Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CS([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)=O>CN(C)C=O>[C:1]([N:9]1[CH2:10][C:11](=[O:16])[N:12]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13](=[O:15])[CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCc1ccccc1
Reactant: O=C1CN(C(=O)c2ccccc2)CC(=O)N1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CC(=O)N(CCc2ccccc2)C(=O)C1
Reaction time: 1 h

Procedure:
12 g (0.055 mol) of 4-benzoyl-2,6-dioxopiperazine are dissolved in 200 ml of dimethylformamide. 3.5 g (0.065 mol) of sodium methylate are added and the reaction medium is left for 1 hour at ambient temperature. To the reaction medium is added, dropwise and in an inert atmosphere, a solution of 16 g (0.080 mol) of (2-methane-sulphonyl ethyl)-benzene in 50 ml of dimethylformamide and is brought to 70° C. for 5 hours. Evaporation to dryness is carried out under vacuum and the residue is taken up in a mixture of water and dichloromethane. The decanted organic phase is dried over dry sodium sulphate. The evaporation of the solvent leaves an oily residue which is purified by silica column chromatography (elutrient: toluene/ethyl acetate 7/3). In this way, there is obtained the 4-benzoyl-2,6dioxo-1-phenethyl piperazine which, after recrystallisation from a cyclohexane/ethyl acetate mixture, melts at 102° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH:10](O)[CH2:11][O:12][CH3:13])[CH2:2][CH3:3].C(Cl)(Cl)[Cl:16].S(Cl)(Cl)=O>ClCl>[CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH:10]([Cl:16])[CH2:11][O:12][CH3:13])[CH2:2][CH3:3]
Reactant: CCCN1CCCCC1C(O)COC
Reactant: ClC(Cl)Cl
Agent: ClCl
Solvent: O=S(Cl)Cl
Product: CCCN1CCCCC1C(Cl)COC

Procedure:
In a first stage, 32 g (0.16 mol) of 1-propyl-2-(α-hydroxy-β-methoxyethyl)piperidine were introduced into a reactor containing 320 ml of anhydrous chloroform, the mixture was brought to 50° C. and 32 ml of thionyl chloride in 32 ml of chlorine were added dropwise, and the mixture was then heated under reflux for 10 h 30 min. After separation and distillation, 24.25 g of 1-propyl-2-(α-chloro-β-methoxyethyl)piperidine were obtained, of boiling point B.p.0.5 95° C.
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].[OH-].[K+].O>O1CCOCC1>[OH:1][CH:2]([C:7]([O:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(O)C(OCCNC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCCOC(c1ccccc1)(c1ccccc1)C(O)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22.2 g of methyl 2-hydroxy-3-(2-benzyloxycarbonylaminoethoxy)-3,3-diphenylpropionate (from Example 10) were dissolved in 300 ml of dioxane, mixed with 148 ml of 1M KOH and stirred at room temperature overnight. The reaction mixture was subsequently mixed with water and the aqueous phase was extracted with ether. The aqueous phase was acidified with hydrochloric acid and extracted with ether, the organic phase was dried over sodium sulfate and the solvent was distilled off. The residue (17.5 g) was directly used further.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@H:12]3[CH2:15][C@@H:16]([OH:18])[CH2:17][N:11]3[C:10]2=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@H:12]3[CH2:15][C@H:16]([O:18][C:43]4[CH:44]=[CH:45][C:40]([Br:39])=[CH:41][CH:42]=4)[CH2:17][N:11]3[C:10]2=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1[C@@H]2C[C@@H](O)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1[C@@H]2C[C@H](Oc3ccc(Br)cc3)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 6.6 %

