Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:43])([F:42])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]#[C:28][C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[C@H:21]2[CH3:41])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.[OH:44][N:45]=[C:46](Cl)[CH3:47]>C1(C)C=CC=CC=1.Cl>[F:43][C:9]([F:8])([F:42])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:46]([CH3:47])=[N:45][O:44][C:28]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[C@H:21]2[CH3:41])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: CC(Cl)=NO
Reactant: COc1cc(F)c(C(C)C)cc1C#CCN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(F)c(C(C)C)cc1-c1onc(C)c1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C

Procedure:
Triethylamine (123.4 mg, 170 μL, 1.21 mmol) was added to a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)prop-2-yn-1-yl]-4-methyl-1,3-oxazolidin-2-one (21.9 mg, 0.0423 mmol) and N-hydroxyethanimidoyl chloride (124.4 mg, 1.33 mmol) in dry toluene (2 mL) at room temperature under N2. The reaction was heated at reflux for 2 days. The reaction mixture was cooled to room temperature, diluted with 1N HCl and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-30% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-methylisoxazol-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.38 (20% EtOAc/hexanes). LCMS calc.=575.2; found=575.3 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 7.84 (s, 1H); 7.64 (s, 2H); 7.31 (d, J=8.3 Hz, 1H); 6.68 (d, J=11.8 Hz, 1H); 5.27 (d, J=8.0 Hz, 1H); 4.78 (d, J=15.6 Hz, 1H); 4.00 (d, J=15.6 Hz, 1H); 3.82 (s, 3H); 3.72-3.68 (m, 1H); 3.22-3.16 (m, 1H); 2.38 (s, 3H); 1.24 (d, J=7.0 Hz, 3H); 1.22 (d, J=7.0 Hz, 3H); 0.42 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[CH3:28][CH:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[CH3:30].[OH-].[Na+].[ClH:44]>CS(C)=O.C(OCC)(=O)C.C(Cl)(Cl)Cl>[ClH:1].[ClH:44].[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:41][C:38]4[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][CH2:32][NH:31][CH:29]([CH3:28])[CH3:30])=[CH:36][CH:37]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CC(C)NCCCc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)NCCCc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1

Procedure:
Using the conditions described above in method A, 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (13.9 g) and 4-[3-(1-methylethyl)aminopropyl]phenol (7.0 g) were reacted in the presence of 9.25 ml 4.0N sodium hydroxide in 100 ml dimethylsulfoxide. The crude free base, isolated by extraction using chloroform, was dissolved in ethyl acetate and treated with hydrogen chloride in ethyl acetate to give the crude trihydrochloride salt. Crystallization from methanol-isopropanol yielded 10.8 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-[2-[4-[3-(1-methylethyl)aminopropyl]phenoxy]ethyl]piperazine trihydrochloride, mp 215°-225°.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][NH2:12].CCN(C(C)C)C(C)C>CCO>[I:8][C:7]1[C:2]([NH:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: NCC(F)(F)F
Reactant: Clc1ncncc1I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)CNc1ncncc1I
Temperature: 120 °C
Yield: 59 %

