Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]([C:14]([NH2:16])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)(Cl)[Cl:26]>P(Cl)(Cl)(Cl)=O>[Cl:26][C:4]1[C:5]([C:14]#[N:16])=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1[nH]c(=O)c(C(N)=O)nc1-c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c(C#N)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 12 1-phenyl-1,2-propanedione and 2-aminomalonamide were heated in an aqueous solution to give 5-methyl-3-oxo-6-phenyl-3,4 -dihydro-pyrazine-2-carboxylic acid amide. Then, the 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide was treated with triethylamine and phosphorus pentachloride in phosphorus oxychloride at reflux to give the 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile. The 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was finally treated with 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) and N-ethyldiisopropylamine in N,N-dimethylformamide at room temperature to yield the 5-methyl-6-phenyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as yellow amorphous solid; MS: 341 (M+H)+.
Reaction SMILES: [N:1]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]=S.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.C(N(CC)CC)C.[NH:24]1[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:26]=[N:25]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:32]([O:31][C:29]([C:27]1[CH:28]=[N:24][N:25]([C:2](=[N:16][C:13]2[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=2)[NH:1][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:26]=1)=[O:30])[CH3:33]
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=Nc1ccc(Br)cc1)n1cc(C(=O)OCC)cn1
Reaction time: 1 h
Yield: 40.5 %

Procedure:
Ethyl isothiocyanatoformate (1.44 mL, 12.2 mmol) was added to a solution of 4-bromo-phenylamine (1.91 g, 11.1 mmol) and DCM (37 mL). After 1 h, triethylamine (4.65 mL, 33.4 mmol) was added to the reaction mixture, followed by ethyl pyrazole-4-carboxylate (1.87 g, 13.3 mmol), and EDCl (3.20 g, 16.7 mmol). After 18 h, the reaction mixture was diluted with DCM (150 mL), washed with brine (50 mL), dried (MgSO4), and concentrated. The residue was purified by FCC (5-40% EtOAc/hexanes) to yield the titled compound (1.84 g, 40% yield). MS (ESI/Cl): mass calcd. for C16H17BrN4O4, 408.1; m/z found, 409.1 [M+H]+.
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13](=[O:23])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][NH:17][S:16]1(=[O:22])=[O:21])[CH2:9]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13](=[O:23])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:16]1(=[O:22])=[O:21])[CH2:9]2
Reactant: BrCCc1ccccc1
Reactant: O=C(CN1CCCNS1(=O)=O)NC1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCCN(CCc2ccccc2)S1(=O)=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.7 %

