Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH:15]1[CH2:18][N:17]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1)(=O)=O>CN(C=O)C>[C:20]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]2[CH2:18][CH:15]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:16]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
To a cooled solution of phenol (149 mg, 1.58 mmol) in DMF (3.9 mL), NaH (60% in oil, 95 mg, 2.37 mmol) was added portionwise and the suspension was stirred at 0° C. for 15 min. 1-(Diphenylmethyl)azetidin-3-yl methanesulfonate (500 mg, 1.58 mmol; which may be prepared as described in Step 1) was then added and the reaction mixture stirred at 80° C. overnight and concentrated under reduced pressure. The residue was purified on column chromatography (eluent: pentane/EtOAc 98/2 to 95/5) to give the title compound (332 mg, 67%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(Cl)cncc1Cl
Reaction time: 0.25 h
Yield: 32.2 %

Procedure:
A solution of 4.44 g (30 mmol) of 3,5-dichloropyridine in 40 mL of THF is added dropwise over 30 minutes to a stirred solution of 23 mL (35 mmol) of 1.5 M LDA in 30 mL THF at −78° C. After a further 15 minutes at −78° C., a solution of 6.13 g (42 mmol) of diethyl oxalate in 15 mL THF is added, and the temperature is allowed to rise slowly to −20° C. The reaction mixture is then quenched with aqueous ammonium chloride, the solvent is removed, and the residue is worked up in EtOAc. Chromatography on silica, eluting with hexane/EtOAc (9:1), gives 2.4 g (32%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][CH2:13][O:14][C:15]([CH3:17])=O>O.[Cl-].C([N+](CC)(CC)CC)C.C(#N)C.[F-].[K+]>[O:14]1[CH:15]=[CH:17][CH:12]=[C:13]1[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: CCOC(C)=O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: O=C1Cc2cc(-c3ccco3)cnc2N1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
5-Bromo-7-azaoxindole (0.75 g, 3.52 mmol), 2-tributyltinfuran (1.26 g, 3.52 mmol), tetraethylammonium chloride hydrate (1.94 g, 10.6 mmol) were combined and dissolved in acetonitrile (10 mL) at room temperature under an atmosphere of nitrogen. Bistriphenylphosphine dichloropalladium (II) (0.25 g, 0.35 mmol) was added and the reaction was warmed to 85° C. for 16 h. The reaction was cooled to room temperature and diluted with aqueous KF (10%, 60 mL). This was stirred for 20 minutes and then diluted with EtOAc (60 mL). The biphasic system was passed through celite, the layers separated, and the volatiles removed in vacuo. The resulting residue was triturated with diethyl ether and the solids were collected by filtration to afford a light yelow solid (0.28 g, 36% yield). 1H NMR 300 MHz (DMSO-d6) δ 11.18 (bs, 1H); 8.45 (s, 1H); 7.92 (s, 1H); 7.79 (s, 1H); 6.95 (d, 1H); 6.60 (d, 1H); 3.64 (s, 2H). APCI m/z 201 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[O:7]>C(O)(=O)C>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:3](=[O:4])[CH:2]=[C:21]([CH3:20])[O:7][C:6]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)COc2ccc(F)cc2F)cc1
Solvent: CC(=O)O
Product: Cc1cc(=O)c(Oc2ccc(F)cc2F)c(-c2ccc(S(C)(=O)=O)cc2)o1
Temperature: 140 °C
Yield: 23.3 %

Procedure:
To a solution of 2-(2,4-Difluorophenoxy)-1-(4-methanesulfonylphenyl)ethanone ( 4.60 g; 14 mmol) in acetic acid (70 ml), polyphosphoric acid (45 g) was added and then heated at 140° C. for 5 hours. After cooling, the reaction was poured into ice-water, extracted with ethyl acetate (2×100 ml), the organic solution dried (Na2SO4) and the solvent removed under reduced pressure. The residual oil was purified by column chromatography with silica gel and ethyl acetate/n-hexane (1:2) as eluent. Recrystallization from ethanol gave 3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one (0.64 g), m.p. 191° C. (Compound 45 in Table 4).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:21])[C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:24]OS(OC)(=O)=O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([NH:8][C:9](=[O:21])[C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:11][O:12][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 109 %

