Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[Cl:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[CH:20]=[C:19]([C:30]2([S:36]([CH3:38])=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:18]=1.[O-2].[Mg+2].[F:41][C:42]([F:47])([F:46])[C:43]([NH2:45])=[O:44]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Cl:16][C:17]1[N:18]=[C:19]([C:30]2([S:36]([CH3:38])(=[O:37])=[N:45][C:43](=[O:44])[C:42]([F:47])([F:46])[F:41])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[CH:20]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[N:22]=1
Reactant: NC(=O)C(F)(F)F
Reactant: C[C@@H]1COCCN1c1cc(C2(S(C)=O)CCOCC2)nc(Cl)n1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@@H]1COCCN1c1cc(C2(S(C)(=O)=NC(=O)C(F)(F)F)CCOCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
Sodium hydroxide (50% w/w) (20.04 ml, 379.60 mmol) was added to (3R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (2.2 g, 7.59 mmol), 1-bromo-2-(2-bromoethoxy)ethane (3.79 ml, 30.37 mmol) and tetraoctylammonium bromide (0.415 g, 0.76 mmol) in methyl THF (20.05 ml). The resulting mixture was stirred at RT for 90 minutes. The reaction mixture was diluted with methyl THF (50 mL), and washed sequentially with water (50 ml) and saturated brine (5 ml). The organic layer was dried over MgSO4, filtered and then evaporated onto silica (30 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to afford (3R)-4-(2-chloro-6-(4-(methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine (1.360 g, 50%); 1H NMR (400 MHz, DMSO-d6) 1.84-1.96 (1H, m), 2.02 (1H, td), 2.09 (3H, d), 2.27-2.45 (2H, m), 3.14 (1H, d), 3.10-3.26 (3H, m), 3.24 (1H, d), 3.33-3.41 (1H, m), 3.45 (1H, td), 3.60 (1H, dd), 3.71 (1H, d), 3.78-3.87 (1H, m), 3.87-3.97 (2H, m), 4.07 (1H, d), 4.32-4.48 (1H, m), 6.76 (1H, s); m/z: (ES+) MH+, 360.11 and 362.06. b) Iodobenzene diacetate (0.788 g, 2.45 mmol) was added to (3R)-4-(2-chloro-6-(4-(methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine (0.88 g, 2.45 mmol), magnesium oxide (0.394 g, 9.78 mmol), 2,2,2-trifluoroacetamide (0.553 g, 4.89 mmol) and rhodium(II) acetate dimer (0.027 g, 0.06 mmol) in DCM (20 ml). The resulting suspension was stirred at RT for 18 hours. The reaction mixture was filtered through Celite and then concentrated in vacuo onto silica (50 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 20 to 60% EtOAc in isohexane. Pure fractions were evaporated to afford N-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (1.018 g, 88%); 1H NMR (400 MHz, DMSO-d6) 1.34 (3H, dd), 2.49 (1H, td), 2.63 (2H, ddd), 2.75-2.82 (1H, m), 3.26 (3H, d), 3.29-3.41 (3H, m), 3.49 (1H, s), 3.51-3.60 (1H, m), 3.63-3.73 (1H, m), 3.80 (1H, d), 3.98-4.11 (4H, m), 6.68 (1H, d); m/z: (ES−) M-H−, 469.04 and 471.03.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([N:11]2C=[CH:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1.[N:16]1NN=CC=1>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([N:11]2[N:12]=[CH:13][CH:14]=[N:16]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)O)n1
Reactant: c1cn[nH]n1
Product: Cc1ccc(-n2nccn2)c(C(=O)O)n1

Procedure:
The title compound was prepared following the same general protocol as described for 6-methyl-3-(1H-pyrazol-1-yl)picolinic acid in Example A164, using 2H-1,2,3-triazole. ESI-MS (m/z): 205 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:13]=1[C:14]#[N:15]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:13]=2[C:14]#[N:15])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1cc(N)c(C#N)cc1OC
Product: COc1cc(C#N)c(NC(=O)c2ccc(Cl)nc2)cc1OC

