Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([O:33][CH3:34])[CH:27]=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][O:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][C:28]=1[O:33][CH3:34])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1c(CCl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: COc1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(COc2ccc(Cl)cc2OC)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxylate (718 mg, 2.0 mmol) in dry N,N-dimethylformamide (3.0 ml) at room temperature was added 4-chloro-2-methoxyphenol (0.301 ml, 2.2 mmol) followed by sodium hydride (88.0 mg of a 60% oil dispersion, 2.2 mol). The mixture was stirred at room temperature for 18 hours, then the reaction mixture was diluted with ethyl acetate and poured into a separatory funnel. The organic phase was washed with saturated sodium bicarbonate and water (2×), then brine. The organic phase was separated, and the solvent removed under reduced pressure to provide a viscous oil. Upon sitting at room temperature overnight a solid formed, to which a mixture of 10% ethyl acetate/hexanes was added, and the resulting solid filtered off. The solid was washed with 20% ethyl acetate/hexanes and dried under reduced pressure to provide ethyl 6-chloro-2-((4-chloro-2-methoxyphenoxy)methyl)-4-phenylquinoline-3-carboxylate then provided PT-011 (558 mg, 58%) as a light yellow powder. TLC Rf=0.38 in 30% ethyl cetate:hexanes on a glass backed silica gel plate. 1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H, J=8.9 Hz); 7.69 (dd, 1H, J=8.9, 2.3 Hz); 7.58 (d, 1H, J=2.3 Hz); 7.48-7.52 (m, 3H); 7.36-7.30 (m, 2H); 6.95-6.92 (app d, 1H, J=8.6 Hz); 6.75 (s, 1H); 6.78-6.70 (m, 1H); 5.50 (s, 2H); 3.90 (q, 2H, J=7.0 Hz); 3.80 (s, 3H); 0.82 (t, 3H, J=7.0 Hz). LC MS (CI) shows M+H 482.
Reaction SMILES: C[NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])=S.[N:17]#CN.[Pb]>>[CH3:16][C:12]1[N:13]=[CH:14][NH:15][C:11]=1[CH2:10][S:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[NH:17])[NH2:2]
Reactant: N#CN
Reactant: CNC(=S)NCCCSCc1[nH]cnc1C
Agent: [Pb]
Product: Cc1nc[nH]c1CSCCCNC(=N)N
Yield: 17.5 %

Procedure:
The reaction of N-methyl-N'-[3-((4-methyl-5-imidazolyl)methylthio)propyl]thiourea (5.9 g.) with lead cyanamide (17.5 g.) by a procedure similar to that described in Example 3(b) afforded N-cyano-N'-methyl-N"-[3-((4-methyl-5-imidazolyl)methylthiopropyl]guanidine (0.91 g.), m.p. 156°-158°, following chromatography on silica gel with successive elution by chloroformethyl acetate (1:1), ethyl acetate and ethyl acetate isopropyl alcohol (5:1) and final recrystallisation from isopropyl alcohol-ether. (Found: C, 49.5; H, 7.0; S, 12.0. C11H18N6S requires: C, 49.6; H, 6.8; S, 12.0).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:15]=1)[O:5][P:6]([CH:9]([NH2:13])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7].CCN(C(C)C)C(C)C.[C:48]1([CH:54]=[CH:55][S:56](Cl)(=[O:58])=[O:57])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[C:26]([O:25][C:23]([N:22]=[C:21]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[NH:20][C:16]1[CH:15]=[C:14]([CH:4]([O:5][P:6]([CH:9]([NH:13][S:56]([CH:55]=[CH:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)(=[O:58])=[O:57])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7])[C:3]([O:2][CH3:1])=[O:38])[CH:19]=[CH:18][CH:17]=1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: COC(=O)C(OP(=O)(O)C(N)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(OP(=O)(O)C(NS(=O)(=O)C=Cc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Yield: 57.3 %

