Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH:5]([NH:10][C:11](=[O:26])[CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=[N:24][NH2:25])=[CH:19][CH:18]=1)=[O:15])[CH:6]([O:8][CH3:9])[CH3:7].[OH-].[Li+].C(O)(C(F)(F)F)=O>O.C(#N)C>[NH2:25][N:24]=[CH:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][CH2:12][C:11]([NH:10][CH:5]([CH:6]([O:8][CH3:9])[CH3:7])[CH2:4][C:3]([OH:27])=[O:2])=[O:26])=[CH:18][CH:19]=1
Reactant: COC(=O)CC(NC(=O)CCC(=O)Nc1ccc(C=NN)cc1)C(C)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(C)C(CC(=O)O)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Methyl-3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-methoxypentanoate prepared in Example 25, Step 2 (500 mg) was added to water/acetonitrile (20 ml) followed by lithium hydroxide (100 mg) at 25° C. The mixture was stirred for 30 min. The course of the reaction was monitored by RPHPLC. After satisfactory product was formed the reaction was neutralized with TFA and purified by reverse phase chromatography (water/acetonitrile) to result in 450 mg of a white solid: 1H NMR (d6 -DMSO) δ1.74 (m, 2H), 2.4 (m, 4H), 2.6 (m, 2H), 3.16 (s, 3H), 3.33 (m, 2H), 4.12 (m, 1H), 7.78 (s, 4H), 7.81 (d, 1H, J=8.5 Hz), 9.02 (bs, 2H), 9.15 (bs, 2H), 10.40 (s, 1H); MS (FAB) m/z 365.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:24][C:25](=[O:27])[CH3:26]>C1COCC1>[O:27]=[C:25]([CH3:26])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CC(=O)CCl
Reactant: Oc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)COc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.6 %

Procedure:
8-Hydroxyquinoline (0.73 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and dry N,N-dimethylformamide (DMF) (40 ml) were stirred at room temperature for 30 min. To this solution was added chloroacetone (0.46 g, 5 mmol) in dry THF (10 ml) in one portion. The resulting mixture was stirred at room temperature for 24 h. (monitored by TLC) and then poured into ice water (100 ml). The pale yellow solid thus obtained was collected and crystallized from dichloromethane and ether to afford 8-(2-oxopropoxy)quinoline (7a) (0.68 g, 67%) as a pale yellow needle crystal. mp: 58°-59° C.; 1H-NMR (CDCl3): δ2.32 (s, 3H, CH3), 4.88 (s, 2H, OCH2), 6.88-8.97 (m, 6H, Ar--H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:46]/[O:47][CH3:48])/[C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([O:30]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:29])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[O:24][CH:25]([CH3:27])[CH3:26])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:46]/[O:47][CH3:48])/[C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([OH:30])=[O:29])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[O:24][CH:25]([CH3:27])[CH3:26])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OC(C)C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(c3c(OC(C)C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Reaction time: 1 h