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2-amino-4,5-dimethoxybenzonitrile as a white solid as described in Example 1. 1H NMR (CDCl3): 8.97 (d, J=2.7, 1H), 8.18-8.15 (m, 3H), 7.52 (d, J=8.4, 1H), 7.02 (s, 1H), 4.01 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:12][CH:13]=[CH:14][CH:15]([CH3:22])[CH2:16][CH:17]=[CH:18][CH:19]([CH3:21])[CH3:20])[CH2:3][O:4]CC1C=CC=CC=1.[H][H]>C(OCC)(=O)C>[CH3:1][CH:2]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:3][OH:4]
Reactant: [H][H]
Reactant: CC(C)C=CCC(C)C=CCC(C)COCc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)CCCC(C)CCCC(C)CO
Reaction time: 5 h
Yield: 85.8 %

Procedure:
A mixture of 0.15 g (0.5 mmole) of rac. benzyl 2,6,10-trimethylundeca-4,8-dien-1yl ether, 0.1 g of 5% by weight palladiumon 95% by weight carbon and 10 ml. of ethyl acetate was stirred in an atmosphere of hydrogen for 16 hours at room temperature. The catalyst was filtered and the filtrate was concentrated in vacuo. The oily residue was dissolved in 10 ml. of ethyl acetate and rehydrogenated over 0.1 g of 5% palladium on carbon, for 5 hours at room temperature. The catalyst was again filtered and the filtrate was concentrated in vacuo. The residue wasevaporatively distilled giving 0.092 g (86%) of rac. 2,6,10-trimethylundecan-1-ol as a colorless oil, b.p. 100°-105° C. (bath temperature) (0.02 mm Hg.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:35][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=1
Reactant: OCCCc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(CCCBr)cc1C(F)(F)F
Yield: 73.1 %

Procedure:
Compound 69-2 (3.05 g) was dissolved in methylene chloride (46 ml), triphenylphosphine (4.00 g) and N-bromosuccinimide (2.69 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.86 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Nc1cc(F)ccc1Cl
Agent: Br
Product: CC(Nc1cc(F)ccc1Cl)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 47.5 %

Procedure:
2-chloro-5-fluoroaniline (119 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(2-chloro-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (45 mg, 47%) as a white solid. Mass Spectrum: M+H+ 474. NMR Spectrum (DMSOd6): 1.62 (d, 3H), 2.74 (bs, 3H), 2.94 (bs, 3H), 3.51-3.65 (m, 4H), 3.69-3.79 (m, 4H), 5.06-5.16 (m, 1H), 5.61 (s, 1H), 5.99 (d, 1H), 6.27 (dd, 1H), 6.40 (ddd, 1H), 7.30 (dd, 1H), 7.59 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[O:21][N:20]=1>>[F:16][CH:2]([F:1])[C:3]1[N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[O:21][N:20]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1C#N
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C#N

Procedure:
Synthesized as described in Example 23 from 2-(difluoromethyl)-1H-indole-4,5-dicarbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: MS (ES) m/z 444 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccccc1
Yield: 73.3 %

