1([CH2:44][CH2:45][CH2:46][C:47](O)=[O:48])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:47](=[O:48])[CH2:46][CH2:45][CH2:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CCCc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 132.9 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.33 g) and diisopropylethylamine (3.2 mL) were added to a solution of N-tert-butoxycarbonylpiperazine (1.13g) and 4-phenylbutyric acid (1.0 g) in dichloromethane (50 mL) at 0° C. After stirring at room temperature for 20 hr, the solvent was evaporated in vacuo. Ethyl acetate and 10% citric acid aqueous solution were added to the residue. The separated organic layer was washed with saturated sodium hydrogen carbonate, dried over sodium sulfate, and evaporated in vacuo to afford the titled compound (2.68 g) as a colorless solid: 1H NMR(400 MHz, CDCl3) δ 1.47(s, 9H), 1.98(t, 2H), 2.32 (t, 2H), 2.68 (t, 2H)3.34-3.59 (m, 8H), and 7.17-7.30 (m, 5H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[N:14]([CH3:18])[C:13]=3[CH:19]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:20]1[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:26])[CH2:21]1>>[OH:1][C:2]1([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[N:14]([CH3:18])[C:13]=3[CH:19]=2)[CH2:7][CH2:6][CH:5]([N:20]2[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=3)=[O:26])[CH2:21]2)[CH2:4][CH2:3]1
Reactant: Cn1c(=O)oc2ccc(C3(O)CCC(=O)CC3)cc21
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cn1c(=O)oc2ccc(C3(O)CCC(N4CC(NC(=O)CNC(=O)c5cccc(C(F)(F)F)c5)C4)CC3)cc21

Procedure:
The title compound was prepared as a white solid by reductive amination of 5-(1-hydroxy-4-oxo-cyclohexyl)-3-methyl-3H-benzooxazol-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH:21]([CH3:30])[C:22]([O:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:3][C:2]=1[NH:1][CH:21]([CH3:30])[C:22]([O:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23]
Reactant: Nc1cc(N2C(=O)c3ccccc3C2=O)ccc1Cl
Reactant: CC(C)CCOC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)CCOC(=O)C(C)Nc1cc(N2C(=O)c3ccccc3C2=O)ccc1Cl
Temperature: 150 °C
Yield: 65.3 %

Procedure:
A mixture of 1.64 g of N-(3-amino-4-chlorophenyl)phthalimide, 2.68 g of isopentyl 2-bromopropionate, and 0.60 g of sodium hydrogencarbonate was heated at 150° C. for 5 hours while stirring. While the reaction mixture was hot, ethyl acetate was added thereto, and the reaction mixture was washed successively with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:8) to give 1.63 g of the title compound (Table 1, Compound No. 5).
Reaction SMILES: [Cl:1][C:2]1[C:7](N)=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([F:12])=[C:4]([F:13])[CH:3]=1.N([O-])=O.[Na+].P(=O)(O)(O)O.O.[PH2]([O-])=O.[Na+]>S(=O)(=O)(O)O.O.CCOCC.[Cu-]=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([F:12])=[C:4]([F:13])[CH:3]=1
Reactant: Nc1c(Cl)cc(F)c(F)c1[N+](=O)[O-]
Agent: O=[Cu-]
Agent: O=N[O-]
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Cl)cc(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A solution of 6-chloro-3,4-difluoro-2-nitroaniline (3.30 g, 15.8 mmol) in concentrated sulfuric acid (8.3 mL) was stirred at rt for 3 h and was then cooled to 0° C. A solution of sodium nitrite (1.3 g, 18.8 mmol) concentrated sulfuric acid (6.7 mL) was added slowly followed by phosphoric acid (85%, 15 mL) added drop wise. A dark brown precipitate formed, and the resulting slurry was stirred for 1 h at 0° C. A suspension of copper(I) oxide (2.4 g, 30 mmol) and sodium hypophosphite hydrate (5.6 g, 64 mmol) in water (6.7 mL) was then added slowly with the temperature remaining at 0° C. Substantial gas evolution was observed during the addition. When the reaction was complete, the mixture was diluted with water and ether. Celite was added to help adsorb insoluble solids. The mixture was filtered, and the filtrate was partitioned. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (90% hexanes: 10% ethyl acetate) to provide the desired 5-chloro-1,2-difluoro-3-nitrobenzene (1.62 g, 8.4 mmol, 53% yield) as a yellow crystalline solid. 1H NMR (400 MHz, CDCl3): 7.88 (m, 1H), 7.53 (m, 1H); GCMS for C6H2ClF2NO2: 193 (M+).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[C:11]([OH:16])(=[O:15])[CH:12]([CH3:14])[OH:13]>>[C:11]([OH:16])(=[O:15])[CH:12]([CH3:14])[OH:13].[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: CC(O)C(=O)O
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Under these microaerobic conditions, strain 246-27 and strain C29/403-7 consumed xylose at about 0.5 g/L/hr and all produced lactic acid at about 0.4 g/L/hr. Strain C29/403-7/425 produced about 10-15% more lactic acid and about 10-15% less xylitol than strain C29/403-7 under these conditions. Strain C29/403-7 produced more xylulose than the others, suggesting that xylulose accumulates in this strain because of xylose isomerase activity.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[CH3:11][Mg+].[Br-]>C(OCC)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([OH:3])([CH3:11])[CH3:1])=[CH:5][CH:6]=1
Reactant: C[Mg+]
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Br)cc1
Temperature: 0 °C