Procedure:
To N-(adamantan-2-yl)-2-(1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamide hydrochloride (50 mg, 0.135 mmol) in DMF (1 mL), were added K2CO3 (93.3 mg, 0.675 mmol) and (2-bromoethyl)benzene (50 mg, 0.27 mmol). The reaction mixture was agitated for 4 hr at room temperature and extracted with ethyl acetate and brine. The organic layer was dried over MgSO4 and the residue was purified by silica gel column chromatography to yield N-(adamantan-2-yl)-2-(1,1-dioxido-6-phenethyl-1,2,6-thiadiazinan-2-yl)acetamide (8 mg, 13%, white solid). 1H NMR (300 MHz, DMSO-d6): δ 7.33-7.19 (m, 5H), 7.01-6.98 (brd, 1H), 4.06-4.047 (m, 1H), 3.71 (s, 2H), 3.53-3.49 (m, 2H), 3.38-3.33 (m, 4H), 2.94-2.87 (m, 2H), 1.92-1.60 (m, 14H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][C:4](=[O:16])[C:3]=1[C:17]#[N:18].Cl.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:36])=[C:32]([NH:34][NH2:35])[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[NH2:18][C:17]1[N:34]([C:32]2[CH:33]=[C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:29]=[CH:30][C:31]=2[CH3:36])[N:35]=[C:2]2[C:11]3[CH:10]=[C:9]([O:12][CH3:13])[C:8]([O:14][CH3:15])=[CH:7][C:6]=3[NH:5][C:4](=[O:16])[C:3]=12
Reactant: COc1cc2[nH]c(=O)c(C#N)c(Cl)c2cc1OC
Reactant: Cc1ccc(OCc2ccccc2)cc1NN
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2[nH]c(=O)c3c(N)n(-c4cc(OCc5ccccc5)ccc4C)nc3c2cc1OC
Temperature: 80 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (53 mg), 5-benzyloxy-2-methylphenylhydrazine hydrochloride (53 mg), triethylamine (84 μl) and ethanol (5 ml) was stirred at 80° C. for 24 hours. After cooling, 10% citric acid was added thereto, extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography to obtain the target compound (68 mg).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[C:5]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:6][C:7]([O-:9])=O.I[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>C(O)C.O>[CH2:2]([O:1][C:7]([CH:6]([CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)[C:5]([O:11][CH2:12][CH3:13])=[O:10])=[O:9])[CH3:3]
Reactant: CC[O-]
Reactant: CCOC(=O)c1ccc(OCCCI)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(OCCCC(C(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
To a solution of sodium ethoxide (90%, 6.79 g) in ethanol (250 ml) was dropwise added ethyl malonate (12.0 g) with cooling with ice. The reaction mixture was allowed to warm to room temperature and stirred for 30 min and ethyl 4-(3-iodopropoxy)benzoate (25.0 g) was dropwise added with cooling with ice. The reaction mixture was allowed to warm to room temperature and stirred for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=10:1) to yield the entitled compound (13.0 g) as an oil.
Reaction SMILES: [F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[N:11]([CH3:16])[CH:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8](=[O:22])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1F.[F:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[CH3:31].O>CS(C)=O.ClCCl>[F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[N:11]([CH3:16])[CH:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8](=[O:22])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[N:35]1[CH2:34][CH2:33][N:32]([C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([F:24])[CH:26]=2)[CH2:37][CH2:36]1
Reactant: Cc1ccc(N2CCNCC2)cc1F
Reactant: CCOC(=O)c1cn(C)c2cnc3c(F)c(F)ccc3c2c1=O
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2cnc3c(F)c(N4CCN(c5ccc(C)c(F)c5)CC4)ccc3c2c1=O
Temperature: 100 °C
Yield: 23.7 %

Procedure:
A stirred suspension of 3 g of ethyl 7,8-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 3.9 g of 1-(3-fluoro-4-methylphenyl)piperazine in 30 cm3 of dimethyl sulphoxide was heated at a temperature in the region of 100° C. for about 100 hours. The reaction mixture was treated with 150 cm3 of water in the region of 10° C. and the precipitate was taken up in 100 cm3 of dichloromethane, dried with 10 g of magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa). The yellow powder obtained was chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 80 cm), eluted at an argon pressure of 1 bar with a mixture of dichloromethane and methanol (98/2 mixture by volume), and 200 cm3 fractions were collected. Fractions 16 to 23 were combined and then concentrated to dryness under reduced pressure (2.7 kPa). The yellow solid obtained was washed with 10 cm3 of diethyl ether, filtered and dried. 1.1 g of ethyl 7-fluoro-8-[4-(3-fluoro-4-methylphenyl)piperazin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of a yellow solid, which melted at a temperature in the region of 290° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:15]([CH3:17])[CH3:16])[C:7]=1[OH:18])[CH3:5].I[CH2:20][CH2:21][CH3:22].[F-].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH:15]([C:8]1[C:7]([O:18][CH2:20][CH2:21][CH3:22])=[C:6]([C:4]([CH3:5])=[CH:3][CH2:2][OH:1])[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=1)([CH3:17])[CH3:16]
Reactant: CCCI
Reactant: CC(=CCO)c1cc(C(C)C)cc(C(C)C)c1O
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1c(C(C)=CCO)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
To a solution of 2-(3-hydroxy-1-methyl-propenyl)-4,6-diisopropyl-phenol (Intermediate 12, 1.82 g, 7.3 mmol) and 1-iodopropane (0.79 mL, 8.1 mmol) in DMF (20 mL) at room temperature was added CsF (3.9 g, 25.6 mmol). The reaction was stirred at room temperature for 1.5 h, diluted with EtOAc, washed successively with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% EtOAc-hexanes) to yield the title compound as an off-white solid (2.06 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([OH:18])[C@H:14]2[C:19](O)=[O:20])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1CCC(N=C=NC2CCCCC2)CC1.C1C([N+]([O-])=O)=CC=C(O)C=1>C(#N)C>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:10]2[C:19](=[O:20])[C@@H:14]3[C@@H:15]([OH:18])[CH2:16][CH2:17][N:13]3[C:11]2=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(NC(=O)N2CC[C@H](O)[C@H]2C(=O)O)ccc(C#N)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC#N
Product: Cc1c(N2C(=O)[C@@H]3[C@@H](O)CCN3C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 61 %