Procedure:
To a solution of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1-amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester (300 mg, 0.53 mmol) in 8 mL methylene chloride was added DIEA (0.44 mL, 1.06 mmol), which was cooled to 0° C. by an ice-water bath. Then a solution of 2-phenylethenylsulfonyl chloride (120 mg, 0.59 mmol) in 1 mL methylene chloride was added dropwise. The resulting mixture was stirred at ambient temperature for thirty minutes. The mixture was washed with water, 2N NaHSO4, and brine. The organic phase was dried over sodium sulfate and concentrated to afford a yellow solid. Purification by chromatograph on silica gel afforded a yellow solid, 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1-(2-phenylethenylsulfonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid, methyl ester, (220 mg).
Reaction SMILES: [CH:1]([CH:3]1[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1)=[CH2:2].C(O)=O.C1(C)C=CC=CC=1>[Cl-].[Na+].O>[CH:1]([CH:3]1[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]1)=[CH2:2]
Reactant: C=CC1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: C=CC1CCC(=O)CC1
Yield: 87.5 %

Procedure:
Sixth Step: 103.3 g of the compound (15), 86.5 g of 98% formic acid and 200 mL of toluene were added to a reactor in a nitrogen atmosphere, and stirred under refluxing and heating for 2 hours. After confirming that the reaction had been completed by GC analysis, the reaction mixture was poured into and mixed with 500 mL of brine at 0° C. The mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with a saturated sodium bicarbonate aqueous solution and brine, followed by drying over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was distilled under reduced pressure to obtain 66.7 g of 4-vinylcyclohexanone (16) as a colorless transparent liquid.
Reaction SMILES: [OH-:1].[Li+].[CH:3]([O:6][C:7]1[CH:8]=[CH:9][C:10](C(OC)=O)=[N:11][CH:12]=1)([CH3:5])[CH3:4].[O:17]1[CH2:22]COCC1>C(OCC)(=O)C>[CH:3]([O:6][C:7]1[C:12]([C:22]([OH:17])=[O:1])=[N:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])[CH3:5]
Reactant: C1COCCO1
Reactant: COC(=O)c1ccc(OC(C)C)cn1
Reactant: [OH-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC(C)Oc1cccnc1C(=O)O
Temperature: 55 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To methyl 5-hydroxypyridine-2-carboxylate (0.6 g, 3.92 mmol) in DMF (3.6 mL) was added potassium carbonate (2.2 g, 15.7 mmol) followed by 2-bromopropane (736 μL, 7.8 mmol) The reaction mixture was heated at 60° C. for 1.5 hours. The reaction mixture was cooled and filtered using EtOAc and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water (3×10 mL) and brine solution (10 mL). The organics were separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0-50% EtOAc:hexanes as eluent to give methyl 5-isopropoxypyridine-2-carboxylate (555 mg, 73%) as a colorless oil. ESI-MS m/z calc. 195.1. found 196.3 (M+1)+; Retention time: 1.09 minutes (3 min run). Lithium hydroxide (5.7 mL of 2 M, 11.37 mmol) was added to a solution of methyl 5-isopropoxypyridine-2-carboxylate (555 mg, 2.84 mmol) in dioxane (4 mL) and stirred at 55° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and layers were separated. The aqueous layer was acidified with 1N HCl solution and extracted with ethyl acetate. The organics were separated and dried over sodium sulfate, filtered and concentrated in vacuo to gives-isopropoxypyridine-2-carboxylic acid (150 mg, 29%). ESI-MS m/z calc. 182.1. found 182.3 (M+1)+; Retention time: 0.33 minutes (3 min run).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[N+:24]([C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][Br:30])([O-:26])=[O:25]>>[Br-:30].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[N+:24]([O-:26])=[O:25])[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccccc3[N+](=O)[O-])cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 125 is prepared according to the procedure reported in Example 38.1 with compound 103 (62 mg, 0.2 mmol) and 2-nitrobenzyl bromide (73 mg, 0.34 mmol) as reactants. White solid. (Yield 87.1 mg, 82%).
Reaction SMILES: [CH2:1]1[NH:6][C@@H:5]([CH2:7][OH:8])[CH2:4][N:3]2[CH2:9][CH2:10][NH:11][CH2:12][CH:2]12.C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:54])([F:53])[C:21]1[CH:22]=[C:23]([C:31]([CH3:52])([CH3:51])[C:32]([N:34]([C:36]2[CH:37]=[N:38][C:39](Cl)=[CH:40][C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])[CH3:35])=[O:33])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>CS(C)=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]([CH3:52])([CH3:51])[C:32]([N:34]([C:36]2[CH:37]=[N:38][C:39]([N:11]3[CH2:10][CH2:9][N:3]4[CH2:4][C@H:5]([CH2:7][OH:8])[NH:6][CH2:1][CH:2]4[CH2:12]3)=[CH:40][C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])[CH3:35])=[O:33])[CH:22]=[C:21]([C:20]([F:54])([F:19])[F:53])[CH:26]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC[C@H]1CN2CCNCC2CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3C[C@H](CO)NCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 23 h