Procedure:
20.0 g (100 mmol) 4-bromoacetophenone are added to 300 mL diethylether and cooled down to 0° C. 35.2 mL MeMgBr (3M in diethylether) are added by a dropping funnel. Cooling is removed and the mixture is stirred at r.t. over night. The reaction quenched by careful addition of 150 mL sat. aq. NH4Cl solution and 150 mL water. The resulting mixture is stirred for 20 min. The layers are separated and the org. layer is washed with water (2×), dried with MgSO4 and the solvent is removed in vacuo.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:19]([O:26][C:27](=[O:38])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:38])[C@H:28]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1)[NH:29][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccc(O)cc1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Product: CC(=O)SCC(C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1)C(C)c1ccc(O)cc1
Yield: 78 %

Procedure:
Using the procedure described in Example 60, but starting with 2-acetylthiomethyl-3-(4-hydroxyphenyl)butanoic acid and tyrosine benzyl ester, N-[2-acetylthiomethyl-3-(4-hydroxyphenyl)-1-oxobutyl]tyrosine benzyl ester is obtained in a 78% yield in the form of a white solid, having the following characteristics: Rf =0.16 [hexane/ethyl acetate (65:35 by volume)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([N+:28]([O-])=O)=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][CH:7]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3](=[O:35])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2CCc2c(C(C)(C)C)[nH]c3cc([N+](=O)[O-])ccc23)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2c(C(C)(C)C)[nH]c3cc(N)ccc23)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of (E)-3-(4-{1-[2-(2-tert-butyl-6-nitro-1H-indol-3-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (0.70 g, 1.5 mmol) in ethanol (14 mL) and water (7 mL) was added iron powder (0.74 g, 13 mmol) and ammonium chloride (87 mg, 1.6 mmol) and the resulting mixture was stirred at 85° C. for 1 h. Additional iron powder (820 mg, 14.7 mmol), ethanol (6 mL) and water (3 mL) were added and the reaction was stirred at 85° C. for 50 h. The reaction mixture was filtered and concentrated in vacuo, and the residue was taken up in water. A brown solid precipitate was recovered via vacuum filtration to yield the title compound (0.40 g, 49% yield). LCMS (m/z): 446.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.O=[C:9]1[CH2:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:9]2[CH2:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10]2)=[N:5][N:6]=1
Reactant: CCOC(=O)C1CC(=O)C1
Reactant: Cc1nnc(N)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(Nc2nnc(C)[nH]2)C1
Temperature: 25 °C
Reaction time: 120 h
Yield: 81.4 %

Procedure:
To a solution of 5-methyl-4H-1,2,4-triazol-3-amine (16.35 g) and ethyl 3-oxocyclobutanecarboxylate (12.41 g) in acetic acid (150 mL) was added sodium triacetoxyborohydride (36.56 g), and the mixture was stirred at room temperature for 5 days. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100-÷10/90 (volume ratio)], and crystallized from diethyl ether to give the title compound as a colorless solid (15.93 g, 62%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1cccc2c(Cl)ccnc12)c1ccccc1
Reactant: CN
Product: CNc1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Yield: 12.8 %

Procedure:
In a similar fashion using route 48 general procedure 114, N-(4-chloro-quinolin-8-yl)-benzenesulfonamide 224 (80 mg, 0.25 mmol), methyl amine (2M in THF; 1.23 ml, 2.50 mmol) at 100° C. for 48 h gave the title compound (10 mg, 13%) after purification by column chromatography with chloroform/MeOH (1 drop NH3) (98:2) as the eluent followed by recrystallisation from MeOH/DCM.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1[NH:26][CH:27]1[CH2:29][CH2:28]1)C.[OH-].[Na+].CO>O1CCCC1>[C:21]([O:20][C:18]([NH:17][CH:14]1[CH2:15][CH2:16][N:12]([C:8]2[C:9]([Cl:11])=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[C:6]([NH:26][CH:27]3[CH2:28][CH2:29]3)[C:7]=2[F:25])[CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cc(Cl)c(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(c2c(Cl)cc(C(=O)O)c(NC3CC3)c2F)C1
Yield: 91.3 %

