Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([N+:26]([O-])=O)=[C:8]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.C(O)=O>C1COCC1.CO.[Pd]>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:7]=1[NH2:26]
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCCl
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Solvent: C1CCOC1
Product: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCCl
Reaction time: 20 h
Yield: 94.4 %

Procedure:
A mixture of 1-[3-(3-chloro-propoxy)-2-nitro-phenyl-methanesulfonyl]-naphthalene (1.9 g, 4.5 mmoles) and 10% Pd/C in THF (20 mL), methanol (20 mL), and formic acid (5 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 lb/in2 for 20 hours. The mixture was filtered through Celite, and the filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 5% EtOAc/CH2Cl2 to afford the title compound as an off-white solid (1.66 g, 4.25 mmoles).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:11]([N:14]([CH:19]([CH3:21])[CH3:20])[C:15](=[O:18])[CH2:16]Br)([CH3:13])[CH3:12]>O1CCCC1>[CH:11]([N:14]([CH:19]([CH3:21])[CH3:20])[C:15](=[O:18])[CH2:16][O:10][C:7]1[CH:8]=[CH:9][C:4]([I:3])=[CH:5][CH:6]=1)([CH3:13])[CH3:12]
Reactant: CC(C)N(C(=O)CBr)C(C)C
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N(C(=O)COc1ccc(I)cc1)C(C)C
Temperature: 0 °C
Yield: 108.9 %

Procedure:
1.38 g of 50% sodium hydride suspended in oil were added under an inert gas atmosphere to a solution of 5.2 g of paraiodophenol in 30 ml of tetrahydrofuran and after stirring at 0° C., then 6.30 g of N,N-bis-(isopropyl)-2-bromo-acetamide (Preparation 8) were added. After stirring for 2 hours while allowing the temperature to rise to 20° C., the reaction medium was poured into ice-cooled water and filtration was carried out followed by drying to obtain 9.3 g of the expected product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 40 h
Yield: 56.1 %