Procedure:
To a suspension of acid 54B (210 mg, 0.649 mmol) in 15 mL of acetonitrile at rt was added DCC (134 mg, 0.649 mmol) followed by p-nitrophenol (180 mg, 1.30 mmol). The suspension was refluxed for 1 h, cooled to rt and filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes, 75:25) to afford the title compound (121 mg) as a white foam. 1H NMR (CD3OD) 1.94-2.05 (m, 1H), 2.18, 2.22 (s, 3H), 2.24-2.33 (m, 1H), 3.34-3.40 (m, 1H), 3.67-3.75 (m, 1H), 4.08, 4.16 (d, J=6.05, 1H), 4.35, 4.42 (m, 1H), 7.33, 7.38 (d, J=8.25, 1H), 7.70 (m, 1H); 13C NMR (CD3OD) 15.90, 16.11, 36.95, 37.05, 44.88, 45.06, 70.91, 70.94, 72.46, 72.90, 115.19, 115.53, 116.60, 116.66, 129.30, 129.46, 132.74, 133.03, 137.41, 137.61, 138.08, 138.37, 138.42, 138.53, 159.69, 159.97, 172.10, 172.43; HPLC a) column: Phenominex LUNA C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.32 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.15 min retention time (100%); HPLC c) column: Daicel Chiralcel OD 4.6×250 mm, Isocratic 25% Isopropanol/Hexanes, 30 min, 1 mL/min, UV detection at 220 nm, 17.65 min retention time (99%); MS (ES) m/z 306 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:14]1=2)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN>CO.[Ni]>[NH2:23][C:20]1[CH:21]=[CH:22][C:14]2[N:13]([CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:18][CH2:17][S:16][C:15]=2[CH:19]=1
Reactant: CN(CCCN1CCSc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN(CCCN1CCSc2cc(N)ccc21)C(=O)OC(C)(C)C
Yield: 99.8 %

Procedure:
A suspension of tert-butyl methyl(3-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)propyl)carbamate (0.6 g, 1.633 mmol) in dry methanol (10 mL) was treated with Raney-Nickel (0.1 g, 1.633 mmol) followed by hydrazine hydrate (0.595 mL, 16.33 mmol) at room temperature. The resulting mixture was refluxed for 10 minutes in a pre-heated oil bath. The reaction was then brought to room temperature, filtered through a pad of Celite, and washed with methanol (3×10 mL). The combined methanol layers were evaporated, and the crude material was purified by flash column chromatography (5:95 (2M NH3 in MeOH):CH2Cl2) on silica gel to obtain title product (0.55 g, quantitative) as a brown syrup. 1H NMR (DMSO-d6) δ 6.46 (d, 1H, J=9.6 Hz), 6.25-6.21 (m, 2H), 4.44 (s, 2H), 3.32-3.28 (m, 2H), 3.19 (t, 2H, J=6.9 Hz), 3.04 (t, 2H, J=7.2 Hz), 3.00-2.97 (m, 2H), 2.77 (s, 3H), 1.74-1.62 (m, 2H), 1.38 (s, 9H); ESI-MS (m/z, %): 338 (MH+, 100), 337 (96), 282 (54).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:11]([OH:13])=O)=[CH:4][C:3]=1[Cl:14].[NH2:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1>C1COCC1>[ClH:14].[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:11]([NH:15][CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[O:13])=[CH:4][C:3]=1[Cl:14]
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCO2
Reactant: NC[C@@H]1CCCN1
Solvent: C1CCOC1
Product: Cl
Product: Nc1c(Cl)cc(C(=O)NC[C@@H]2CCCN2)c2c1CCO2
Temperature: -30 °C
Reaction time: 6 h
Yield: 145.6 %