Procedure:
To a solution of (7aS,6R)-2-(3,5-dichloro-phenyl)-6-hydroxy-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (0.5 g) (1.67 mmol) (Preparation 2), Ph3P (0.44 g) (1eq.) and 4-bromophenol (0.29 g) (1 eq.) in 5 mL of dry THF at 0° C. was added DIAD (0.337 g) in a minimal volume of THF. The reaction mixture was warmed to RT overnight. After evaporating the solvent, the residue was dissolved in DCM, washed with NaHCO3 solution, water, dried over MgSO4, and the solvent was evaporated under reduced pressure, to afford after SiO2 chromatography (eluent: DCM) the titled compound as a white solid (50 mg). Mp=116° C. NMR (DMSO, 200 MHz): 7.75 (1H, m), 7.5-7.4 (4H, d+d), 6.85 (2H, d), 5.1 (1H, m), 4.6 (1H, dd), 3.95 (1H, dd), 3.35 (1H, dd), 2.7-2.5 (1H, m), 2.25 (1H, bd).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:14])[C:5](=[O:15])[C:4]=1[C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].[C:29](OC(=O)C)(=[O:31])[CH3:30].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:14][C:29](=[O:31])[CH3:30])[C:5](=[O:15])[C:4]=1[C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cc(C)cc(OC)c1C1=C(OC)C(=O)c2c(O)cccc2C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc(C)cc(OC)c1C1=C(OC)C(=O)c2c(OC(C)=O)cccc2C1=O
Reaction time: 8 h

Procedure:
In pyridine (3 ml) was dissolved methyl 2-(3-methoxy-5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoate (20 mg) as obtained in Example 3, followed by addition of acetic anhydride (3 ml). The mixture was allowed to stand at room temperature overnight. After addition of water, the mixture was extracted with ethyl acetate. The solvent layer was washed with dilute HCl, water and dilute aqueous sodium hydrogen carbonate in that order, and dried over magnesium sulfate. The solvent was then distilled off and the residue was crystallized by addition of methanol. The above procedure gave methyl 2-(3-methoxy-5-acetoxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoate (13 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][S:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][NH2:5].C(N(CC)CC)C.[Cl:36][CH2:37][CH2:38][CH2:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl.O1CCCC1>[Cl:36][CH2:37][CH2:38][CH2:39][S:40]([NH:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][S:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CN)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCCCl)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 93 mg (0.223 mM) of 2-methoxy-3-octadecylcarbamoylthiopropylamine IVa6 and 40.4 μl (3.9 mM) of triethylamine in 5 ml of dichloromethane and 2 ml of tetrahydrofuran is added 29.8 μl (3.3 mM) of 3-chloropropanesulfonyl chloride with ice-cooling, and the mixture is stirred for 2 hours and at room temperature for an additional 30 minutes. The product is isolated by dichloromethane extraction and the dichloromethane layer is washed with an aqueous sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by the column chromatography on silica gel with a benzene-ethyl acetate (4:1) mixture as an eluent to give 83 mg (0.149 mM) of 3-(3-chloropropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane IIIa6 as a colorless powder in 67% yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:21]2[CH:26]=[C:25]([CH2:27][OH:28])[CH:24]=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)#[N:7].C(N(C(C)C)C(C)C)C>C1COCC1>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:21]2[CH:26]=[C:25]([CH2:27][O:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:24]=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)#[N:7]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CO)cc(OCC)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(COS(C)(=O)=O)cc(OCC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methanesulphonyl chloride was added slowly at 0° C. to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxymethyl-phenyl)-acetate (200 mg, 0.564 mmol) obtained in Example 234.2 and N-ethyldiisopropylamine (88 mg, 0.68 mmol) in THF (3 ml). The mixture was stirred for 1.5 h. at 0° C. and for 1.5 h. at room temperature. The mixture was poured into ice-water/1M HCl and extracted with EtOAc. The organic phase was washed with H2O, dried and filtered, and the filtrate was concentrated. There were obtained 232 mg of ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-methanesulphonyloxymethyl-phenyl)-acetate as a yellow oil, which was used for the next reaction without additional purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[C:4]([F:13])([F:12])[C:5]([F:11])([F:10])[S:6]([O-:9])(=[O:8])=[O:7].C([O:22][C:23]1[CH:28]=[CH:27][C:26]([S+:29]([C:41]2[CH:46]=[CH:45][C:44]([O:47]CCCC)=[CH:43][CH:42]=2)[C:30]2[CH:35]=[CH:34][C:33]([O:36]CCCC)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)CCC.FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(O)(=O)=O>C(O)C.CN(C)C=O>[F:17][C:2]([F:1])([F:16])[C:3]([F:14])([F:15])[C:4]([F:12])([F:13])[C:5]([F:10])([F:11])[S:6]([O-:9])(=[O:8])=[O:7].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([S+:29]([C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)[C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1
Reactant: CCCCOc1ccc([S+](c2ccc(OCCCC)cc2)c2ccc(OCCCC)cc2)cc1
Agent: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Product: Oc1ccc([S+](c2ccc(O)cc2)c2ccc(O)cc2)cc1