Procedure:
A mixture of 2.06 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole and 3.08 g of activated manganese dioxide in 20 mL of methylene chloride at 25° C. was stirred for 40 hours. The reaction mixture was filtered through Celite®, and the filtrate concentrated in vacuo. Column chromatography (elution: ethyl acetate/benzene) provided 1.15 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde. NMR (200 MHz, CDCl3) δ9.76 (s, 1H); 7.83 (d of d, 1H); 7.52 (t of d, 1H); 7.40 (t of d, 1H); 7.31 (d of d, 1H); 7.17 (A2B2, 4H); 5.58 (s, 2H); 3.63 (s, 3H); 2.67 (t, 2H); 1.70 (quint., 2H); 1.38 (sext., 2H); 0.90 (t, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH2:11][C@H:12]([C:20](O)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:13]([C@@H:12]1[NH:11][C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:20]1=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2N[C@H]1Cc1ccccc1
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To ortho-fluoronitrobenzene (18) (6.5 g, 46 mmol) in ethanol (200 mL) and water (200 mL) under nitrogen was added L-phenylalanine (5.10 g, 31 mmol) and sodium bicarbonate (5.19 g, 62 mmol) and the suspension heated at reflux for 48 h. The red solution was coled, extracted with ether (2×50 mL—to remove any unreacted ortho-fluoronitrobenzene and concentrated to ½ volume. Pd/C (20%, 0.5 g) was added and a hydrogen balloon was attached. After stirring overnight the mixture was filtered, acidifed with 1N HCl to pH 4 and the solid that formed was collected. This was dried under high vacuum to afford the title compound (4.66 g, 53%) of sufficient purity (19) to use directly.
Reaction SMILES: [CH3:1][C:2]([S:8][CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=1[O:20][CH3:21])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[Cl:27][CH2:28][C:29]([CH2:31]Cl)=[O:30]>CN(C=O)C>[CH3:7][C:2]([S:8][CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=1[O:20][CH3:21])([CH3:1])[CH2:3][C:4]([O:6][CH2:31][C:29](=[O:30])[CH2:28][Cl:27])=[O:5]
Reactant: O=C(CCl)CCl
Reactant: COc1cc(OC)c(CSC(C)(C)CC(=O)O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(CSC(C)(C)CC(=O)OCC(=O)CCl)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
To a mixture of 3-methyl-3-[(2,4,6-trimethoxyphenyl)methylthio]butanoic acid (3 g, 9.54 mmol) and sodium bicarbonate (975 mg, 11.6 mmol) in DMF (30 mL) was added a solution of 1,3-dichloroacetone (4.23 g, 33.4 mmol) in DMF (15 mL) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature, and stirred for 48 hours. The residue after evaporation of the solvent was partitioned between EtOAc and H2O. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel eluting with EtOAc:Hex (20-30%) to give the title compound as a yellow oil (2.19 g, 57%). 1H NMR (300 MHz, CDCl3) δ 6.12 (s, 2H), 4.87 (s, 2H), 4.21 (s, 2H), 3.86-3.80 (mult, 11H), 2.83 (s, 2H), 1.52 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 196.5, 170.1, 160.4, 158.6, 107.3, 90.7, 66.4, 55.8, 55.3, 46.3, 45.9, 43.8, 28.2, 20.9; mass spectrum (API-TIS) m/z 422 (M+NH4).
Reaction SMILES: Br[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1)[CH:8]([CH3:10])[CH3:9]>C1COCC1>[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:13][CH:12]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)Cc1ccc([Mg]Br)cc1
Reactant: CC(Br)C(=O)O
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
67 ml of a 1.5 M solution of a mixed magnesium chloride complex of α-bromopropionic acid in THF was slowly added to 67 ml of a 1.5 M solution cooled to 10° C. of p-isobutylphenyl magnesium bromide in THF at such a rate that the temperature of the mixture was maintained at not more than 55° C. The resulting slurry was stirred at 50° C. for 1 hour, and then heated under reflux to allow about 50% of THF to distill. The reaction mixture was cooled, and diethyl ether and dilute hydrochloric acid were added. The organic layer was washed with water, dried, concentrated, and purified by silica gel column chromatography to give 4.4 g (yield 21.3%) of α-(p-isobutylphenyl)propionic acid.
Reaction SMILES: OC1C(C(N[C@@H](C2C=CC=CC=2P(C)(=O)OCC)C2C=CC=CC=2)=O)=CN=C(N2C=CC=N2)N=1.[OH:35][C:36]1[C:41]([C:42]([NH:44][C@H:45]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:46]2[CH:47]=[C:48]([P:52]([CH3:57])(=[O:56])[O:53]CC)[CH:49]=[CH:50][CH:51]=2)=[O:43])=[CH:40][N:39]=[C:38]([N:64]2[CH:68]=[CH:67][CH:66]=[N:65]2)[N:37]=1.[OH-].[Na+]>O1CCOCC1>[OH:35][C:36]1[C:41]([C:42]([NH:44][C@H:45]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:46]2[CH:47]=[C:48]([P:52]([CH3:57])(=[O:53])[OH:56])[CH:49]=[CH:50][CH:51]=2)=[O:43])=[CH:40][N:39]=[C:38]([N:64]2[CH:68]=[CH:67][CH:66]=[N:65]2)[N:37]=1
Reactant: CCOP(C)(=O)c1cccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)c1
Agent: CCOP(C)(=O)c1ccccc1[C@H](NC(=O)c1cnc(-n2cccn2)nc1O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1cccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)c1
Temperature: 80 °C