Procedure:
To a suspension of 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (71.1 g, 0.33 mol) in 1400 ml of anhydrous THF was added N,N'-carbonyldiimidazole (54 g, 0.33 mol) at room temperature under argon. After 6 hours, an additional 0.02 equivalent (1.08 g) of N,N'-carbonyldiimidazole was added, and the mixture stirred overnight. The TLC analysis showed the disappearance of the starting material. The temperature was lowered to -30° C. with CCl4 /dry ice bath and (S)-2-aminomethylpyrrolidine (35 g, 0.35 mol, 1.06 equivalent) in 50 ml of THF was added dropwise over a period of 1 hour while the temperature was maintained at -30° C. After stirring at -20° C. to -30° C. for another 2 hours, the reaction was completed. The solvent in the reaction mixture was evaporated and the remaining dark brown oil was diluted with 1000 ml of methylene chloride. The organic solution was washed with 1N NaOH (350 ml, 150 ml), brine (150 ml), and filtered through a pad of anhydrous MgSO4. To the organic filtrate was added 24 g of HCl (gas) in 100 ml of 2-propanol with stirring and then sonicated overnight. The resulting precipitates were collected on a filter, washed with methylene chloride to give 79.8 g of the hydrochloride of the target compound (72.8% yield) as a white solid. A total of 140 g of the hydrochloride was recrystallized by first dissolving in 300 ml of H2O and then adding 900 ml of 2-propanol to yield 102 g of pure product after drying at 60-70° C. (water bath) under pump vacuum overnight, mp 232.5-233.5° C. (dec);[β]D20 =+9.6° (C=1.0; MeOH).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH:7]=O)([O:3][CH3:4])=[O:2].[Na].[PH2:10]([O-:12])=[O:11].[CH:13]([NH3+:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:13]([NH:26][CH:7]([P:10]([OH:12])[OH:11])[CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[PH2][O-]
Reactant: [NH3+]C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCC=O
Agent: [Na]
Product: COC(=O)CCC(NC(c1ccccc1)c1ccccc1)P(O)O

Procedure:
5.8 parts of freshly distilled 3-carbomethoxypropionaldehyde in 10 parts of sodium-dried dioxan was added to a suspension of 12.4 parts benzhydrylammonium hypophosphite in 60 parts of sodium-dried dioxan at 100° and under nitrogen over 15 minutes. 40 Parts water/dioxan was removed by distillation during the addition such that the temperature remained at 100° or above. The resulting clear solution was cooled and diluted with an equal volume of alcohol to give DL-1-benzhydrylamino-3-carbomethoxypropanephosphonous acid, melting point 162°-164°.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26]C(=O)[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=O)C.C(N(CC)CC)C.O>CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:28][CH2:29][C@H:30]2[C:25](=[CH:24][CH2:23][C@@H:22]3[C@@H:31]2[CH2:32][CH2:33][C@@:18]2([CH2:19][CH3:20])[C@H:21]3[CH:15]=[CH:16][C:17]2=[O:35])[CH:26]=1)[CH3:10]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Triethyl orthoformate (15 ml, 90.3 mmol) and p-Toluenesulfonic acid (250 mg, 1.31 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (25 g, 72.7 mmol) in EtOH (150 ml). The mixture was stirred at room temperature for 1 h. Triethylamine (25 ml, 179.4 mmol) was added. The mixture was heated under reflux for 2 h, cooled to 5° C. and water (75 ml) was then added. The precipitate was filtered, washed with a 1/1 EtOH/water solution and dried under vacuum to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (20 g, yield: 88%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:13]2[C:16]3[C:6]=1[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]=2[C:17](=[O:20])[CH2:18]Cl)=[O:4].[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].[I-].[K+]>O1CCCC1>[ClH:1].[ClH:1].[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:13]2[C:16]3[C:6]=1[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]=2[C:17](=[O:20])[CH2:18][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:4])[CH3:22]
Reactant: CCNCC
Reactant: O=C(CCl)c1ccc2c(C(=O)CCl)ccc3c2c1CC3
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)c1ccc2c(C(=O)CN(CC)CC)ccc3c2c1CC3
Product: Cl
Reaction time: 192 h