Procedure:
Diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[3,4-dioxo-2-(2-propoxy)-1-cyclobutenyl]-3-cephem-4-carboxylate (33 mg) was added to a stirred, cooled (ice/H2O bath) solution of trifluoroacetic acid (100 μL) and anisole (50 μL). The cooling bath was removed, and stirring was continued for 1 hr at ambient temperatures. The solution was diluted with diethyl ether to precipitate the trifluoroacetic acid salt of the title compound as a yellow powder.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[C:14]([CH3:20])([CH3:19])[C:15](=[O:18])[NH:16][N:17]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].CC1C=CC(S(O[CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)(=O)=O)=CC=1.C1(C)C(S([O-])(=O)=O)=CC=CC=1.[Na+].OS(O)(=O)=O>CN(C=O)C.C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[C:14]([CH3:20])([CH3:19])[C:15](=[O:18])[N:16]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:17]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1ccc(C2=NNC(=O)C2(C)C)cc1OC
Agent: Cc1ccccc1S(=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 g NaH (60% in mineral oil) is suspended in 500 ml of dry DMF under a blanket of dry nitrogen. 124 g 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C1) is added in portions and stirred for an additional 30 min at RT. The solution becomes slightly yellow. 168 g tert-butyl 4-{[(4-methylphenyl)sulfonyl]oxy}piperidine-1-carboxylate (compound E1) in 150 ml of DMF is added in one portion and the mixture is placed in a preheated oil bath (140° C.) and heated for 1.0 hr. The mixture is cooled to 50° C. (part of the sodium toluenesulfonate crystallizes) 1000 ml of water is added and the mixture is extracted with 200 ml of ethyl acetate (five times). The combined organic layers are washed with 100 ml of water (five times), 50 ml of brine, dried over MgSO4 and concentrated in vacuo. The oil obtained is dissolved in 300 ml of ethanol and 300 ml of 1M H2SO4 is added and heated at reflux for 60 min. The ethanol is removed in vacuo, 200 ml of water is added and washed with 100 ml DCM (five times). The aqueous layer is basified with 40 g NaOH in 250 ml water and extracted with 200 ml of dichloromethane (three times), dried over MgSO4 and concentrated in vacuo. The oil is suspended in 300 ml of ethanol with 30 ml of concentrated hydrochloric acid and heated until it dissolves. Cooling in ice causes precipitation. The collected precipitates are dried resulting in the hydrochloride salt of the title compound. (compound B1*HCl)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Cl[CH2:13][C:14]([OH:16])=[O:15].[I-].[Na+].[O-2].[Mg+2].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[NH:1][CH2:13][C:14]([OH:16])=[O:15])(=[O:5])[NH2:6]
Reactant: NC(=O)c1ccc(Cl)cc1N
Reactant: O=C(O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)cc1NCC(=O)O
Reaction time: 2.5 h
Yield: 43.9 %

Procedure:
To a mixture of 0.34 g of 2-amino-4-chlorobenzamide, 0.57 g of monochloroacetic acid, 0.90 g of sodium iodide and 0.24 g of magnesium oxide was added 2 ml of dimethylformamide and the mixture was stirred at a temperature between 90° and 100° C. for 2.5 hours. After cooling, the reaction mixture was poured into 50 ml of a 2.6% aqueous sodium carbonate solution. The resulting precipitates were filtered off and the filtrate was extracted with 50 ml of chloroform. The aqueous layer was acidified with concentrated hydrochloric acid to precipitate crystals. The crystals were collected by filtration and recrystallized from aqueous methanol to obtain 0.20 g of N-(2-carbamoyl-5-chlorophenyl)glycine as needles having a melting point of 217°-222° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1ccc(C=O)cn1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1ccc(C=CC(=O)O)cn1
Reaction time: 3 h
Yield: 59.4 %

Procedure:
A mixture of 6-methylpyridine-3-carboxaldehyde (51.57 g), malonic acid (44.30 g), piperidine (6 ml) and pyridine (300 ml) was stirred at 100° for 3 hours and was allowed to cool. The mixture was evaporated to dryness, water was added to the residue and the solid was filtered off and recrystallised from ethanol-acetic acid to give 3-(6-methyl-3-pyridyl)acrylic acid (41.25 g) m.p. 213.5°-215°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:26][CH2:25][CH2:24][C@H:12]1[C:13]([NH:15][C@H:16]([C:21]([OH:23])=O)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[CH3:29].C(N(CC)CC)C.C1(C)C=CC(S(ON2C3C=C([N+]([O-])=O)C=CC=3N=N2)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH:33][C:21](=[O:23])[C@H:16]([CH2:17][CH:18]([CH3:19])[CH3:20])[NH:15][C:13](=[O:14])[C@@H:12]1[CH2:24][CH2:25][CH2:26][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:29]
Reactant: CCOC(=O)CN
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)On2nnc3ccc([N+](=O)[O-])cc32)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 52.8 %