Procedure:
Ethyl ((R)-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl(methyl)phosphinate, 24-f, (18.8 g, 390 mmol) was dissolved in 200 ml of dioxane and treated with 50 ml of 3N NaOH. The mixture was heated at 80° C. for one hour. The mixture was then concentrated under vacuum and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with conc. HCl to pH=1 and the expected product crashed out, 24-1, (11 g of crude). The product can be further purified via prep-HPLC. 1H NMR (300 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.44 (s, 1H), 8.07 (s, 1H), 7.50 (m, 2H), 7.38 (m, 7H), 6.73 (s, 1H), 6.35 (d, 1H), 1.53 (d, 3H). (M+H)+=450.1.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][CH3:12])(=[O:10])=[O:9]
Reactant: CNS(=O)(=O)CCCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CNS(=O)(=O)CCCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-azido-N-methylbutane-1-sulfonamide (Example 6; 202 mmol), in methanol (200 ml) was added Pd/C (20 mmol Pd). The mixture put under an hydrogen atmosphere and was stirred overnight at r.t. The mixture was filtered and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH2:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([NH:7][C@@H:8]([CH2:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](COC(C)(C)C)Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC[C@H](Nc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of methyl (2S)-2-phenylamino-3-tert-butoxypropanoate (230 mg) in methanol (2.30 mL) was added 1N sodium hydroxide aqueous solution (2.75 mL) and the mixture was stirred at ambient temperature for 2 hours. The resulting solution was acidified with 1N HCl (2.7 mL) to pH=4 and diluted with water (2.7 mL). The mixture was stirred at 0° C. for 20 minutes and the precipitate was collected by filtration followed by washing with water (2.7 mL) to give (2S)-2-phenylamino-3-tert-butoxypropanoic acid (100 mg) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([S:10]([CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[O:11])=[N:9][C:5]=2[CH:4]=1.[C:25]([NH:28][C:29]1[S:30][C:31]([S:35](Cl)(=[O:37])=[O:36])=[C:32]([CH3:34])[N:33]=1)(=[O:27])[CH3:26].ClCCl.C(#N)C.CO>ClCCl.C(N(CC)CC)C>[C:25]([NH:28][C:29]1[S:30][C:31]([S:35]([N:7]2[C:6]3[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=[C:8]2[S:10]([CH2:12][C:13]2[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=2)=[O:11])(=[O:36])=[O:37])=[C:32]([CH3:34])[N:33]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc2c(c1)nc(S(=O)Cc1ncc(C)c(OC)c1C)n2S(=O)(=O)c1sc(NC(C)=O)nc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.7 %

Procedure:
172 mg of 5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole was dissolved in 10 ml of dichloromethane and 0.4 ml of triethylamine, and 128 mg of 2-acetamido-4-methyl-5-thiazolyl sulfonyl chloride was added. The reaction mixture was stirred at room temperature for 15 hr. Product spot was shown at slightly higher position than 5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole in thin layer chromatography (developing solvent: dichloromethane-acetonitrile-methanol=100: 10: 5). Product was separated by silica gel column chromatography. 145 mg of the titled product was isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH:12]1([NH:15][C:16](=[O:21])[CH2:17][C:18]([CH3:20])=[O:19])[CH2:14][CH2:13]1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[CH:12]1([NH:15][C:16](=[O:21])[CH2:17][C:18]([CH:20]=[CH:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])=[O:19])[CH2:14][CH2:13]1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)CC(=O)NC1CC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=C(C=Cc1ccccc1[N+](=O)[O-])CC(=O)NC1CC1
Yield: 75.8 %