Procedure:
To a stirred solution of 3.2 g (0.01 mol) of Intermediate 4 in 50 mL of toluene was added 0.61 g of tetrabutylammonium bromide and 5 ml of water. The resulting mixture was cooled to 10° C. and a solution of 2.4 g of sodium hydroxide in 2.5 ml of water was added dropwise maintaining the temperature below 10° C. Then, 5.54 g of dimethylsulfate was added dropwise maintaining the temperature below 10° C. After stirring at 10° C. for 2 hours, water (80 mL) was added and the reaction stirred at room temperature overnight. The layers were separated and the aqueous layer was washed twice with dichloromethane (50 mL). The combined organic phase was washed with sodium bicarbonate solution (2×30 mL) and brine. The solvent was removed under vacuum yielding 3.36 g of a pale red-oil. The oil was not purified and used directly in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][O:13][CH3:14])[CH:7]=[CH:6]2.CCCCCC.C([Li])CCC.[C:26](Cl)(=[O:29])[CH2:27][CH3:28].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][O:13][CH3:14])[C:7]([C:26](=[O:29])[CH2:27][CH3:28])=[CH:6]2
Reactant: COCn1ccc2cc(OC)ccc21
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(=O)c1cc2cc(OC)ccc2n1COC
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 34.5 %

Procedure:
3.00 g of 5-methoxy-1-methoxymethylindole was dissolved in 15 ml of anhydrous tetrahydrofuran. Thereto was dropwise added 11.0 ml of 1.5 M n-butyllithium hexane solution, in 5 minutes with stirring at -30° C. The resulting mixture was stirred at 0° C. for 30 minutes. This solution was dropwise added to a solution of 1.59 g of propionyl chloride dissolved in 15 ml of anhydrous tetrahydrofuran, in 30 minutes with stirring at -60° C. The reaction mixture was stirred at room temperature for 10 minutes, and then was added to 50 ml of an aqueous saturated sodium hydrogencarbonate solution in one portion. Thereto was added 150 ml of ethyl acetate. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=50/1) to obtain 1.34 g (yield: 35%) of 5-methoxy-1-methoxymethyl-2-propionylindole as a light yellow oily material.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)C#CC1(C)COC1.Br[C:34]1[CH:35]=[C:36]2[C@:47]3([CH2:52][CH2:51][O:50][C:49]([NH2:53])=[N:48]3)[C:46]3[C:41](=[CH:42][CH:43]=[C:44](C4C(F)=NC=CC=4)[CH:45]=3)[O:40][C:37]2=[N:38][CH:39]=1>C1COCC1.CO.CCOC(C)=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:50]1[CH2:51][CH2:52][C:47]2([C:36]3[C:37](=[N:38][CH:39]=[CH:34][CH:35]=3)[O:40][C:41]3[C:46]2=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:48]=[C:49]1[NH2:53]
Reactant: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C#C[Si](C)(C)C)COC1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NC1=NC2(CCO1)c1ccccc1Oc1ncccc12
Temperature: 80 °C
Yield: 72 %