Procedure:
N-(N-Benzyloxycarbonyl-L-prolyl)-L-leucine (4.6 g), glycine ethyl ester hydrochloride (1.8 g) and triethylamine (1.78 ml) are dissolved in dry chloroform (40 ml) and thereto is added 1-(p-toluenesulfonyloxy)-6-nitro-1,2,3-benzotriazole (4.25 g) under ice-cooling and the mixture is stirred for 1 hour. After allowing to stand overnight, to the mixture are added water and ethyl acetate. The ethyl acetate layer is washed with 1 N aqueous ammonia containing 5% NaCl (six times), water, 1 N hydrochloric acid and water in order, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The resulting residue is washed with ether-petroleum ether to give N-[N-(N-benzyloxycarbonyl-L-prolyl)-L-leucyl]glycine ethyl ester (3.0 g), melting point: 149°-150° C.
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([NH2:9])=[N:7][N:8]=1)[CH2:2][CH3:3].[CH3:10][N:11]=[C:12]=[O:13]>CN(C)C=O>[CH2:1]([C:4]1[S:5][C:6]([NH:9][C:12]([NH:11][CH3:10])=[O:13])=[N:7][N:8]=1)[CH2:2][CH3:3]
Reactant: CN=C=O
Reactant: CCCc1nnc(N)s1
Solvent: CN(C)C=O
Product: CCCc1nnc(NC(=O)NC)s1
Reaction time: 1 h

Procedure:
To 14.9 g (0.1 mol) 2-n-propyl-5-amino-1,3,4-thiadiazole dissolved in 100 ml dimethyl formamide there are added dropwise, at 20° C., 5.7 g (0.1 mol) methyl isocyanate. After the subsidence of the heat effect, stirring is continued for 1 hour at 50° C., and distillation to one half of the original volume is then effected in a vacuum, followed by pouring into 400 ml of water. The crude N-(2-n-propyl-1,3,4-thiadiazol-5-yl)-N'-methyl urea (13) is obtained in solid form and is filtered off with suction.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([N:9]1[CH2:17][C@H:15]([OH:16])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=[O:4].[C:21](=O)([O:37]N1C(=O)CCC1=O)[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2.C([O-])([O-])=O.[Na+].[Na+]>C([O-])([O-])=O.[Na+].[Na+].O.C(COC)OC>[NH:1]([C:21]([O:22][CH2:23][CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([N:9]1[CH2:17][C@H:15]([OH:16])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=[O:4]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NCC(=O)N1CCC[C@H]1C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCC(=O)N1CCC[C@H]1C(=O)N1C[C@H](O)C[C@H]1C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 4 °C
Reaction time: 21 h