Procedure:
To a solution of 4-chloro-5-iodopyrimidine (0.250 g, 1.040 mmol) and 2,2,2-trifluoroethanamine (0.216 g, 2.184 mmol) in EtOH (volume: 2.080 ml) was added Hunig's Base (0.200 ml, 1.144 mmol). The reaction mixture was heated in a microwave for 4 hr at 120° C. and then allowed to cool to room temperature. The solvent was evaporated. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 0-90% EtOAc in hexanes over 25 min, tr=12 min) gave the title compound (0.188 g, 0.614 mmol, 59.1% yield) as a yellow residue. ESI MS (M+H)+=303.9.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][OH:15].CN(C=O)C>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][OH:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(I)ccc1O
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1OCCO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 2.34 g (10 mmol) of 4-iodo-2-methylphenol was added batchwise to a suspension of 0.48 g (11 mmol) of NaH in 50 mL of THF cooled to 0° C. and the mixture was stirred for a further 30 minutes at this temperature. Then 0.85 mL (12 mmol) of 2-bromoethanol dissolved in 5 mL of THF was added dropwise and the mixture was stirred for 18 hours at RT. 5 mL of DMF was added and the reaction mixture was heated to 70° C. for 8 hours. It was evaporated down in vacuo, the residue was taken up in water, extracted exhaustively with EtOAc and dried over sodium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography on silica gel (cyc/EtOAc 7:3). Yield: 0.39 g (14% of theoretical); C9H11IO2 (M=278.091); calc.: molpeak (M+H)+: 279; found: molpeak (M+H)+: 279; Rf value: 0.28 (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].[NH2:25][C:26]1[N:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1>>[F:13][CH:12]([F:14])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:29]3[CH:28]=[CH:27][C:26]([NH2:25])=[N:31][CH:30]=3)=[C:7]2[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[CH:10]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: Nc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and commercially available 6-amino-3-bromo-pyridine (87 mg, 0.5 mmol) according to general procedure II. Obtained as a red solid (48 mg, 22%). MS (EI) 429.1 [(M)+]; mp 164° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([CH3:28])([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[N:11]1[CH2:16][CH2:15][C:14]2[NH:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)C.C(O)C.[OH-].[Na+]>O>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:10]([N:11]1[CH2:16][CH2:15][C:14]2[NH:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:28])([CH3:27])[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1)C(=O)O
Temperature: 96.5 °C
Reaction time: 26 h
Yield: 55.5 %

Procedure:
7-(2-Chlorophenyl)-2,2 dimethyl-7-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-heptanoic acid ethyl ester (0.21 g, 0.51 mmol) was added to a mixture of ethanol (10 mL), water (2.70 mL), and sodium hydroxide (0.14 g, 3.54 mmol). The mixture was heated to reflux (95-98° C. oil bath) for 16 hours. After 26 hours, the flask was cooled to room temperature and the solvent was evaporated under reduced pressure. Water (15 mL) was added to the residue and the product was extracted with diethyl ether (15 mL). The extract was discarded and the aqueous portion was adjusted pH=6 with 10 N hydrochloric acid. The product was extracted with dichloromethane (3×15 mL) and the combined dichloromethane layers were washed with water (20 mL) and brine (20 mL). The dichloromethane solution was dried over sodium sulfate, filtered, and concentrated in under reduced pressure. The crude product was purified by column chromatography (silica gel, MeOH/CH2Cl2=1/9) to afford 7-(2-chlorophenyl)-2,2 dimethyl-7-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-heptanoic acid (Compound Ik, 0.11 g, 57.9% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: DMSO/TMS) δ (ppm): 12.10 (br, 1H), 10.30 (br, 1H), 7.53 (m, 1H), 7.43 (d, 1H, J=7.2 Hz), 7.36-7.25 (m, 2H), 6.50 (s, 1H), 5.71 (s, 1H), 4.10 (m, 1H), 3.39 (m, 2.75 (m, 1H), 1.14 (m, 2H), 1.34 (m, 2H), 1.23-1.07 (m, 4H), 1.03 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: DMSO/TMS) δ (ppm) 178.45, 178.97, 133.83, 129.07, 128.23, 126.93, 123.97, 115.83, 113.99, 104.19, 63.11, 48.27, 47.60, 41.19, 40.06, 31.59, 25.84, 25.03, 24.96, 24.55, 23.34.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:7][N:6]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]1[C:8]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=2)[N:10]=1
Reactant: NCCNc1ncc(CN2CCOCC2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(CN3CCOCC3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Yield: 60 %