Procedure:
A mixture of 30.7 g (0.1 mole) of 3,6-bis(2-chloroacetyl)acenaphthene, 100 ml of diethylamine and 2 g of potassium iodide is dissolved in 500 ml of tetrahydrofuran and allowed to stand in a stoppered flask for 8 days. The resulting amine salt which forms is filtered, washed with tetrahydrofuran and the combined filtrates reduced to dryness in vacuo. The residue is dissolved in methylene chloride, treated with charcoal and acidified using ethereal hydrochloric acid. The resulting solid which forms is filtered, recrystallized from a methanol-ether solution and further recrystallized from a methanol-ethyl acetate solution to yeild a product, hygroscopic in nature, which indicated by its analysis to be a tetrahydrate having a m.p. 220.5°-222° C. (dec), λmax(EtOH) 283.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][N:27]([C:30](=[O:32])[CH3:31])[CH2:28][CH3:29])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].C(Cl)Cl.Cl>C1COCC1.CCO>[C:30]([N:27]([CH2:26][C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:25])[F:24])[CH:20]=[CH:21][C:16]=1[C:10]1[C:11]([O:14][CH3:15])=[CH:12][CH:13]=[C:8]([C:5]([CH3:6])([CH3:7])[C:4]([OH:33])=[O:3])[CH:9]=1)[CH2:28][CH3:29])(=[O:32])[CH3:31]
Reactant: CCOC(=O)C(C)(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)(C)C(=O)O)ccc1OC)C(C)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 2-{2′-[(acetyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-2-methyl-propionic acid ethyl ester (0.290 g, 0.63 mmol) in THF (2.6 mL) and EtOH (2 mL) was added 1N aqueous NaOH (1.9 mL), and the reaction was stirred at 50° C. overnight. Analytical LCMS indicated that starting material was still present, so additional 1N aqueous NaOH (1 mL) was added, and the reaction was stirred at 70° C. for 2 hours. Additional 1N aqueous NaOH (1 mL) was added, and the reaction was stirred for another 6 hours. The mixture was worked-up with CH2Cl2 and 1N aqueous HCl, and the organic layer was dried over Na2SO4, decanted, and concentrated. The residue was purified by preparative HPLC to give the title compound. M+H is 438.
Reaction SMILES: [NH:1]1[C:10]2[N:9]=[C:8]3[CH2:11][CH:12]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:14][C:7]3=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH2:20]([O:22][C:23](=[O:36])[CH2:24][C@H:25]([NH2:35])[C:26]1[CH:34]=[CH:33][C:29]2[CH2:30][CH2:31][O:32][C:28]=2[CH:27]=1)[CH3:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:36])[CH2:24][C@@H:25]([C:26]1[CH:34]=[CH:33][C:29]2[CH2:30][CH2:31][O:32][C:28]=2[CH:27]=1)[NH:35][C:17](=[O:19])[CH2:16][CH2:15][CH:12]1[CH2:11][C:8]2=[N:9][C:10]3[NH:1][CH2:2][CH2:3][CH2:4][C:5]=3[CH:6]=[C:7]2[CH2:14][CH2:13]1)[CH3:21]
Reactant: CCOC(=O)C[C@H](N)c1ccc2c(c1)OCC2
Reactant: O=C(O)CCC1CCc2cc3c(nc2C1)NCCC3
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](NC(=O)CCC1CCc2cc3c(nc2C1)NCCC3)c1ccc2c(c1)OCC2

Procedure:
A solution of 14-4 (0.110 g, 0.39 mmol), β-aminoester 6—6 (0.106 g 0.39 mmol), EDC (0.075 g, 0.39 mmol), HOBT (0.053 g, 0.39 mmol) and N-methylmorpholine (0.164 mL, 1.17 mmol) in degassed DMF (5 mL) was stirred at room temperature for 12 h. The solution was concentrated. The residue was purified by flash chromatography to give 14-5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:16]2[CH2:15][C@H:14]([CH3:13])[O:19][C@H:18]([CH3:20])[CH2:17]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2C[C@@H](C)O[C@@H](C)C2)cc1
Yield: 11.8 %

Procedure:
A solution of 4-fluorobenzoic acid ethyl ester (3 g), cis-2,6-dimethylmorpholine (2.26 g) and potassium carbonate (2.47 g) in dimethylsulfoxide (60 ml) was stirred for 18 hours at 80° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (5:1 hexane-ethyl acetate elution) to give 4-(cis-2,6-dimethylmorpholin-4-yl)benzoic acid ethyl ester (555 mg).