Procedure:
Fmoc-Gly-Pro-Hyp was synthesized from Gly-Pro-Hyp as follows: 3.0 g Gly-Pro-Hyp (10.5 mmol) was dissolved in 54 mL Na2CO3 --H2O (1:9) and stored at 4° C. 4.05 g 9-fluorenylmethyl succinimidyl carbonate (12.0 mmol) was dissolved in 45 mL dimethoxyethane and stirred at 4° C. The aqueous Na2CO3 solution was added slowly to the dimethoxyethane solution, and the reaction proceeded for 2.5 h at 4° C. and 21 h at room temperature. The solution was filtered, and 360 mL H2O was added to the filtrate. The aqueous layer was extracted with 300 mL of diethyl ether, acidified to pH 2 with concentrated HCl, reduced to half volume at 80° C. under reduced pressure, and stored at 4° C. for 24 h. The aqueous layer was decanted from the oily precipitate, reduced to ~30 mL at 81° C. under reduced pressure, and stored at 4° C. for 24 h. The aqueous layer was decanted from the oily precipitate. Both oily precipitates were dissolved in a total of 20 mL methanol, then 250 mL ethyl acetate was added. A white residue was recovered by evaporation at 73° C. for 1 h under reduced pressure; yield 3.23 g (6.39 mmol, 60.6%). The identity of the product as Fmoc-Gly-Pro-Hyp and its homogeneity was verified by thin layer chromatography [chloroform-methanol-HOAc (95:20:3)], scanning UV spectroscopy, and Edman degradation sequence analysis.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:25]1([C@H:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:33][C@@H:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:32])[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(N[C@H](C)c2ccccc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(1R)-1-phenylethyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03-1.87 (m, 16H), 2.13 (s, 3H), 3.80 (s, 1H), 4.95-5.02 (m, 1H), 6.73 (s, 1H), 7.14-7.41 (m, 5H), 8.38 (s, 1H); MS (ESI) m/z 325.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[CH:20]([CH:22]=[CH2:23])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:15]([C:12]([CH2:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH2:21]/[CH:20]=[CH:22]/[CH3:23])[CH:13]=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC(C=O)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C/C=C/CC(C=O)(CCCC)CS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred solution of 2-(((4-chlorophenyl)-sulfonyl)methyl)hexanal (3.38 g, 11.73 mmol) in 30 ml of toluene in a RBF fitted with a Dean-Stark trap is added 2-hydroxy-3-butene (5 mL, 57.73 mmol), followed by p-toluenesulfonic acid (0.13 g) at room temperature under nitrogen. The mixture is heated to reflux for 20 hours. After cooling to room temperature, the toluene solution is diluted with 10 mL of ethyl acetate and washed with 10 mL of saturated NaHCO3 solution. The aqueous phase is extracted with ethyl acetate. The combined organic extract is washed with water (2×10 mL), brine (1×10 mL), and dried with MgSO4. After removing solvents, the product is obtained as a brownish oil in 98% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:24][C:25]1[C:34]2[CH2:33][NH:32][CH2:31][CH2:30][C:29]=2[N:28]=[C:27]2[CH2:35][CH2:36][CH2:37][CH2:38][C:26]=12.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>O1CCCC1.O.C(OCC)(=O)C>[NH2:24][C:25]1[C:34]2[CH2:33][N:32]([C:11](=[O:13])[CH2:10][CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:31][CH2:30][C:29]=2[N:28]=[C:27]2[CH2:35][CH2:36][CH2:37][CH2:38][C:26]=12
Reactant: O=C(O)CC(C(=O)OCc1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1c2c(nc3c1CNCC3)CCCC2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1c2c(nc3c1CN(C(=O)CC(C(=O)OCc1ccccc1)c1ccc(Cl)c(Cl)c1)CC3)CCCC2
Temperature: 20 °C
Reaction time: 2 h
Yield: 168.1 %

Procedure:
108.08 g (0.300 mol) of (+)-3-(3,4-dichlorophenyl)-3-benzyloxycarbonylpropionic acid and 154.11 g (0.300 mol) of 10-amino-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine were suspended in 600 ml of tetrahydrofuran, and the solution was cooled to an internal temperature of 20° C. Then 127.50 g (0.126 mol) of triethylamine was added at an internal temperature of 30° C. or below over a period of 15 minutes and the solution was further cooled to an internal temperature of 20° C., after which 210.00 g (0.330 mol) of a 50% ethyl acetate solution of T3P was added dropwise at an internal temperature of 25° C. over a period of 20 minutes and the solution was stirred at this temperature for 2 hours. The internal temperature of the solution was lowered to 20° C., then 1,200 ml of water was added dropwise at an internal temperature of 25° C. over a period of 10 minutes, and the precipitated crystals were centrifugally filtered by a centrifuge and washed twice with 360 ml of a 1/2 mixture of THF and water to obtain 271.48 g (100% yield) of the title compound.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[O:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[O:12]([C:4]1[CH:3]=[C:2]([N:26]2[CH2:27][CH2:28][C:23]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:24][CH2:25]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(F)cc1Oc1ccccc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1Oc1ccccc1
Temperature: 130 °C