Procedure:
In a microwave vial, tetrabutylammonium fluoride trihydrate (0.059 g, 0.187 mmol), trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.031 g, 0.187 mmol), copper(I) iodide (2.374 mg, 0.012 mmol), Pd(PPh3)4 (0.014 g, 0.012 mmol), and (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (0.055 g, 0.125 mmol) were suspended in THF (1.25 mL). Argon gas was blown through the vessel, which was sealed and heated in an 80° C. oil bath for 1.5 h. The mixture was taken up in 10% MeOH-EtOAc (60 mL) and the organic layer was extracted with dilute brine (8 mL) then with saturated brine (8 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (5% MeOH/DCM), to afford (S)-7-(2-fluoropyridin-3-yl)-3-(3-methyloxetan-3-yl)ethynyl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (41 mg, 0.09 mmol). MS (m/z) 457 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm: 8.32 (d, 1 H, J=2.0 Hz), 8.20 (d, 1 H, J=4.9 Hz), 7.90 (m, 1 H), 7.78 (s, 1 H), 7.53 (m, 2 H), 7.38 (d, 1 H, J=8.4 Hz), 7.27 (m, 1 H), 4.94 (d, 2 H, J=5.3 Hz), 4.50 (d, 2 H, J=5.5 Hz), 4.44 (br, 2 H), 4.28 (m, 2 H), 1.95 (m, 1 H), 1.85 (m, 1 H), 1.74 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1([NH2:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:10]1[N:11](C(=O)C)[CH2:12][C:13]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[C:14]=2[N:15]=1.[OH-].[Na+]>CO>[NH2:8][C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:10]2[NH:11][CH2:12][C:13]3[N:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[C:14]=3[N:15]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)N1Cc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2N=C1Cl
Reactant: CC1(N)CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(N)CCN(C2=Nc3c(nc(Cl)nc3Nc3ccc(F)c(Cl)c3)CN2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
At 60° C. a mixture of 30.8 g (0.270 mol) of 4-methylpiperidin-4-ylamine and 100 ml of methanol is added dropwise to a suspension of 100 g (0.257 mol) of (3) in 690 ml of methanol. The mixture is stirred for 1 hour at 60° C., allowed to cool to 40° C., 280 ml of 2N sodium hydroxide solution are added and the resulting mixture is stirred for 3 hours at 60° C. Then 300 ml of methanol are distilled off and 600 ml of water are added. The mixture is stirred for 5 minutes at ambient temperature, filtered off and the residue is washed with 250 ml of water, 3 times 50 ml of acetone and 100 ml of methyl-tert-butylether and dried at 40° C. in vacuo. Yield: 100.5 g (92.2%), melting point 211.5° C. 400 MHz-1H-NMR (DMSO) (ppm)=8.55 br s, 1H, NH; 8.05 dd, 1H, aniline-H; 7.78 ddd, 1H, aniline-H; 7.47 t, 1H, aniline-H; 6.90 br s, 1H, NH; 4.28 s, 2H, CH2; 3.68 m, 2H, CH2; 3.45 m, 2H, CH2, 3.32 br s, 2H, NH2; 1.37 m, 4H, 2CH2; 1.05 s, 3H, CH3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:27][OH:28].O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[N:27][OH:28])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2c(c1)COC2c1ccc(F)cc1
Reactant: NO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: ON=Cc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 2.5 °C
Yield: 79.3 %

Procedure:
1-(4′-Fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (5.96 g) was dissolved in toluene (30 ml) and triethylamine (2.75 g) was flown in. Thereto was added hydroxylamine hydrochloride (1.88 g) and the mixture was reacted at 80-90° C. for 1 hr. Hot water (30 ml) was added to the reaction mixture and the mixture was partitioned while hot at 90° C. The organic layer was cooled to 0-5° C. and the resulting crystals were collected by filtration to give the title compound (5.02 g, yield: 79.2%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][OH:9].[H-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C)C=O>[F:12][C:13]1[CH:20]=[CH:19][C:18]([O:9][CH2:8][CH:2]2[CH2:3][CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: OCC1CC2CCC1C2
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC2CC3CCC2C3)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
A solution of 2-norbornane methanol (1.3 g, 10.3 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (450 mg, 11.33 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (1.58 g, 11.33 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed-ice water, stirred. The reaction mixture was extracted with ethyl acetate, dried, filtered and concentrated. Purification by silica gel chromatography (1:1 hexanes in dichloromethane) yielded 986 mg of 2-fluoro-5-(bicyclo[2.2.1]hept-2-ylmethoxy)benzonitrile.
Reaction SMILES: O[C:2]1[C:3]2[CH:16]=[N:15][N:14]([CH3:17])[C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Cl)(Cl)([Cl:20])=O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:20][C:2]1[C:3]2[CH:16]=[N:15][N:14]([CH3:17])[C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(O)c2cnn(C)c2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(Cl)c2cnn(C)c2[nH]c1=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of ethyl 4-hydroxy-1-methyl-6-oxo-6,7-dihyrdo-1H-pyrazolo-[3,4-b]pyridine-5-carboxylate (10 g, 42.2 mmol) in acetonitrile is treated with benzyl triethyl ammonium chloride (40.4 g, 169 mmol), followed by phosphorous oxychloride (17.6 mL, 190 mmol), heated at 40° C. for 0.5 h, then at reflux temperature for 2.5 h, cooled to room temperature, diluted with water (caution exotherm), stirred at ambient temperatures for 16 h and filtered. The filtercake is washed with cyclohexane and dried in vacuo to give the title compound as a white solid, 7.87 g (73% yield), identified by HNMR analysis.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[Br:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH2:25])[N:20]=[CH:19]2>CS(C)=O.O.Cl>[Br:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([C:24]1([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:1][CH2:25]1)[N:20]=[CH:19]2
Reactant: C=C(c1ccccc1)c1ncc2cccc(Br)c2n1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: Cl
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: Brc1cccc2cnc(C3(c4ccccc4)CC3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.4 %