Procedure:
o-Nitrobenzaldehyde (7.6 g, 0.05 mole) and acetoacetic cyclopropylamide (7.1 g, 0.05 mole) are dissolved in benzene (40 ml) and thereto are added piperidine (0.2 ml) and acetic acid (0.6 ml), and the mixture is refluxed for 2 hours and the produced water is removed. After the stoichiometic amount of water is distilled off, the reaction is stopped. After the reaction, the reaction mixture is washed with 5% hydrochloric acid and then with water, and the solvent is distilled off under reduced pressure, and to the residue is added diethyl ether, and the obtained crude crystals are recrystallized from ethanol to give the title compound (10.4 g, yield 75.6%) as colorless needles, m.p. 133°-134° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16]COC)[C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3]>C([O-])(=O)C.[Hg+]>[OH:16][C:15]1[C:9]2[CH:8]=[C:7]([C:5]3[O:6][C:2]([CH3:3])=[CH:1][N:4]=3)[S:11][C:10]=2[CH:12]=[CH:13][CH:14]=1
Reactant: C#CCNC(=O)c1cc2c(OCOC)cccc2s1
Agent: CC(=O)[O-]
Agent: [Hg+]
Product: Cc1cnc(-c2cc3c(O)cccc3s2)o1
Yield: 47.8 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using N-propargyl-4-(methoxymethyloxy)benzo(b)thiophene-2-carboxamide (6.00 g) and mercury acetate (765 mg), the title compound (2.41 g) was obtained as yellow crystals, melting point 188–189° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 78 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[CH2:27]([NH2:30])[CH:28]=[CH2:29].C(N(CC)CC)C>N1C=CC=CC=1>[CH2:27]([NH:30][C:15]1[C:16]([Cl:18])=[C:17]2[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]2[C:6]2[C:5]([F:25])=[CH:4][C:3]([F:26])=[C:2]([NH2:1])[N:7]=2)=[CH:13][C:14]=1[F:20])[CH:28]=[CH2:29]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: C=CCN
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: C=CCNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 40 °C
Reaction time: 63 h
Yield: 60.8 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), allylamine (35 mg) and triethylamine (300 mg) were added to pyridine (400 mg), and the mixture was stirred for 2 hours at 40° C. and for 63 hours at room temperature. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (1.5 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (100 mg) as a pale brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:7]=[O:8].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[C-:28]#[N:29].[K+]>COCCOCCOC.O.C(O)C>[OH:8][CH:7]([CH:6]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[O:5][C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=1[O:2][CH3:1])[C:28]#[N:29]
Reactant: [C-]#N
Reactant: COc1ccccc1OC(C=O)c1ccccc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Solvent: CCO
Product: COc1ccccc1OC(c1ccccc1)C(O)C#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.9 %

Procedure:
150 g of α-(2-methoxy-phenoxy)-phenyl acetaldehyde dissolved in approximately 1800 ml of diglyme was stirred with 176.5 g of sodium metabisulphite in 500 ml of water and 200 ml of ethanol at 50° C. for 16 hours. The whole was cooled to room temperature and addition was made of 44.4 g of potassium cyanide in 200 ml of water. The whole was stirred at 90° C. (external temperature) for 5 hours, concentrated to approximately 800 ml and poured into water: extraction was performed with 4×750 ml of ethyl ether and the whole washed with water, dried over Na2SO4 and evaporated to dryness to obtain 156.5 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile as a viscous oil. Yield=94%.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:14]=[C:13]([Br:15])[C:12]([Cl:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].O.[Sn](Cl)Cl>O.Cl>[ClH:16].[Br:15][C:13]1[C:12]([Cl:16])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:5][NH2:1])[CH:14]=1
Reactant: Nc1cc(Br)c(Cl)cc1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)c(Cl)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 213.5 %