Procedure:
Methyl 4-fluoro-2-phenoxybenzoate (2 g) and 1,4-dioxa-8-azaspiro[4.5]decane (1.279 g) were combined in dimethylsulfoxideO (12 mL) in a 250 mL round-bottom flask. Sodium carbonate (1.291 g) was added. The reaction flask was sealed and heated to 130° C. overnight. The reaction mixture was diluted with ethyl acetate, washed thoroughly with water and with brine, and dried over MgSO4, filtered and concentrated to obtain the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.CN(C)[CH:10]=[CH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=O>>[CH3:7][C:5]1[N:6]=[C:2]2[N:1]=[CH:10][CH:11]=[C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[N:3]2[N:4]=1
Reactant: Cc1nc(N)n[nH]1
Reactant: CN(C)C=CC(=O)c1cccs1
Product: Cc1nc2nccc(-c3cccs3)n2n1

Procedure:
By the procedure described in Example 5, 3-amino-5-methyl-1,2,4-triazole was reacted with 3-dimethylamino-1-(2-thienyl)-2-propene-1-one to give 1.05 g of the product of the Example as pale yellow needles, mp 184°-185° C.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12](O)=[O:13])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].O.Cl>C1(C)C=CC=CC=1>[CH2:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](CC(=O)O)CC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC[C@H]1CC[C@H](CCO)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
37 g (0.19 mol) of trans-4-butylcyclohexyl acetic acid was dispersed in 190 cm) of anhydrous toluene, 160 cm3 (0.57 mol) of 70% of NaAlH2 (OC2H4OCH3)2 in toluene was added dropwise while stirring at a rate where the toluene refluxed quietly, after which it was stirred for 3 hours on a 90° C. hot water bath. The reactant was cooled to room temperature, 40 cm3 of water and 500 cm3 of 15% HCl were added dropwise while stirring, the oily layer was taken off, and the water layer was extracted with toluene, combined with the oily layer and washed with 10% HCl and water. The toluene was removed, and the remaining oily substance was distilled under reduced pressure (b. p. 103° C./3 mmHg) to obtain 31 g (0.17 mol) of 2-(trans-4'-butylcyclohexyl)ethanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].C[Si](C)(C)N[Si](C)(C)C.C(N(C(C)C)[CH:20]([CH3:22])[CH3:21])C.C(Br)C#C.C1OC1C>CO.COCCOCCOC>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:22][C:20]#[CH:21])(=[O:7])[OH:6]
Reactant: NCCCP(O)O
Reactant: CCN(C(C)C)C(C)C
Agent: C#CCBr
Agent: CC1CO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: COCCOCCOC
Solvent: CO
Product: C#CCP(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 1,23 g (10 mmol) of 3-aminopropylphosphonous acid in 10.4 ml (50 mmol) of hexamethyldisilazane is heated to reflux under argon for 24 hours. 5 ml of diethylene glycol dimethyl ether are added to the clear solution obtained and the mixture is heated for additional 2 hours and then cooled to 0°. 8.5 ml (50 mmol) of N-ethyl-N,N-diisopropyl-amine are added, followed by slow addition of 3.8 ml (50 mmol) of propargyl bromide over a period of 40 minutes. The mixture is stirred for 1 hour at 0° and 4 hours at room temperature, filtered and evaporated under high vacuum. The residue is dissolved in 10 ml of dichloromethane and extracted with 3×10 ml of 1 N hydrochloric acid solution. The water layer is evaporated under high vacuum and the residue obtained dissolved in 4 ml of methanol at 0°. 20 ml of propylene oxide are added during a period of 1 hour, after which time a crude product precipitates. Chromatography (silicagel Merck 230-400 ASTM, methanol) followed by recrystallization (methanol/ether) yields 3-aminopropyl(propargyl)-phosphinic acid, m.p. 172°-173°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27](OCC)[O:28]CC)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[O:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
To a solution of diethyl 2-methyl-4-(3-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (462.5 mg) in acetone (4 ml) was added 6N-hydrochloric acid (0.4 ml) and stirred at room temperature for an hour. After the reaction, the solvent was removed from the resultant solution. To the residue was added water, and the residue was pulverized. The powder was collected by filtration, washed with water and dried to give diethyl 2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (360 mg), m.p. 130° to 133° C.