Procedure:
A solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropylamino-3-fluorobenzoic acid ethyl ester (Example 3k, 2.00 g, 4.50 mmol) and aqueous sodium hydroxide (2.0N, 20 mL) in tetrahydrofuran (20 mL), and methanol (20 mL) is refluxed for 1 hour. The solution is partially concentrated in vacuo, acidified to pH 6, and extracted with chloroform. The combined organic extracts are dried over Na2SO4, filtered, and concentrated to give the title compound (1.70 g). 1H NMR (CDCl3): δ 7.71 (d, 1H), 4.91–4.82 (bd, 1H), 4.40–4.25 (m, 1H), 3.77–3.69 (m, 2H), 3.53–3.34 (m, 2H), 3.00–2.88 (m, 1H), 2.24–2.15 (m, 1H), 1.90–1.80 (m, 1H), 1.46 (s, 9H), 0.72–0.54 (m, 4H).
Reaction SMILES: C(OC(=O)C[CH:6]([C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:7]([CH3:9])=[O:8])C.ClC1C=CC(C(=O)C)=CC=1.[H-].[Na+]>C(OC(=O)C)C>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([CH2:6][C:7](=[O:8])[CH3:9])=[O:18])=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)c1ccc(Cl)cc1
Agent: CC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
The 3-(p-chlorobenzoyl)-levulinic acid ethyl ester used in Example 20 as the starting material was obtained in the following manner: p-chloro-acetophenone, acetic acid ethyl ester and sodium hydride were condensed to form p-chloro-benzoylacetone by the method described by Swamer and Hauser, J. Am. Chem. So. 72, 1352 (1952). The p-chlorobenzoylacetone thus obtained was alkylated by reaction with bromoacetic acid ester and sodium hydride in dimethyl formamide to produce 3-(p-chlorobenzoyl)-levulinic acid ethyl ester in a yield of 83%, having a boiling point Kp0.001 of 140°-150° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:27](=[O:28])[N:7]2[CH:8]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:29])[C:5]1=[O:30])=[CH:15][C:14]([Cl:19])=[CH:13][CH:12]=4.[NH3:31]>CO>[NH2:31][CH2:2][CH2:3][N:4]1[C:27](=[O:28])[N:7]2[CH:8]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:29])[C:5]1=[O:30])=[CH:15][C:14]([Cl:19])=[CH:13][CH:12]=4
Reactant: N
Reactant: CC12Cc3c([nH]c4ccc(Cl)cc34)C(c3cccc(O)c3)N1C(=O)N(CCBr)C2=O
Solvent: CO
Product: CC12Cc3c([nH]c4ccc(Cl)cc34)C(c3cccc(O)c3)N1C(=O)N(CCN)C2=O
Temperature: 140 °C

Procedure:
To a solution of 200 mg (3aSR,10RS)-2-(2-Bromo-ethyl)-6-chloro-10-(3-hydroxy-phenyl)-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 26) in 3 ml methanol are added 1.2 ml of a 7 M solution of ammonia in methanol. The mixture is heated in a sealed tube to 140° C. for 1 h using a microwave reactor. The solvent is removed under reduced pressure. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried with magnesium sulfate. The solvent is removed under reduced pressure. The crude product is purified by preparative HPLC. 24 mg of the title compound are obtained. MS: m/z (MH+)=425.1
Reaction SMILES: N.O.Cl[C:4]1[C:9]([CH2:10][NH2:11])=[CH:8][C:7]([F:12])=[C:6](Cl)[N:5]=1>CO.[Pd]>[F:12][C:7]1[CH:8]=[C:9]([CH2:10][NH2:11])[CH:4]=[N:5][CH:6]=1
Reactant: NCc1cc(F)c(Cl)nc1Cl
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CO
Product: NCc1cncc(F)c1
Reaction time: 16 h