Procedure:
To a solution of (3R)-octahydro-2H-pyrazino[1,2-a]pyrazin-3-ylmethanol (D89, Mixture of diastereoisomers of unknown ratio, 83.5 mg, 0.496 mmol) in 1.6 mL of DMSO were added K2CO3 (78 mg) and 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (100 mg). The reaction was left at 150° C. for 23 h. It was checked by UPLC/MS, which showed a peak for the expected product at 0.71 min. (m/z=668 (M+1), 334 (M+2)/2). The solution was diluted with dichloromethane, extracted with water and dried (Na2SO4). The title ccompound obtained (113.5 mg) was taken to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[N:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[C:19](OCC)(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[C:7]2[C:8](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]1=[O:26]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccccc1CNc1ncccc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cccnc2n(Cc2ccccc2OC)c1=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 74.7 %

Procedure:
7.40 g (30.5 mmol) of 2-(2-methoxybenzylamino)nicotinaldehyde was dissolved in ethanol (100 mL), and 7.34 g (45.8 mmol) of diethyl malonate and 0.95 g (10.0 mmol) of piperidine were added thereto. The resulting mixture was stirred for 48 hours at 100° C. The mixture was cooled, and a solid precipitated thereby was separated by filtration. The solid was washed with hexane, and thus 7.71 g (yield: 75%) of the title compound was obtained as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]([O:39][Si](CC)(CC)CC)[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][O:14][C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH3:31])=[N:20][N:21]3C(OC(C)(C)C)=O)=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)Cl.NC1C=C([C@@H](O[Si](CC)(CC)CC)CN(C(OC(C)(C)C)=O)CCOC2C=C3C(C(C)=NN3C(OC(C)(C)C)=O)=CC=2)C=CC=1Cl.[C:96]1([S:102](Cl)(=[O:104])=[O:103])[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=1.C(Cl)Cl.C(O)C(N)(CO)CO>C(Cl)Cl.N1C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C@@H:9]([OH:39])[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH3:31])=[N:20][NH:21]3)=[CH:17][CH:16]=2)=[CH:3][C:2]=1[NH:1][S:102]([C:96]1[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=1)(=[O:104])=[O:103].[ClH:8]
Reactant: CC[Si](CC)(CC)O[C@@H](CN(CCOc1ccc2c(C)nn(C(=O)OC(C)(C)C)c2c1)C(=O)OC(C)(C)C)c1ccc(Cl)c(N)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1n[nH]c2cc(OCCNC[C@H](O)c3ccc(Cl)c(NS(=O)(=O)c4ccccc4)c3)ccc12
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A (R)-tert-butyl 6-(2-((2-(3-amino-4-chlorophenyl)-2-(triethylsilyloxy)ethyl)(tert-butoxycarbonyl)amino)ethoxy)-3-methylindazole-1-carboxylate-CH2Cl2 solution [0.5 mL; solution prepared by dissolving (R)-tert-butyl 6-(2-((2-(3-amino-4-chlorophenyl)-2-(triethylsilyloxy)ethyl)(tert-butoxycarbonyl)amino)ethoxy)-3-methylindazole-1-carboxylate (1.324 g) that can be produced by the method described in Reference Example 101 or the like in dehydrated CH2Cl2 (10 mL)], dehydrated pyridine (42 μL), a benzenesulfonyl chloride-CH2Cl2 solution [0.5 mL; solution prepared by dissolving benzenesulfonyl chloride (466.3 mg; manufactured by Wako Pure Chemical Industries, Ltd.) in dehydrated CH2Cl2 (4 mL)], and dehydrated CH2Cl2 were added, and the mixture was shaken (600 min−1) overnight at room temperature. PS-Trisamine [300 mg (3.6 mmol/g); manufactured by Argonaut Technologies, Inc.] was added to the reaction solution, and the mixture was shaken (600 min−1) for 5 hours at room temperature. The reaction solution was filtered, and nitrogen gas was blown into the filtrate to evaporate the solvent. The resulting residue was purified by column chromatography (“COLUMN-I”; methanol). The obtained purification product was dissolved in 1,4-dioxane (0.2 mL), and a 4 mol/L hydrochloric acid-1,4-dioxane solution (1.5 mL) was added thereto. The mixture was shaken (600 min−1) overnight at room temperature. Nitrogen gas was blown into the reaction solution to evaporate the solvent, and MTBE was added to the obtained residue to obtain a suspension. Nitrogen gas was blown into the suspension to evaporate the solvent, and thus the title compound was obtained in the form of hydrochloride (46.4 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:14])[C:6]([OH:13])=[N:7]2.O.[CH:16]([CH:18]=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>[OH-].[Na+]>[OH:14][C:5]1[C:6]([OH:13])=[N:7][C:8]2[C:3]([N:4]=1)=[C:2]1[C:11](=[CH:10][CH:9]=2)[N:12]=[CH:18][CH:16]=[N:1]1
Reactant: Nc1ccc2nc(O)c(O)nc2c1N
Reactant: O=CC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1nc2ccc3nccnc3c2nc1O
Temperature: 50 °C
Yield: 35.9 %