Procedure:
In a 250 mL round bottom flask was dissolved 10.0 g (55 mmol) of trans-4-hydroxyproline methyl ester hydrochloride 14 (Bachem) in 100 mL anhydrous pyridine at 0° C. with stirring to give a cloudy white mixture. To this was added 7.9 mL (62 mmol, 1.1 equiv.) of benzenesulfonyl chloride in four portions over 15 minutes to give a bright yellow mixture. This reaction mixture was stirred under a CaCl2 drying tube at 4° C. (cold room) overnight, then concentrated in vacuo, and the residue dissolved in ethyl acetate (˜200 mL.) The solution was washed with 1 N HCl (three times), with H2O, 1 N NaOH (three times), then brine, and the organic solution was dried (MgSO4), filtered, and concentrated to give a yellow oil. This was dissolved in ethyl acetate, loaded onto silica, and eluted with 3:2 ethyl acetate/hexanes to give 11.5 g (40.3 mmol, 73%) of compound 15 as a white crystalline solid. 1H-NMR (400 MHz, CDCl3, δ ppm) 7.85 (dt, J=2 Hz, 7 Hz, 2H), 7.57 (tt, J=1 Hz, 8 Hz, 1H), 7.49 (td, J=2 Hz, 7 Hz, 2H), 4.41 (br s, 1H), 4.37 (t, J=8 Hz, 1H), 3.70 (s, 3H), 3.57 (dd, J=4 Hz, 11 Hz, 1H), 3.37 (dt, J=2 Hz, 11 Hz, 1H), 2.17 (m, 2H), 2.06 (m, 1H); 13C-NMR (400 MHz, CDCl3, δ ppm) 173.01, 138.05, 133.43, 129.42, 128.05, 70.37, 59.85, 56.83, 52.99, 39.81; m/z: 286 (M+1)+. See, for example, DiCesare, P., et al.; J. Med. Chem.; 35(22), pp. 4205–4213 (1992), which is incorporated by reference in its entirety.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH:20]=[CH:19][NH:18][CH2:17]2)[CH:11]=1.C([O-])(O)=O.[Na+]>>[N+:6]([CH:17]1[N:16]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:20]=[CH:19][NH:18]1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: C1=CN(c2cccnc2)CN1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])C1NC=CN1c1cccnc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a stirred solution of sulfuric acid (14 ml, 95-97%) and HNO3 (10 ml, fum.) was added at 0° C. 3-(3-pyridinyl)-1H-imidazole [CAS No. 51746-85-1, commercially available] (4.25 g, 29.3 mmol). The reaction mixture was stirred at room temperature for 45 min and at 50° C. for 6 h and poured into ice-water (100 ml). Solid NaHCO3 was added to the stirred mixture until the pH reached 5-6, the precipitated product was collected by filtration and washed with water and hexane to yield 2-nitro-3-(3-pyridinyl)-1H-imidazole (5.53 g, 99%) as an off-white solid; mp 261° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[NH2:9][C:4]1[CH:3]=[C:2]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)[CH:7]=[N:6][C:5]=1[CH3:8]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: Cc1ncc(Br)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)Nc1nc2ccc(-c3cnc(C)c(N)c3)cc2s1
Temperature: 100 °C
Reaction time: 1.33 h
Yield: 50.1 %

Procedure:
5-bromo-2-methylpyridin-3-amine (224.9 mg, 1.202 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (413.7 mg, 1.300 mmol), potassium carbonate (549.4 mg, 3.975 mmol), and Pd(dppf)Cl2*DCM complex (108.7 mg, 0.133 mmol) were suspended in DME (5.0 ml) and water (1.25 ml), and the flask was fit with a reflux condensor and argon was bubbled through for about 15 seconds. Then, the flask was placed in a preheated oil bath (100° C.) and stirred under argon for 80 minutes. The reaction was cooled to room temperature, and the aqueous phase was removed via pipette. The reaction was then concentrated, treated with MeOH, and filtered. Solid washed with MeOH, water, MeOH, and Et2O. Solid then collected and dried under high vacuum to afford N-(6-(5-amino-6-methylpyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (179.7 mg, 50% yield). MS (ESI pos. ion) m/z: 299. Calculated exact mass for C15H14N4OS: 298.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:6]=1N)([CH3:4])([CH3:3])[CH3:2].[F:13][B-](F)(F)F.[H+].N([O-])=O.[Na+]>O>[F:13][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:12]
Reactant: F[B-](F)(F)F
Reactant: Cc1cccc(C(C)(C)C)c1N
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C(C)(C)C)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
157 g (0.96 mole) of 2-tert-butyl-6-methylaniline are added dropwise to 500 ml of 40% strength tetrafluoroboric acid at 50° C., followed by a solution of 66.2 g (0.96 mole) of sodium nitrite in 270 ml of water. The mixture is stirred for 1 hour at 10° C. The precipitated diazonium salt is filtered off under suction, washed in succession with 50 ml of ice water, 50 ml of cold ethanol and 50 ml of diethyl ether and then suspended in 500 ml of liquid paraffin. The suspension is then added dropwise to a flask preheated at 150° C. After evolution of gas is ended, the product is obtained by distillation over a Claisen still (bath temperature 140° C., pressure 26 mbar) at a distillation temperature of 83° C. 47 g (29%) of 2-fluoro-3-tert-butyltoluene are obtained.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+]>O>[NH:12]([CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][C:1]1([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8]3)[CH2:4]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: Nc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc(NC2C3CC4CC(C3)CC2(Nc2ccccc2)C4)cc1
Temperature: 200 °C
Yield: 18.1 %