Procedure:
Using the conditions described in the previous example, (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-(morpholin-4-ylmethyl)pyrimidin-2-yl]amine and 9.7 mg (0.061 mmol) of 2-chloro-5-nitropyridine gave [4-(2,4-dichlorophenyl)-5-(morpholin-4-ylmethyl)-pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine in 60% yield following chromatography (silica gel, 5% methanol/methylene chloride).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:21][C@H:22]([CH2:31][OH:32])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([NH:21][C@H:22]([CH2:31][O:32][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: CC(C)(C)OC(=O)C[C@@H](CO)Nc1ccc(C#N)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](CC(=O)OC(C)(C)C)Nc2ccc(C#N)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
p-Toluenesulfonyl chloride (18.2 g, 96 mmol) was added portion-wise to an ice cold solution of 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-hydroxybutanoate (27.0 g, 87 mmol) in pyridine (75 mL). After stirring at 0° C. for 15 min, ice bath was removed and the reaction was stirred at room temperature for 2.5 h. The reaction was poured into stirred, ice/H2O (400 mL). When the product solidified, it was filtered, and the solid washed well with H2O. The solid was dissolved in EtOAc (350 mL), and washed successively with H2O, aq. citric acid, and H2O. The EtOAc solution was treated with charcoal, dried (MgSO4), filtered, and the solvent evaporated. The crude product was triturated with a mixture of Et2O (150 mL) and petroleum ether (50 mL) to afford the pure product (35.0 g, 87%). 1H-NMR (CDCl3) δ: 1.42 (9H, s), 2.47 (3H, s), 2.60 (2H, m), 4.04 (1H, m), 4.22 (2H, m), 6.45 (1H, dd, J=8 Hz, 4 Hz), 6.56 (1H, d, J=2.4 Hz), 7.35 (3H, m), 7.75 (2H, d, J=8.4 Hz). LC-MS (ES) m/e 465.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([OH:17])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1.C(OC1C=C(C=CC=1)N)C1C=CC=CC=1.COCCC(Cl)=O.C(OC1C=CC(N)=CC=1)C1C=CC=CC=1.C(OCC(Cl)=O)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:100]1[CH2:105][CH2:104][N:103]([C:106]([O:108][C:109]([CH3:112])([CH3:111])[CH3:110])=[O:107])[CH2:102][CH2:101]1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:100]4[CH2:105][CH2:104][N:103]([C:106]([O:108][C:109]([CH3:112])([CH3:111])[CH3:110])=[O:107])[CH2:102][CH2:101]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCCn1c(CCOC)nc2cnc3cc(O)ccc3c21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCOCC(=O)Cl
Agent: COCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCn1c(CCOC)nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A modification on the methods described in Parts A-H of Example 2 were used to prepare 2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol, with 3-benzyloxyaniline and 3-methoxypropanoyl chloride used in lieu of 4-benzyloxyaniline and ethoxyacetyl chloride, respectively. A solution of diisopropyl azodicarboxylate (6.28 mL, 31.9 mmol) in tetrahydrofuran (25.5 mL) was added dropwise to a mixture of 2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (7.28 g, 25.5 mmol), triphenylphosphine (8.36 g, 31.9 mmol), and t-butyl 4-hydroxypiperidine-1-carboxylate (6.42 g, 31.9 mmol) in tetrahydrofuran (191 mL) at 5° C. The mixture was allowed to warm to room temperature. After 2 days, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, gradient elution with 1.5-4% methanol in dichloromethane) to yield 9.77 g of tert-butyl 4-{[2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as a gray amorphous solid.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:28])([CH3:27])[CH2:6][NH:7][C:8](=[O:26])[C@H:9]([N:17](C(OC(C)(C)C)=O)[CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][C:5]([CH3:28])([CH3:27])[CH2:6][NH:7][C:8](=[O:26])[C@H:9]([NH:17][CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C)CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccccc1)C(=O)NCC(C)(C)OC(C)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
2-((2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethyl acetate (426 mg, 1.1 mmol) was dissolved in dichloromethane (2 ml) and cooled to 0° C. Trifluoroacetic acid (2 ml) was added and the reaction mixture was stirred for 15 min at 0° C. The solvent was removed in vacuo at 20° C. The residue was dissolved in dichloromethane (50 ml) and the solvent was removed in vacuo. This latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (45 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 312 mg of 1,1-dimethyl-2-((2R)-2-methylamino-3-phenylpropionylamino)ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[N:6]([CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].O.[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:5]2[N:6]([CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CCOC(=O)c1cn2c(n1)c(OCC)nc1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1nc2ccccc2n2cc(C(=O)O)nc12
Reaction time: 8 h

