Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].C([NH2:18])=O.C(O)=O.Cl>C(NC(C1(C2C=CC(Cl)=C(Cl)C=2)CCC1)C)=O>[Cl:15][C:10]1[CH:9]=[C:8]([C:4]2([CH:1]([NH2:18])[CH3:2])[CH2:7][CH2:6][CH2:5]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: NC=O
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: CC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Solvent: O=CO
Product: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 180 °C

Procedure:
The 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane (9,1 g) prepared above, formamide (6.5 ml) and 98% formic acid (3 ml) were heated at 180° C. for 16 hours to result in N-formyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine. Concentrated hydrochloric acid (20 ml) was added, and the mixture was refluxed for 3 hours. The solution was then cooled and washed with ether, and sodium hydroxide solution was added. The product was extracted with ether, and the ether extract was washed with water, dried and evaporated. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine was isolated by distillation (boiling point: 112 to 118° C. under 0.27 mbar). The amine was dissolved in 2-propanol and concentrated hydrochloric acid, and the solution was evaporated to dryness to result in 1-[1-(3,4-dichlorophenyl)cyclobutyl]-ethylamine.hydrochloride (melting point: 185 to 195° C.). (Formula III: n=0; R1 =methyl; R2, R3 and R4 =H; R5 =4-Cl; R6 =3-Cl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN1CCN([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)CC1.[CH3:31][N:32](C)C=O>>[NH2:30][C:27]1[CH:28]=[C:29]([CH:24]=[CH:25][CH:26]=1)[CH2:31][NH:32]/[CH:14]=[C:5]1\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]2[C:4]\1=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: CN(C)C=O
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: Nc1cccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 33 %

Procedure:
A mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (141 mg, 0.5 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (61.1 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is stirred at room temperature for 40 min. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 61 mg (33%) of yellow solid mp 214-215° C.; HRMS (ESI) m/z calcd for C17H14BrN3O2 370.01966. found 370.01900 (M+H)−1, Analysis for C17H14BrN3O2 (0.33H2O); Calcd: C, 53.98; H, 3.91; N, 11.11. Found: C, 54.07; H, 3.52; N, 10.91.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:2][C:1]1[C:3]2[C:4](=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[NH:5][N:13]=1
Reactant: O=N[O-]
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
Following generally the procedure reported by Organic Synthesis 1955, Coll. Vol. 3, 660; 1940, 20, 73, 2-ethyl-5-nitroaniline (1.021 g, 6.14 mmol) was dissolved in glacial acetic acid (40 ml) and the mixture was cooled to 0° C. A solution of sodium nitrite (1 eq, 424 mg) in water (1 ml) was added all at once. Stirring was continued for 15 minutes at 25° C. After 3 hours, residual solids were filtered off and discarded, and the filtrate was allowed to stand for 3 days at room temperature. The solution was concentrate in vacuo, and the residue was diluted with 2 ml of water and stirred vigorously. The solid product was filtered and washed thoroughly with cold water, dried and purified by flash chromatography (4:1 hexanes/ethyl acetate) to give 3-methyl-6-nitro-1H-indazole (436 mg, 40.5%) as a solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]([C:14]([O:16]CC)=O)=[N:4]1)[CH3:2].[OH-].[NH4+:20]>>[CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]([C:14]([NH2:20])=[O:16])=[N:4]1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(CCS(C)(=O)=O)n(CC)n1
Agent: [OH-]
Product: CCn1nc(C(N)=O)cc1CCS(C)(=O)=O

Procedure:
The method described in Part C of Example 10 was used to treat ethyl 1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carboxylate (4.6 g, 17 mmol) with ammonium hydroxide (100 mL). The solid was isolated by filtration and washed with water to provide 3.0 g of 1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carboxamide as a white powder, which was mixed with material from another run.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2N=N1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1(N)CCCCC1>ClCCl>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH:13][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:16]2)=[O:6])=[C:2]([CH3:1])[N:10]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1nc(Cl)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: NC1CCCCC1