Procedure:
A mixture of 0,5 g (2,6 mmol) 5,6-diamino-2,3-dihydroxyquinoxaline and 20 ml water was added 0,6 ml (3,9 mmol) 40% aqueous glyoxal and 0,41 g (3,9 mmol) sodium carbonate. The reaction mixture was stirred at 50° C. for 1,5 h. After cooling to 25° C., the precipitate was filtered off and washed with water to give 0,49 g. The crude product was dissolved in 2N sodium hydroxide and reprecipitated with 2N hydrochloric acid to pH 6-7 to give 0,2 g (36%) 2,3-dihydroxypyrazino(2,3-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 8.30 (1H,d), 8.20 (1H,d), 7.27 (1H,d), 7.0 (1H,d).
Reaction SMILES: [C:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:8]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])[CH3:9]>>[C:8]([N:11]1[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])[CH3:9]
Reactant: O=CC1=CCCC1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Product: CCOC(=O)C1(C(=O)OCC)C2CCCC2CN1C(C)=O

Procedure:
The title compound was prepared from cyclopenten-1-aldehyde (1 eq) and diethyl acetamidomalonate (1 eq) using the procedure by Chung et al. (J. Org. Chem. 1990, 55, 270). MS (ESI) 298 (M+H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([CH2:15][C:16]#[N:17])[C:12]([N+:18]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Ni].CCO.C(O)(=O)C>[NH2:18][C:12]1[C:13]([CH2:15][C:16]#[N:17])=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: N#CCc1nc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CCc1nc(OCc2ccccc2)ccc1N

Procedure:
11 g (40 mmol) (6-benzyloxy-3-nitro-pyridin-2-yl)-acetonitrile and 1.7 g Raney nickel (washed with abs. EtOH) in 120 mL EtOH and 50 mL acetic acid were hydrogenated at RT in a hydrogen atmosphere of 3 bar. The catalyst was filtered off and the filtrate was evaporated down. The residue was combined with 30 mL water and adjusted to pH=10 with solid sodium carbonate. The aqueous phase was extracted several times with EtOAc. The combined organic phases were dried on magnesium sulphate, filtered and evaporated down. The residue was purified by flash chromatography. The product-containing fractions were combined and evaporated down.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[O:15]=[C:16]([CH3:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:17]([C:16](=[O:15])[CH3:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
1 g (5.31 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 680 mg (5.84 mmol) of methyl 3-oxobutanoate, 456 μl (7.97 mmol) of acetic acid and 105 μl (1.06 mmol) of piperidine in 50 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is diluted with dichloromethane (100 ml) and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from isopropanol. 1.43 g (94% of theory) of the title compound are obtained as an E/Z mixture.
Reaction SMILES: [C:1]([C:4]1[NH:5][N:6]([CH2:10][CH2:11][C:12]#[N:13])[C:7](=[O:9])[CH:8]=1)(=O)[NH2:2].C(#N)C.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]([C:4]1[NH:5][N:6]([CH2:10][CH2:11][C:12]#[N:13])[C:7](=[O:9])[CH:8]=1)#[N:2]
Reactant: N#CCCn1[nH]c(C(N)=O)cc1=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#CCCn1[nH]c(C#N)cc1=O
Temperature: 0 °C