Procedure:
A suspension of 0.5 g of the product of Step B, 50 ml of water, 15 ml of ethanol and 8 ml of 1 N sodium hydroxide solution was stirred overnight to obtain a clear colorless solution which was acidified with concentrated hydrochloric acid. The mixture was filtered to obtain 4-ethoxy-imidazo-[1,2-a]-quinoxaline-2-carboxylic acid melting at 220°-222° C.
Reaction SMILES: FC1C=CC(C2C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=2)=CC=1C.[F:26][C:27]1[CH:28]=[C:29]([C:34]2[CH:35]=[C:36]([C:45]([O:47]C)=[O:46])[C:37](=[O:44])[N:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[N:39]=2)[CH:30]=[CH:31][C:32]=1[F:33]>>[C:45]([C:36]1[C:37](=[O:44])[N:38]([CH2:40][CH:41]([CH3:42])[CH3:43])[N:39]=[C:34]([C:29]2[CH:30]=[CH:31][C:32]([F:33])=[C:27]([F:26])[CH:28]=2)[CH:35]=1)([OH:47])=[O:46]
Reactant: COC(=O)c1cc(-c2ccc(F)c(F)c2)nn(CC(C)C)c1=O
Agent: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Product: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(C(=O)O)c1=O
Yield: 91.4 %

Procedure:
Following the procedure of Example 1 (7), 6-(3,4-difluorophenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as colorless fine needles (yield: 91.4%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C=CC1C=NC(C(C#N)(C)C)=C(Cl)C=1)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=CCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)C=Cc1cnc(C(C)(C)C#N)c(Cl)c1
Product: CCOC(=O)CCCCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared analogously to step 4 of example B(29)where 4-(4-ethoxycarbonyl-but-3-enyl)-piperidine-1-carboxylic acid tert-butyl ester from step 2 above, was substituted in place of 3-[5-chloro-6-(cyano-dimethyl-methyl)-pyridin-3-yl]-acrylic acid ethyl ester of that example. 1H NMR (400 MHz, CDCl3): δ 0.99-1.12 (m, 2H), 1.23-1.40 (m, 8H), 1.45 (s, 9H), 1.56-1.66 (m, 4H), 2.27-2.32 (m, 2H), 2.61-2.70 (m, 2H), 4.04-4.16 (m, 4H). ESIMS (MH+): 314.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16]C1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.N#N.N[C@@H](CC1C=CC=CC=1)[C@H](O)C[C@@]1(C(N)=O)CCCN1CC1C=CC=CC=1.C(N1CCC[C@H]1C(NC[C@@H](O)[C@@H](N[C:86](=[O:103])[C@H:87]([CH2:99][C:100](=[O:102])[NH2:101])[NH:88][C:89]([O:91][CH2:92][C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)=[O:90])CC1C=CC=CC=1)=O)C1C=CC=CC=1>>[CH2:92]([O:91][C:89]([NH:88][C@H:87]([C:86]([OH:103])=[O:16])[CH2:99][C:100](=[O:102])[NH2:101])=[O:90])[C:93]1[CH:94]=[CH:95][CH:96]=[CH:97][CH:98]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)[C@@H]1CCCN1Cc1ccccc1
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: N#N
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
In a manner analogous to that described in Example 33, from 0.225 g of dicyclohexylcarbodiimide, 0.135 g of hydroxybenzotriazole, 0.115 g of N-ethylmorpholine, 0.38 g of N2 -[3(S)-amino-2(R)-hydroxy-4-Phenylbutyl]-N1 -benzyl-L-prolinamide and0.266 g of N-(benzyloxycarbonyl)-L-asparagine there was obtained 0.056 g ofN1 -benzyl-N2 -[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl] amino]-2(R)-hydroxy-4-phenylbutyl]-L-prolinamide as a white solid: MS: m/e616 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]3)[C:20]([N+:31]([O-])=O)=[CH:19][N:18]=2)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C1COCC1>[NH2:31][C:20]1[C:21]([NH:23][C@H:24]2[CH2:25][CH2:26][C@H:27]([OH:30])[CH2:28][CH2:29]2)=[N:22][C:17]([NH:16][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@H]2CC[C@H](O)CC2)n1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc(N)c(N[C@H]2CC[C@H](O)CC2)n1
Reaction time: 0.08 h