Procedure:
A mixture of 13 g of 2-adamantanone, 55 g of aniline, and 15 g of aniline hydrochloride was introduced to a flask with a water remover. The mixture was heated and refluxed at 200° C. (oil bath) under nitrogen atmosphere. Forty hours later, a KOH solution was added so that the pH was approximately 10, and the mixture was extracted with chloroform and washed with water. The mixture was then dried with sodium sulfate, evaporated, and purified with silica gel column chromatography, to obtain 5 g of dianilinoadamantane as a colorless amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([C:7]1[CH:12]=[C:11]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:22][C:23](=O)[CH3:24])=O.[NH3:29].CC(O)C>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([C:11]2[CH:12]=[C:7]3[C:8](=[CH:9][CH:10]=2)[N:22]=[C:23]([CH3:24])[N:29]=[C:5]3[C:4]2[CH:26]=[CH:27][CH:28]=[C:2]([Cl:1])[CH:3]=2)=[O:21])=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1C(=O)c1cccc(Cl)c1
Reactant: N
Solvent: CC(C)O
Product: Cc1nc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Temperature: 0 °C
Yield: 36 %

Procedure:
A mixture of N-[2-(3-chlorobenzoyl)-4-(4-chlorobenzoyl)phenyl]acetamide (0.008 mol), described in International Patent Specification WO97/16443, in NH3/iPrOH (4.5M) (17 ml) was stirred at 160° C. for 6 hours in a small bomb, cooled, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/20; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (1.2 g) was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 1.13 g (36%) of (4-chlorophenyl)[4-(3-chlorophenyl)-2-methyl-6-quinazolinyl]-methanone, mp. 182° C. (intermediate 4).
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>>[CH3:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@@H:4]([C:3]([OH:2])=[O:28])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:22][CH:23]=1)=[O:33]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1ccc(C[C@H](NC(=O)C2(Cc3ccccc3)CCCC2)C(=O)O)cc1
Yield: 69 %

Procedure:
4-Amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (35.3 mg, 0.093 mmol) and 2-methyl-5-nitrobenzoic acid 20 mg, 0.11 mmol) were reacted as described in example 34 to give 4-[[(2-methyl-5-nitrophenyl)carbonyl]amino]-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine (34 mg, 69%), HR-FAB-MS: obs. mass 530.2298. Calcd. mass 530.2291 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>C(O)C.O>[O:1]=[C:2]1[CH:11]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(=O)n(-c2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1cc(=O)n(-c2ccccc2)c2ccccc12
Yield: 51 %