Procedure:
A solution of sodium nitrite (3.03 g, 43.9 mmol) in water (14.8 mL) was added dropwise to a cooled (−10° C., NaCl-ice bath) suspension of 2-amino-4-bromo-5-chlorobenzoic acid (10.0 g, 39.9 mmol) in 37% aqueous HCl (39.9 mL) and water (13.3 mL), at such rate that the temperature did not exceed 0° C. The resulting suspension was stirred at 0° C. for 15 min, then was treated with a solution of tin(II) chloride hydrate (22.7 g, 120 mmol) in 37% aqueous HCl (17 mL). The resulting mixture was warmed to room temperature and stirred for 60 min. The precipitate was collected by filtration, washed with water and air-dried overnight to give 4-bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride as an off-white solid (12.86 g, 96% yield). Mass spectrum m/z 365, 267 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (br. s., 1H), 7.95 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15]C(=O)C)[CH:10]=2)[C:5]2[N:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.C(=O)(O)[O-].[Na+]>Cl>[CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)[C:5]2[N:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1
Reactant: CC(=O)Nc1cccc(-n2c(=O)c(C)nc3cccnc32)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2cccnc2n(-c2cccc(N)c2)c1=O
Yield: 100.4 %

Procedure:
The suspension of 2-methyl-4-(3-acetamidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (8.6 g) in 3N hydrochloric acid (50 ml) was refluxed for an hour. The mixture was made basic by sodium bicarbonate (15 g) to obtain 2-methyl-4-(3-aminophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (7.4 g) in yellow powder.
Reaction SMILES: [Li+].[I-].[CH2:3]([Mg]Br)[CH2:4][CH2:5][CH2:6][CH3:7].Cl[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[O:17]=[C:11]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCCCC[Mg]Br
Reactant: CCOC(=O)C(=O)Cl
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(=O)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 23.7 %

Procedure:
To a suspension of LiI (23.61 g, 176.44 mmol) in THF (200 mL) at rt was slowly added Cu2Br2 (25.30 g, 88.22 mmol). A vigorous exothermic reaction occurred, and the mixture was then cooled to −78° C. Pentylmagnesium bromide (2M, 36.76 mL, 88.22 mmol) was slowly added at −78° C., and followed soon after by ethyl chloro(oxo)acetate (10 g, 73.52 mmol). The resulting solution was stirred 10 minutes at −78° C., then quenched by dropwise addition of water. The mixture was allowed to warm to rt, and then the organic phase was separated, dried (MgSO4), and evaporated. Purification by flash chromatography using 9:1 hexane/EtOAc as eluant gave ethyl 2-oxoheptanoate as a colorless oil (3.0 g, 23%). 1NMR (400 MHz, CDCl3) δ 4.33-4.21 (m, 2 H), 2.82 (m, 2 H), 1.63-1.59 (m, 2 H), 1.63-11.19 (m, p H), 0.9-0.83 (m, 3 H), LC-MS m/z 279.21 (MH+), retention time 2.42 min (method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:21]1[CH2:25][CH2:24][N:23]([C@@H:26]([CH3:35])[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[C:22]1=[O:36])[CH2:16][C:17]([O:19]C)=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:21]1[CH2:25][CH2:24][N:23]([C@@H:26]([CH3:35])[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[C:22]1=[O:36])[CH2:16][C:17]([OH:19])=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: COC(=O)CN([C@H]1CCN([C@@H](C)C(=O)N2CCOCC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N(CC(=O)O)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Yield: 61.6 %

Procedure:
To a solution of methyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate (0.010 g) in THF (2 ml) was added lithium hydroxide (0.003 g) in water (2 ml), and the resultant solution stirred for 16 h. The mixture was acidified to pH5 using hydrochloric acid (2N), and then concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.006 g) as a white solid.
Reaction SMILES: C(OC(=O)[C:5]([NH:16][C:17](=[O:19])[CH3:18])([C:11]([CH:13]1[CH2:15][CH2:14]1)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O>CS(C)=O>[CH2:9]([O:8][C:6]([C:5]1[N:16]=[C:17]([CH3:18])[O:19][C:11]=1[CH:13]1[CH2:14][CH2:15]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(=O)C1CC1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1nc(C)oc1C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 34 %

Procedure:
2-Acetylamino-2-cyclopropanecarbonyl-malonic acid diethyl ester in DMSO was treated with 2 eq H2O and stirred at room temperature for 6 h then extracted with Et2O to give after concentration the title compound in 34% yield.