Procedure:
A mixture of potassium tert-butoxide (284 mg, 2.532 mmol) and trimethylsulfoxonium iodide (Aldrich; 557 mg, 2.532 mmol) in anhydrous DMSO (6.5 mL) was stirred under argon at 25° C. for 10 min. A solution of 8-bromo-2-(1-phenylvinyl)quinazoline (393.9 mg, 1.266 mmol) in DMSO (10.0 mL) was added (dropwise, over 8 min), and the resulting brown solution was stirred at 25° C. for 30 min. The reaction was diluted with water (20 mL) and 1.0N aq. HCl (1.2 mL), then partitioned between DCM (120 mL) and water (70 mL). The aq. layer was extracted with additional DCM (70 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-40% EtOAc/hexanes) provided 8-bromo-2-(1-phenylcyclopropyl)quinazoline (153.8 mg, 0.473 mmol, 37% yield) as a light-yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.18 (1H, s), 8.11 (1H, d, J=7.4 Hz), 7.78 (1H, d, J=8.0 Hz), 7.50 (2H, d, J=7.6 Hz), 7.38 (3H, td, J=7.6, 2.6 Hz), 7.30 (1H, t, J=7.4 Hz), 1.92-1.98 (2H, m), 1.51-1.55 (2H, m). m/z (ESI, +ve) 325.1 (M+H)+.
Reaction SMILES: CC(O)C.CCOC(C)=O.N[C@H](C([N:26]1[CH2:45][CH2:44][CH2:43][C@H:27]1[C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:38]([NH:40][CH2:41][CH3:42])=[O:39])[CH3:37])=[O:34])[CH3:32])=[O:29])=O)CC(=O)OCC1C=CC=CC=1.Cl.[NH:47]([C:56]([CH3:58])=[O:57])[C@H:48]([C:53]([OH:55])=O)[CH2:49][C:50](=[O:52])[OH:51]>CO.CCOCC.CN(C)C=O>[CH2:41]([NH:40][C:38](=[O:39])[C@H:36]([CH3:37])[NH:35][C:33](=[O:34])[C@H:31]([CH3:32])[NH:30][C:28](=[O:29])[C@@H:27]1[CH2:43][CH2:44][CH2:45][N:26]1[C:53](=[O:55])[C@H:48]([CH2:49][C:50](=[O:52])[OH:51])[NH:47][C:56](=[O:57])[CH3:58])[CH3:42]
Reactant: CC(=O)N[C@@H](CC(=O)O)C(=O)O
Reactant: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(C)=O

Procedure:
The condensation of Z-Pro-Ala with Ala-NH-Et by the procedure in Example 7 yields Z-Pro-Ala-Ala-NH-Et; m.p. 219°-220° C. from 2-propanol--AcOEt); (α)D20 =-36.2°; c=0.2 (dimethylformamide). This intermediate is successively converted, as described in Example 2, into (1) BOC-Asp(Obzl)-Pro-Ala-Ala-NH-Et, m.p. 133°-136° C. (AcOEt--petroleum ether), (α)D20 =-61.1°, c=0.2 (MeOH); (2) Asp(OBzl)-Pro-Ala-Ala-NH-Et.HCl, m.p. 189°-193° C. (MeOH--Et2O), and (3) Ac-Asp(OBzl(-Pro-Ala-Ala-NH-Et, m.p. 191°-193° C. (AcOEt--petroleum ether), (α)D20 =-68.5°, c=0.2 (MeOH). Hydrogenolysis of the latter product by the procedure in Example 1 yields the title compound, Nα -Acetylaspartyl-prolyl-alanyl-alanine ethylamide; m.p. 153°-155° C. (melting begins at 143° C.).
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH:11]=2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[NH3:31]>CO>[N:1]1([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:28])[F:30])[CH:11]=2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3ncccc32)cc1OCc1ccccc1C(F)(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ncccc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 130 °C
Reaction time: 12 h