Procedure:
Diethyl 1,2-dihydro-2-oxo-1-phenylquinol-4-ylmalonate (2.7 g.) was dissolved in ethanol (50 ml.), and a solution of sodium hydroxide (2.85 g.) in water (3 ml.) was added. The mixture was heated under reflux for 1 hour, and then cooled and poured into water (200 ml.) to give a solution which was treated with decolourising carbon, filtered, and adjusted to pH 3 by addition of hydrochloric acid. The precipitate was collected by filtration, washed with water, drained, and crystallised from methanol to give 1,2-dihydro-2-oxo-1-phenylquinol-4-ylacetic acid, m.p. 185.5°-186° C. (decomposition), in 51% yield.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][C:9]=1[NH:26][C:27]([C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][C:34]([O:38][CH3:39])=[C:33]([O:40][CH3:41])[C:32]=2[O:42][CH3:43])=[O:28])(=O)=O.[Li+].[Cl-:45].CCOC(C)=O>CN(C=O)C>[CH2:19]([O:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH2:7][CH2:6][Cl:45])=[C:9]([NH:26][C:27]([C:29]2[NH:30][C:31]3[C:36]([CH:37]=2)=[CH:35][C:34]([O:38][CH3:39])=[C:33]([O:40][CH3:41])[C:32]=3[O:42][CH3:43])=[O:28])[CH:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCOS(C)(=O)=O)[nH]c2c(OC)c1OC
Reactant: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCCl)[nH]c2c(OC)c1OC
Reaction time: 72 h
Yield: 80.9 %

Procedure:
To a solution of 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl methanesulfonate (0.11 g, 0.17 mmol) in dry DMF (2 mL) was added LiCl (0.29 g, 6.94 mmol) at room temperature under N2 atmosphere and stirred for 3 days. The reaction mixture was diluted AcOEt (100 mL) and washed with H2O (20 mL) and saturated aqueous NaCl (10 mL), and then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica-gel column (AcOEt:Petroleum ether=1:4) to yield as a white solid 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl chloride (75 mg, 81%): mp 180-184° C.; 1H NMR (CDCl3, 500 MHz) δ 9.23 (s, 1H), 8.63 (s, 1H), 8.42 (d, 7.5, 1H), 7.84 (d, 8.5, 1H), 7.53-7.60 (m, 4H), 7.49 (t, 8.0, 1H), 7.44 (t, 7.0, 2H), 7.38 (t, 7.5, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 5.29 (s, 2H), 4.10 (s, 3H), 4.05 (t, 6.0, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.60 (t, 6.0, 2H); EIMS m/z 545 (M+); IR (neat) νmax 3271, 2932, 1722, 1634, 1592, 1537, 1503, 1464, 1409, 1370, 1306, 1258, 1237, 1111, 1076, 1050, 998, 910, 830, 761, 736, 700cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)[CH2:18][C:19]1[NH:23][CH:22]=[CH:21][N:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc([N+](=O)[O-])cc1)Cc1ncc[nH]1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1ccc(N)cc1)Cc1ncc[nH]1
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
The compound (325 mg) obtained in Example 34-2 was dissolved in ethanol (15 ml) and then cooled with ice. The solution was carefully added with 10% palladium-carbon (Mitsuwa Chemicals Co., Ltd.) (300 mg), followed by stirring under a hydrogen atmosphere for 30 minutes. The solution was subjected to Celite filtration and the filtrate was then concentrated, thereby obtaining the subject compound (233 mg) as a pale-red white solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:32])[NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH3:25])=[CH:18][CH:17]=2)[N:11]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:48]I>O1CCCC1>[Si:1]([O:8][C@H:9]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:32])[N:23]([CH3:48])[CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH3:25])=[CH:18][CH:17]=2)[N:11]1[C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(NC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1)c1ccccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(c1ccccn1)N(C)C(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Reaction time: 3 h

Procedure:
To tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-{[1-(pyridine-2-yl)ethyl]carbamoyl}benzyl)pyrrolidine-1-carboxylate (350 mg, 0.556 mmol) in tetrahydrofuran (1.1 mL), was added sodium hydride (26.7 mg of a 60 wt % dispersion, 0.667 mmol) at 0° C. The reaction was stirred for 30 minutes before methyl iodide (38.2 μl, 0.611 mmol) was added. The resulting red colored reaction was stirred for 3 hours before being quenched by pouring into a separatory funnel containing water and was extracted with ethyl acetate (3×50 mL). The organic extracts were combined and dried with Na2SO4, filtered, and evapourated in vacuo and taken directly to the next step. LC-MS=644.3 (M+1)+.