Solvent: ClCCl
Product: Cc1nc(Cl)ccc1C(=O)NC1CCCCC1
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
A solution of 2-methyl-6-chloronicotinic acid (300 mg, 1.75 mmol) and 1-hydroxybenzotriazole (260 mg, 1.92 mmol) was stirred in dichloromethane (25 ml) then triethylamine (561 ul, 4.02 mmol) and EDAC (401 mg, 2.1 mmol) were added and stirred for 5 minutes then cyclohexylamine (201 ul, 1.75 mmol) was added and the reaction was stirred for a further 16 hours at room temperature. The reaction was diluted with dichloromethane (25 ml), washed with sat. NaHCO3, 1M HCl, water, brine and dried over MgSO4, filtered and the solvent evaporated to give 6-chloro-2-methyl-N-cyclohexylnicotinamide (340 mg, 77%) as a fawn coloured powder
Reaction SMILES: [OH-].[K+].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]=[O:14])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[N+:15]([CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])#[C-:16]>CO>[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([C@@H:13]3[O:14][CH:16]=[N:15][C@H:17]3[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccc2c(c1)OCCO2)N1CCCC1
Yield: 68.2 %

Procedure:
To a stirred and cooled (0° C.) solution of potassium hydroxide (2.70 g, 48.1 mmol) in methanol (30 ml) was added a mixture of 1,4-benzodioxan-6-carboxaldehyde (8.20 g, 50.0 mmol) and the product from Example 1 (6.30 g, 45.6 mmol). The solution was stirred overnight with continued cooling and then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was combined with additional ethyl acetate extracts, washed with aqueous sodium chloride and dried (magnesium sulfate). Concentration afforded crude product as a golden, glassy solid. Flash chromatography over silica (ethyl acetate) yielded 9.40 g (68%) of product as a colorless glassy solid. 1H NMR (CDCl3) δ 6.99 (s, 1H), 6.90–6.78 (m, 3H), 6.00 (d, J=7.3, 1H), 4.58, (d, J=7.3, 1H), 4.26 (s, 4H), 3.95–3.87 (m, 1H), 3.55–3.41 (m, 3H), 2.04–1.80 (m, 4H) ppm.
Reaction SMILES: O=[C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[C:24]2=O.[OH-:32].[K+]>C(O)C.O>[C:8]([O:7][C:6]([NH:5][CH:3]([C:2]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:24]([C:25]([OH:30])=[O:32])[C:23]2[C:27](=[CH:28][CH:29]=[C:21]([F:20])[CH:22]=2)[N:26]=1)[CH3:4])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccn1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2c(C(=O)O)c1-c1ccccn1
Temperature: 82 °C

Procedure:
(S)-tert-Butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (910 g, 3.44 mol, 1.0 equiv) and 5-fluoroisatin (597 g, 3.62 mol, 1.05 equiv) were dissolved in ethanol/H2O (1:1, 6.0 L each). To this solution was added KOH pellets (609 g, 10.84 mol, 3.15 equiv). The reaction mixture was then heated at 82° C. (internal temperature) overnight. The reaction was monitored using LCMS. Upon completion, the reaction mixture was cooled and evaporated in vacuo to remove ethanol. The aq layer was then washed with DCM (3×4.0 L) and acidified using concd HCl to pH 4. (The acidification procedure was carried out in the following way: The aq layer was taken in a wide mouth flask assembled with mechanical stirrer and pH meter and the flask was cooled using ice-water bath. To this cooled solution was slowly added conc. HCl. To suppress the heat and fumes, small portions of crushed ice was periodically added inside the solution. A yellow solid precipitated out during the addition of conc. HCl). The resultant yellow solid was filtered immediately, thoroughly washed with water (3×1.0 L), triturated with methanol (3×1.0 L), (Note: the product solubility in methanol is very low) then with hexanes (2.0 L), and dried under high vacuum at 60° C. to obtain 2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxylic acid as a creamy white solid: 1H NMR (300 MHz, DMSO-d6): δ 1.10 (s, 2H), 1.21 (d, J=6.3 Hz, 3H), 1.30 (s, 7H), 4.82-4.89 (m, 1H), 7.10 (d, J=7.5 Hz, 1H), 7.45-7.49 (m, 1H), 7.56-7.61 (m, 2H), 7.76-7.83 (td, J=3.0 Hz, 1H), 7.93-7.99 (td, J=2.0 Hz, 1H), 8.16-8.21 (m, 1H), 8.71 (d, J=4.8 Hz, 1H); LC-MS (ESI) m/z 412.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:6][C:5]([CH3:24])=[CH:4][N:3]=1.C1N2CCN(CC2)C1.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:2]3=[N:3][CH:4]=[C:5]([CH3:24])[CH:6]=[C:7]3[NH:8][C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][CH:13]=1