Procedure:
A solution of 62.2 g (0.08 mol) of tris-(4-butoxyphenyl) sulfonium nonafluorobutane sulfonate and 2.40 g (0.008 mol) of nonafluorobutane sulfonic acid in 200 ml of ethanol was refluxed for 8 hours with stirring. After evaporation of the solvent, the crude product of tris-(4-hydroxyphenyl) sulfonium nonafluorobutane sulfonate (yield about 100%) was dissolved in 160 g of N,N-dimethylformamide and reacted with 55.4 g (0.40 mol) of anhydrous potassium carbonate and 60.3 g (0.40 mol) of t-butyl chloroacetate at 80° C. for 3 hours. The cooled reaction mixture was poured into 700 ml of water and extracted with dichloromethane. The organic phase was washed with water and dried. The solvent was removed. The oily residue was purified by column chromatography on silica gel using a dichloromethane and methanol as the eluent. The white product was collected to yield 34.4 g (yield 45%) of analytically pure tris-(4-t-butoxycarbonylmethoxyphenyl) sulfonium nonafluorobutane sulfonate. The 1H-NMR spectrum gave the following signals (CDCl3): δ=1.45 (s, 27H), 4.76 (s, 6H), 7.15-7.18 (d, 6H). 7.74-7.87 (d, 6H).
Reaction SMILES: [C:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1CCCCC1.CN(C)[CH:28]=[O:29]>O1CCCC1.C(OCC)(=O)C>[F:19][C:14]1[C:13]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:28]=[O:29]
Reactant: CCCCCCCCCCC#Cc1ccccc1F
Reactant: CN(C)C=O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 7.00 g (27.0 mmol) of 2-(1-dodecynyl)fluorobenzene in tetrahydrofuran (60 ml) at -78° C. was added slowly secobutyllithium (1.3M, cyclohexane) (21 ml). The mixture was stirred at -78° C. for 30 min, and dimethylformamide (2.8 ml) was added dropwise. The mixture was stirred for 5 min at -78° C. and allowed to warm to room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated in vacuo. The residue was flash chromatographed on silica gel (eluted with ethyl acetate/heptane/1:10). The appropriate fractions were collected and evaporated. The residue was chromatographed a second time over silica gel (eluted with dichloromethane) to afford 7.10 g (91%) of product.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1)[CH3:2].C(N(CC)CC)C.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc(O)ncn1
Solvent: CCN(CC)CC
Product: CCc1cc(Cl)ncn1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
6-Ethyl-4-pyrimidinol (Intermediate 11, 0.93 g, 7.49 mmol) was treated with triethylamine (1.044 mL, 7.49 mmol) and phosphorus oxychloride (3.49 mL, 37.5 mmol) and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, evaporated under reduced pressure and the residue was poured into 2M aqueous hydrochloric acid solution (10 mL). This solution was extracted with DCM (×2). The DCM layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (552 mg);
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[CH3:5][N:4]1[C:3]2[C:2](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[NH:1][C:16](=[O:17])[C:15]1=[O:19]
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A mixture of 1.0 g (5.9 mmol) 2-amino-4-nitro-N-methylaniline and 1.5 g (11.9 mmol) oxalic acid dihydrate in 50 ml 4N hydrochloric acid was refluxed for 3 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was recrystallized (dimethylformamide-water) to give 1.0 g (78%) of 1-methyl-6-nitroquinoxaline-2,3-(1H,4H)-dione. M.p. 356° C. NMR (DMSO-d6): 12.2 (1H, broad s), 7.9 (1H, d), 7.8 (1H, s), 7.4 (1H, d), 3.47 (3H, s).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]2[C:19]([CH2:20][CH3:21])=[CH:18][C:17]([CH2:22][CH3:23])=[N:16]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:25].O1CCOCC1>CO>[ClH:25].[CH2:22]([C:17]1[CH:18]=[C:19]([CH2:20][CH3:21])[N:15]([CH2:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)[N:16]=1)[CH3:23]
Reactant: CCc1cc(CC)n(C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCc1cc(CC)n(C[C@H]2CC[C@H](N)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trans-[4-(3,5-Diethyl-pyrazol-1-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (80 mg, 0.24 mmol) was dissolved in MeOH (1 ml). 4M HCl/dioxan (1 ml) was added and the RM was stirred at RT for 2 hours. The solvent was removed in vacuo to afford the title product which was used without further purification; LC-MS Rt 1.59 mins [M+H]+ 236.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].[CH2:25]([O:27]C(=O)CC1C2C(=CC=C(OC)C=2)N(CC2C=CN=CC=2)C=1C)C.NN>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].[CH3:25][OH:27]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccncc2)c2ccc(OC)cc12
Agent: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccncc1
Agent: NN
Product: CO
Yield: 38 %