Procedure:
A mixture of 2.50 g of methyl 5-(1H-imidazo[4,5-b]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B5a) and 250 ml of a saturated solution of ammonia in methanol was stirred in an autoclave at 130° C. for 12 h. The reaction mixture was allowed to cool down to room temperature, concentrated, and the resulting residue was purified by flash chromatography (neutral alumina oxide, eluents: ethyl acetate/methanol). After crystallization from acetonitrile the title compound was obtained.
Reaction SMILES: [N:1]#[N:2].[C:3]([O:7][C:8](=[O:25])[C@H:9]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22]C#N)[NH:10][C:11]([O:13][C:14](C)(C)C)=O)([CH3:6])([CH3:5])[CH3:4].N#N.[ClH:28].C(OC(=O)[C@H](CCCCNC=NOCC)[NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])(C)(C)C.N#N.Cl.C(OC(=O)[C@H](CCCNCOC=NC(OC(C)(C)C)=O)N)(C)(C)C.CO>ClCCl>[N:1]#[N:2].[ClH:28].[C:3]([O:7][C:8](=[O:25])[C@H:9]([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[NH:10][CH2:11][O:13][CH:14]=[N:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC#N)C(=O)OC(C)(C)C
Reactant: CCON=CNCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=COCNCCC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N=COCN[C@@H](CCCCN)C(=O)OC(C)(C)C

Procedure:
From 1.6 g (4.89 mmol) N2 -(tert-butoxycarbonyl)-N6 -(cyano)-L-lysine tert-butyl ester was prepared 1.5 g (75%) of foamy solid N2 -(tert-butoxycarbonyl)-N6 -(ethoxyiminomethyl)-L-lysine tert-butyl ester hydrochloride by the method described for N2 -(tert-butoxycarbonyl)-N5 -(iminomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride. TLC (methanol:dichloromethane/1:9) Rf=0.36. Mass spectrum (CI) 360 (MH+, 60%).
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.C[O:8][C:9]([CH:11]1[CH2:16][CH2:15][CH:14]([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([N:13]1[C@H:14]([CH3:17])[CH2:15][CH2:16][C@@H:11]([C:9](=[O:8])[NH2:2])[C@@H:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C1CCC(C)N(C(=O)OCc2ccccc2)C1c1ccccc1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: C[C@@H]1CC[C@@H](C(N)=O)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
(A mixture of two diastereomers and their enantiomers.). To ammonium chloride (1.18 g, 22.1 mmol) in 20 mL of benzene at 0° C. was added trimethylaluminum (22.1 mmol, 11.0 mL of a 2.0 M solution in toluene) The resultant mixture was stirred for 30 minutes at 0° C., and warmed to room temperature for an additional 30 minutes. To the mixture was then added 6-Methyl-2-phenyl-piperidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester as a solution in 20 mL of benzene, and the resultant mixture was heated to reflux for 6 hours. The reaction was then cooled to 0° C. and quenched carefully with 10 mL of 1 M HCl. The mixture was stirred for 30 minutes, filtered through celite, and the filter pad was rinsed with CH2Cl2. The filtrate was concentrated and the residue was dissolved in EtOAc, washed with saturated NaHCO3, dried over MgSO4 and concentrated. Silica gel chromatography (CHCl3 to eluted nonpolar material followed by 95:5 CHCl3/MeOH to elute the product) gave 560 mg (36%) of a mixture of the title compounds as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.10–7.42 (comp, 20H, both diastereomers), 5.99 (d, J=5.1 Hz, 1H), 5.68–5.90 (br, 2H, both diastereomers), 5.67 (d, J=4.3 Hz, 1H), 5.00–5.26 (comp, 4H, both diastereomers), 4.53 (m, 1H), 4.17 (br, 1H), 3.15 (m, 1H), 2.75 (m, 1H), 2.28 (app dq, J=4.1, 13.2 Hz, 1H), 1.9–2.08 (m, 2H), 1.50–1.90 (comp, 5H), 1.34 (d, J=6.6 Hz, 3H), 0.68 (d, J=7.1 Hz, 3H); 13C NMR (100 MHz) δ 174.2, 128.6, 128.4, 128.3, 128.2, 128.1, 127.8, 127.6, 127.2, 127.1, 126.7, 67.6, 67.1, 56.9, 52.8, 47.4, 46.6, 30.2, 25.5, 22.3, 19.8, 16.3; Mass spectrum m/e calcd. for M+H=353.2. Found 353.0, 309.1, 219.0 (base).