Reactant: Cc1cnc(Cl)c(N=C(Cc2ccc(F)cc2)c2ccncc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(-c3ccc(F)cc3)c(-c3ccncc3)[nH]c2c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
6.15 g (18.1 mmoles) of (2-Chloro-5-methyl-pyridin-3-yl)-[2-(4-fluoro-phenyl)-1-pyridin-4-yl-ethylidene]-amine are dissolved in 100 mL of dimethylformamide under nitrogen. 6.4 g of DABCO (56 mmoles) and 610 mg of bis(triphenylphosphine)palladium dichloride are subsequently added to the reaction mixture which is stirred for 5 hours at 120° C. The cooled reaction mixture is then poured into water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is recrystallized into ethyl acetate to afford 5.3 g of 3-(4-Fluoro-phenyl)-6-methyl-2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine as a yellowish solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N=C=N.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: N=C=N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(OCc2ccccc2)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 4-benzyloxybenzoic acid (116 mg, 0.51 mmol) and PS-carbodiimide (500 mg, 0.66 mmol, 1.32 mmol/g) in 5% DMF in CH2Cl2 (5 mL) is added (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (80 mg, 0.51 mmol). The mixture is stirred at room temperature for 3 days. The reaction mixture is filtered, and the resin is washed with CH2Cl2. The filtrate is concentrated and applied to silica-gel column chromatography (in CH2Cl2 followed by 5% 2M NH3 in MeOH/CH2Cl2) to give the product. 62.7 mg (34%): Observed mass: 365 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:11]=[C:10]([CH3:12])[NH:9][N:8]=2)=[CH:4][CH:3]=1.[I:13]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([I:13])=[C:10]([CH3:12])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(-c2ccc(Cl)s2)n[nH]1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]nc(-c2ccc(Cl)s2)c1I
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
3-(5-Chloro-2-thienyl)-5-methyl-1H-pyrazole (40.3 mmol) was dissolved in 70 mL dry N,N-dimethylformamide and cooled to 0° C. under nitrogen atmosphere. N-Iodosuccinimide (42.7 mmol) was added in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solution was poured into a mixture of saturated aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution (1:1) at room temperature. The precipitate was filtered, washed thoroughly with water, dissolved in ethyl acetate, dried over MgSO4, filtered and evaporated to afford 9.9 g of 3-(5-chloro-2-thienyl)-4-iodo-5-methyl-1H-pyrazole (76% yield) that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[O:10])=[C:4]([CH:11]=[O:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[O:10])=[C:4]([CH:11]=[O:12])[CH:3]=1
Reactant: O=CNc1ccc(Br)cc1C=O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C=O)c1ccc(Br)cc1C=O
Temperature: 70 °C
Reaction time: 24 h
Yield: 79.5 %

Procedure:
To 4-bromo-2-formylphenylformamide (18.07 g), ethyl 4-bromobutyrate (30.9 g) and potassium carbonate (21.9 g) was added DMF (160 ml), and the mixture was stirred at 70° C. for 24 hours. The mixture was dilute with ethyl acetate (1400 ml), washed with water (300 ml×3) and saturated brine (150 ml), and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (300 g, hexane:ethyl acetate=4:1→1:1) to give ethyl 4-(4-bromo-2, N-diformylanilino)butyrate (21.56 g, 80%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:13][CH2:12]4)[C@H:9]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].C1C=C[NH+]=CC=1.[Br:42][Br-]Br.[S-2].[Na+].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:26][CH2:25][CH2:24][O:23]3)[C@H:13]([Br:42])[CH2:12]4)[C@H:9]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](CCC34OCCO4)[C@H]12
Agent: [Na+]
Agent: [S-2]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](C[C@@H](Br)C34OCCO4)[C@H]12
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A solution of 63.2 g of 3-acetoxy-7α-(5-acetoxypentyl)-17,17-ethylenedioxy-estra-1,3,5(10)-triene in 630 ml of tetrahydrofuran is mixed in portions at 0° C. with 61.7 g of pyridine hydrobromide perbromide, and it is stirred for 2 hours at 0° C. Then, a solution of 15 g of sodium sulfide in 70 ml of water is added, diluted with ethyl acetate, washed with sodium bicarbonate and common salt solution and dried on sodium sulfate and concentrated by evaporation in a vacuum. 74.1 g of 3-acetoxy-7α-(5-acetoxypentyl)-16α-bromo-17,17-ethylenedioxy-estra-1,3,5(10)-triene is obtained as oil.