Procedure:
To a Parr reaction bottle was added Pd—C (10%, 560 mg, 0.52 mmol), followed by 28% NH3.H2O (50 ml) and a solution of (2,6-dichloro-5-fluoropyridin-3-yl)methanamine (Compound 144, 10.1 g, 52 mmol) in MeOH (100 ml). The mixture was placed under 51 psi H2 on a shaker type Parr apparatus for 16 h, filtered and concentrated. The resulting aqueous solution was basified with NaOH, extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by distillation under vacuum to yield the title compound as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:30])([O:27]CC)[O:24][CH2:25][CH3:26])[CH:20]=[CH:21][CH:22]=1.[OH-:32].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:32])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:30])([OH:27])[O:24][CH2:25][CH3:26])[CH:20]=[CH:21][CH:22]=1
Reactant: [OH-]
Reactant: CCOP(=O)(OCC)c1cccc(Cn2c(Br)nc3c(N)nc(OCCOC)nc32)c1
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(O)c1cccc(Cn2c(O)nc3c(N)nc(OCCOC)nc32)c1

Procedure:
Diethyl 3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate (100 mg, 0.194 mmol) was dissolved in methanol (5 mL) and 1 N aqueous NaOH solution was added. The reaction mixture was heated at reflux and progress was monitored by HPLC. As soon as all the starting material had been consumed, the reaction mixture was acidified with conc. HCL. After heating at reflux for 1 h, the mixture was evaporated to dryness under vacuum. The product was purified by preparative reverse phase HPLC, yielding ethyl hydrogen 3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate Example (K) (18 mg, 22%) as a white powder. 1H-NMR (DMSO) δ: 10.0 (s, 1H), 7.65-7.42 (m, 5H), 6.51 (br, 2H), 4.90 (s, 2H), 4.25 (t, J=4.5 Hz, 2H), 3.84 (quint, J=7 Hz, 2H), 3.57 (t, J=4.5 Hz, 2H), 3.26 (s, 3H), 1.13 (t, J=7 Hz, 3H). 31P-NMR (DMSO) δ: 13.04. MS: 424 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([NH:29][CH3:30])=[O:28]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:23][CH2:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:21])=[CH:18][CH:19]=1
Reactant: CNC(=O)c1ccccc1CN
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: CNC(=O)c1ccccc1CNC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
2′-Methyl-N-{2[(methylamino)carbonyl]benzyl}-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-(aminomethyl)-N-methylbenzamide using method M. NMR; δH [2H6]—DMSO 9.03,(1H, t), 8.41,(1H, q), 7.98,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.52,(3H, m), 7.43-7.37,(3H, m), 7.30,(1H, m), 4.62,(2H, d), 2.79,(3H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.02 min, MH+ 441.
Reaction SMILES: O[NH:2][C:3](=N)[NH:4][CH2:5][CH2:6][CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9].N[C@H](C(O)=[O:24])CCCNC(=N)N.CC(O)=O.C(CN=C(NO)N)C[C@H](N)C(O)=O.[N]=O>>[NH2:9][C@H:8]([C:10]([OH:12])=[O:11])[CH2:7][CH2:6][CH2:5][NH:4][C:3]([NH2:2])=[O:24]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: N=C(NO)NCCC[C@H](N)C(=O)O
Agent: NC(=NCCC[C@H](N)C(=O)O)NO
Agent: [N]=O
Solvent: CC(=O)O
Product: NC(=O)NCCC[C@H](N)C(=O)O

Procedure:
Nω-hydroxy-L-arginine is the physiologically occurring intermediate of the NO synthase catalysed oxidation L-arginine. NOHA is oxidised in a further step of NO synthase, nitrogen monoxide being released and L-citrulline being formed.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[Cl-].[Na+]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.8 %

Procedure:
A mixture of ethylene glycol monobenzyl ether (36 ml, 252 mmol), 60% sodium hydride (11.0 g, 275 mmol) and N,N-dimethylformamide (300 ml) was stirred at room temperature for 1.5 hours. To the resulting suspension was added dropwise a solution of ethyl bromoacetate (34 ml, 302 mmol) in N,N-dimethylformamide (50 ml), followed by stirring at room temperature for another 3 hours. The reaction mixture was poured into a 10% aqueous sodium chloride solution and extracted with ethylacetate, and the extract solution.was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=9:95) to obtain 18.5 g of ethyl (2-benzyloxyethoxy)acetate as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: O=C(N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1coc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (680 mg, 1.58 mmol) (obtained as described in Reference Example 76(2)) in methylene chloride (34 ml) were added methanesulfonyl chloride (366 μl, 4.73 mmol) and triethylamine (663 μl, 4.73 mmol) in an ice bath and the mixture was stirred for 10 minutes and at room temperature for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (96:4) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (760 mg, yield 95%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1[CH:41]=[CH:40][C:39]([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:46][CH2:47][C:42]([C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)([C:48]([NH2:50])=[O:49])[CH2:43][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccncc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccncc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-(pyridin-4-yl)-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.