Procedure:
13.5 g of 3-carbamoyl-1-(2-cyanoethyl)-5-pyrazolone and 120 ml of acetonitrile were put into a 200 ml 3-neck flask. A mixture solution of 27 ml of phosphorus oxychloride and 76 ml of N,N-dimethylformamide was added dropwise at a temperature below 15° C. After completion of the addition, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was concentrated and the crystals (white color) formed were collected by filtration. Yield: 7.8 g (64.2%), Melting Point: 162° to 164° C.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C([NH:43][C:44]1C=C[C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=1)=O>>[O:50]1[CH2:48][CH2:47][CH2:46][C@H:45]1[CH2:44][NH:43][C:29]([C:26]1[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Agent: NCCCc1ccccc1
Product: O=C(NC[C@@H]1CCCO1)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting (S)-(tetrahydrofuran-2-yl)methamine for 3-phenylpropan-1-amine and 6-(isoindoline-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.85 (t, J=6.1 Hz, 1H), 8.32 (d, J=9.3 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H), 7.41-7.28 (m, 4H), 5.04-4.72 (m, 4H), 4.04 (p, J=6.2 Hz, 1H), 3.85-3.74 (m, 1H), 3.69-3.58 (m, 1H), 3.38 (dd, J=11.2, 5.0 Hz, 2H), 2.01-1.74 (m, 3H), 1.71-1.54 (m, 1H); MS (ESI(+)) m/e 368 (M+H)+.
Reaction SMILES: [CH:1]([C:19]1[CH:25]=[C:24](O)[CH:23]=[CH:22][C:20]=1[OH:21])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:2].[OH-].[Na+].S([O:34][CH3:35])(OC)(=O)=O.[CH3:36]C(C)=O>>[CH3:36][O:21][C:20]1[CH:22]=[CH:23][C:24]([O:34][CH3:35])=[CH:25][C:19]=1[CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:2]
Reactant: CC(C)=O
Reactant: COS(=O)(=O)OC
Reactant: CCCCCCCCCCCCCCCCC(C)c1cc(O)ccc1O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCC(C)c1cc(OC)ccc1OC

Procedure:
Alternatively, the above 2-sec-octadecylhydroquinone dimethyl ether was also obtained by the etherification of 2-sec-octadecylhydroquinone. Thus, 5.0 g of 2-sec-octadecylhydroquinone were dissolved in 50 ml of acetone and 1.2 g sodium hydroxide were added. After the dropwise addition of 3.8 g of dimethyl sulfate at room temperature, the reaction mixture was refluxed for 2 hours. The solvent was distilled off under reduced pressure and the residue was extracted with ether. After being washed with water and dried, the residue was distilled under reduced pressure to give 2.0 g of 2-sec-octadecylhydroquinone dimethyl ether having b.p. 200°-206° C./0.6 mmHg. IR and NMR data of both products were completely identical.
Reaction SMILES: [NH2:1][N:2]1[C:13](=[O:14])[C:12]2[C:15]3[N:4]([CH:5]([CH3:18])[CH2:6][O:7][C:8]=3[C:9](F)=[C:10]([F:16])[CH:11]=2)[C:3]1=[O:19].[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][N:29]([C:9]2[C:8]3=[C:15]4[C:12]([C:13](=[O:14])[N:2]([NH2:1])[C:3](=[O:19])[N:4]4[CH:5]([CH3:18])[CH2:6][O:7]3)=[CH:11][C:10]=2[F:16])[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)n(N)c(=O)n1c23
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1COc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)n(N)c(=O)n1c23
Yield: 104.1 %

Procedure:
A solution of 0.2 g (0.75 mmol) of 5-amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione (Example 24h), 0.58 g (2.0 mmol) of (S)-3-pyrrolidinylcarbamic acid tert-butyl ester (J. Med. Chem., 1992; 35:1764), 0.5 g (0.5 mmol) of triethylamine and 20 mL of acetonitrile is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane-water. The organic layer is washed with water, dried (MgSO4) and concentrated in vacuo. The residue is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane/ethanol (95:5) to give 0.34 g of the title compound, mp 114–116° C.