Reaction SMILES: C(=O)(O)[O-].[Na+].O.F[C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[NH2:11].[C:21](Cl)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CC(C)=O>[C:21]([NH:11][C:10]1[CH:12]=[CH:13][C:14]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:8][CH:9]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(N2CCOCC2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Sodium bicarbonate (17 g, 202 mmol) and 150 mL water were added to a solution of 3-fluoro-4-morpholinyl aniline (26 g, 133 mmol) of acetone (200 mL). The reaction mixture was cooled to −10˜0° C. Carbobenzoxy chloride (26 g. 152 mmol) was added dropwise within 1 hour. The mixture raised to room temperature (25° C.) naturally, and stirred at this temperature for 2 hours. Then the material liquid was poured into 500 mL ice water, filtered, and dried to provide 39 g of off-white solid in 90% yield.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1.N>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:14][CH:13]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 4-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.39 (t, J=8.9 Hz, 2H), 7.64 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 8.27-8.35 (m, 2H), 8.55 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.74 (dd, J=5.0, 1.8 Hz, 1H), 9.29 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:21]=[C:22]4[C:27]=3[N:26]=[CH:25][CH:24]=[CH:23]4)[CH:13]=2)=[CH:6][CH:5]=1.[Li+].[OH-].Cl>C1COCC1.CO>[CH:28]([C:20]1[CH:21]=[C:22]2[C:27](=[C:18]([C:14]3[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=3)[O:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=3)[CH:19]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)([CH3:30])[CH3:29]
Reactant: COC(=O)c1ccc(COc2cccc(-c3cc(C(C)C)cc4cccnc34)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc(-c2cccc(OCc3ccc(C(=O)O)cc3)c2)c2ncccc2c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of the ester of EXAMPLE 9 (1.0 eq) in THF/MeOH (2/1; 0.1M) was added of aqueous solution of LiOH (1N; 5.0 eq). The resulting mixture was stirred 1 hour at 70° C., acidified to pH 5 using HCl (1N) and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1 to 1:9 in 15 min) afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].Cl>C(=O)([O-])O.[Na+]>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:15])[CH3:14]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
After 4.96 g of L-phenylalanine was dissolved in 5% sodium hydrogencarbonate aqueous solution, 3.4 ml of acetic anhydride was dropwise added to the solution over an hour under ice cooling. After completion of the dropwise addition, the mixture was stirred for 2 hours at room temperature. Then 17 ml of hydrochloric acid was added to the reaction mixture to render the system acidic. The precipitated white solid was extracted once with 100 ml of ethyl acetate and twice with 40 ml each of the same solvent. The oily layer was dried over anhydrous sodium sulfate and the solvent was distilled off to give 5.61 g of N-acetyl-L-phenylalanine as white crystalline powders. Yield, 90.3%.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]3)[CH2:13][CH2:14]2)[CH3:26])=[CH:21][CH:20]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(F)cc1
Yield: 74 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-fluoro-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 74% of theory; Mass spectrum (ESI+): m/z=366 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([CH2:36][O:37][CH3:38])[CH2:33][C@H:32]1[C:39]([OH:41])=[O:40])=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH3:38][O:37][CH2:36][C@@H:34]1[CH2:35][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:30])[C@H:32]([C:39]([O:41][CH2:2][C:3](=[O:4])[C:5]2[CH:6]=[CH:7][C:8]3[C:17]4[CH:16]=[C:15]5[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]5=[CH:13][C:12]=4[O:11][CH2:10][C:9]=3[CH:23]=2)=[O:40])[CH2:33]1
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
3-(2-Bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (7.47 g, 20.1 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (5.22 g, 20.1 mmol) were suspended in 2-Me-THF (75 mL) and treated with Cs2CO3 (3.27 g, 10.1 mmol). After stirring 4 h at RT, the reaction mixture was diluted with DCM. The organic layer was washed with H2O. The aqueous layer was then back extracted 2× with DCM. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 50% EtOAc/DCM) to afford (2S,4S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.73 g, 70%).