Procedure:
A solution of tert-butyl 4-fluoro-2-(4-(trans-4-hydroxycyclohexylamino)-5-nitropyrimidin-2-ylamino)phenylcarbamate (110 mg) in THF (30 mL) was treated with a mixture containing sodium hydrosulfite (600 mg in 20 ml H2O) and sodium bicarbonate (10 ml, saturated). The resulting mixture was stirred for 5 minutes during which the color changed from yellow to almost colorless. Saturated sodium chloride was added and the mixture was extracted with EtOAc twice. The combined organic layers were washed with saturated sodium chloride and separated. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to provide 111 mg of the title compound.
Reaction SMILES: N[C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1.N([O-])=[O:19].[Na+]>C(O)(=O)C.Cl>[OH:19][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(-c2ccccc2)cnc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1nc(-c2ccccc2)cnc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of acetic acid/hydrochloric acid (1:1, 20 mL) at 0° C. was added methyl 3-amino-6-phenylpyrazine-2-carboxylate (1.02 g, 4.50 mmol). Aqueous solution of sodium nitrite (0.77 g, 11.2 mmol) was added drop wise. During the addition, the temperature of the reaction was controlled at 0-5° C. The reaction was slowly warmed to room temperature and stirred overnight. The reaction mixture was extracted with ethyl acetate (2×50 mL). The organic layer was washed with water (30 mL), saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford the crude methyl 3-hydroxy-6-phenylpyrazine-2-carboxylate which was used in the next step with out any purification. The crude product was treated with phosphorus oxychloride (30 mL) and heated to 90° C. for 2 h. The reaction was cooled to room temperature and poured into ice-water mixture and extracted with ethyl acetate (3×40 mL). The organic layer was washed with water (30 mL), saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate, filtered, and concentrated to give crude product. Column purification on silica (8:2 hexanes/ethyl acetate) afforded methyl 3-chloro-6-phenylpyrazine-2-carboxylate (0.22 g, 20% yield) as yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.90 (s, 1H), 8.02 (t, 2H), 7.40 (t, 1H), 7.20 (br s, 2H), 3.90 (s, 3H): MS (EI) for C12H9N2O2Cl: 249 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O[Na])(C)=O.O.O.O.CC(O)=O>CO.O>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(Cl)c1
Agent: CC(=O)O[Na]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1ccc(N)c(Cl)c1
Temperature: 110 °C
Yield: 48.3 %

Procedure:
A mixture of methyl 3-chloro-4-nitrophenylacetate (10.9 g, 47.5 mmol), reduced iron powder (8.58 g, 153.6 mmol), AcONa.3H2O (6.05 g, 44.5 mmol) and AcOH (17.6 ml) in MeOH/H2O (100/400 ml) was heated at 110° C. for 1 h. After cooled to room temperature, the reaction mixture was filtered through Celite and the filtered cake was washed with MeOH. The combined filtrate were evaporated and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel [150 g, CHCl3/EtOAc (10/1)] to give methyl 4-amino-3-chlorophenylacetate (4.58 g, 48%) as a red oil. 1H-NMR (CDCl3) δ 3.49 (s, 2H), 3.68 (s, 3H), 4.01 (br, 2H), 6.70 (d, J=7.4 Hz, 1H), 6.96 (dd, J=8.1, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H).