Procedure:
5-Methoxy-2-methyl-1-[(4-pyridyl)methyl]-1H-indole-3-acetic acid hydrazide. Using the method described in Example 1, Part G, 410 mg (1.2 mmol) of 5-methoxy-2-methyl-1-[(4-pyridyl)methyl]-1H-indole-3-acetic acid ethyl ester was reacted with 1.2 mL of hydrazine to give on crystallization from MeOH 148 mg (38% yield) of 5-methoxy-2-methyl-1-[(4-pyridyl)methyl]-1H-indole-3-acetic acid hydrazide, mp, 192°-193.5° C.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([CH3:15])[N:13]=[C:12]([CH3:16])[C:11]=1[CH3:17])(=O)C.Cl>CO>[CH3:15][N:14]1[C:10]([NH:9][C:5]2[NH:6][CH2:7][CH2:8][N:4]=2)=[C:11]([CH3:17])[C:12]([CH3:16])=[N:13]1
Reactant: CC(=O)N1CCN=C1Nc1c(C)c(C)nn1C
Agent: Cl
Solvent: CO
Product: Cc1nn(C)c(NC2=NCCN2)c1C

Procedure:
1-Acetyl-2(1,3,4-trimethyl-5-pyrazolyl) amino-2-imidazoline (29.6 g.) was treated with HCl in methanol as described in Example II to give 21.70 g. product (crystallized from CH3CN)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30](=O)[C:31](O)=[O:32])[CH:24]=1>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:15]2[C:31](=[O:32])[C:30]([CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[N:22][C:21]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]2=3)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(NC(C)=O)cc(Nc2ncccc2N)c1
Reactant: O=C(O)C(=O)Cc1cccnc1
Solvent: CO
Product: COC(=O)c1cc(NC(C)=O)cc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Yield: 70.6 %

Procedure:
A mixtue of 2-[3-acetylamino-5-methoxycarbonylphenylamino]-3-aminopyridine (1.07 g) and 3-(3-pyridyl)pyruvic acid (0.65 g) in methanol (15 ml) was stirred under reflux for 5 hours. The precipitate was collected and washed with methanol to give 4-(3-acetylamino-5-methoxycarbonylphenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.08 g).
Reaction SMILES: [C:1]12([CH:11]([OH:37])[CH2:12][O:13][C:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C@H:25]5[CH2:30][CH2:29][C@H:28]([CH2:31][C:32]([O:34]CC)=[O:33])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[NH:16][N:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+].O1CCCC1.Cl>O>[C:1]12([CH:11]([OH:37])[CH2:12][O:13][C:14]3[CH:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([C@H:25]5[CH2:26][CH2:27][C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][CH2:30]5)=[CH:23][CH:24]=4)[NH:16][N:15]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(OCC(O)C45CC6CC(CC(C6)C4)C5)n[nH]3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(OCC(O)C45CC6CC(CC(C6)C4)C5)n[nH]3)cc2)CC1
Reaction time: 8 h

Procedure:
A scintillation vial was charged with the product from Example 1G (18 mg, 0.036 mmol), lithium hydroxide monohydrate (5 mg, 0.12 mmol) and a mixed solvent (2 mL of tetrahydrofuran, 1 mL of H2O). The reaction vessel was placed in a shaker at room temperature overnight. After this time the mixture was acidified with 10% HCl, concentrated, and purified via RP-HPLC (Preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7 μM 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min.) to provide the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (m, 2H), 1.42-1.86 (m, 19H), 1.94 (m, 3H), 2.14 (d, J=7.01 Hz, 2H), 2.47 (m, 1H), 3.89 (dd, J1=10.38 Hz, J2=7.94 Hz, 1H), 4.24 (dd, J1=10.68 Hz, J2=2.74 Hz, 1H), 4.70 (d, J=5.49 Hz, 2H), 6.07 (s, 1H), 7.28 (d, J=8.24 Hz, 2H), 7.59 (d, J=8.24 Hz, 2H), 12.13 (br s, 2H); MS (ESI) m/z 479.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([NH:11][NH2:12])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=1.C([O:15][C:16](=O)[CH:17]=[C:18]([NH2:22])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[NH2:22][C:18]1[NH:12][N:11]([CH:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=2)[C:16](=[O:15])[CH:17]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: CC(NN)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Product: CC(c1ccc(Cl)c(Cl)c1)n1[nH]c(N)cc1=O
Reaction time: 2 h

Procedure:
41 g of α-methyl-3,4-dichlorobenzylhydrazine, dissolved in absolute ethanol, were added dropwise to a solution of 31.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 150 ml of ethanol at room temperature under nitrogen gas. After stirring for 2 hours and standing overnight, the reaction solution was concentrated as far as possibile on a rotary evaporator. The residue which remained was dissolved in 2 N sodium hydroxide solution. Any unconverted starting products or by-products were extracted with ether. The aqueous phase was then brought to pH 5 with acetic acid. The oil thereby produced was taken up in methylene chloride and the organic phase was dried over Na2SO4. After evaporating off the solvent, the reaction product crystallized out. It was recrystallized from methanol. Melting point 127°-129°C; yield 21 g (38.5% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-])=O)[CH2:15][CH2:14][CH:13]([O:20][C:21](=[O:23])[CH3:22])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O>C(O)C.C(O)(=O)C.[Cu].[Zn].[Zn].O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:17][CH:16]1[CH2:15][CH2:14][CH:13]([O:20][C:21](=[O:23])[CH3:22])[CH2:12][CH:11]1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2[N+](=O)[O-])cc1OC
Agent: [Cu+2]
Agent: [Cu]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC

Procedure:
A solution of 10.37 g of acetic acid (1RS,3RS,4RS)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexyl ester (compound O2) in 240 ml of ethanol is added to a zinc-copper couple, prepared from 16.8 g of zinc powder and 920 mg of copper (II) acetate monohydrate in acetic acid, the resulting suspension is refluxed and treated with 26 ml of acetic acid, 3.2 ml of water and 26 ml of ethanol. The resulting mixture is refluxed for further 15 min. The precipitate is filtered off with suction and the solvent is removed. Chromatographical purification on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 21711 and concentration of the corresponding eluate fractions afford 5.13 g (55% of theory) of the title compound as a pale brown oil.