Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:50][CH2:49]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:35])[CH3:36])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12i) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 699.4 [(M+H)+]
Reaction SMILES: C([O:8][C:9](=[O:33])[CH2:10][N:11]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[C:29]([O:28][C:26]([N:11]([CH2:10][C:9]([OH:33])=[O:8])[CH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:14][CH2:13]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1CCC(N(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(N(CC(=O)O)C(=O)OC(C)(C)C)CC1
Reaction time: 19 h

Procedure:
A solution of [tert-Butoxycarbonyl-(4-tert-butoxycarbonylamino-cyclohexyl)-amino]-acetic acid benzyl ester (0.277 g, 0.599 mmol) in methanol (6 mL) was purged with argon for 5 min. Palladium hydroxide (20%, 0.053 g) was added, the flask evacuated, and the reaction stirred under a H2 atmosphere for 19 hr. The reaction was filtered through a Celite-plugged filter frit, washed with methanol and DCM, and concentrated. The crude product was carried forward without purification. ESI-MS m/z 395 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:4](=[O:17])[C:3]=1[N:18]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:18][C:3]1[C:4](=[O:17])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:6](=[O:8])[NH:7][C:2]=1[NH2:1]
Reactant: Nc1[nH]c(=O)n(Cc2ccccc2F)c(=O)c1N=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1[nH]c(=O)n(Cc2ccccc2F)c(=O)c1N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of 6-amino-3-(2-fluoro-benzyl)-5-nitroso-1H-pyrimidine-2,4-dione in water at 80° C. was treated with sodium hydrosulfite (5.94 g, 34.16 mmol). The reaction was stirred at 80° C. for 30 min. At this time, the reaction mixture was cooled to 0° C. for 10 min. The resulting solids were collected by filtration, rinsed with cold water and cold ether, and dried in vacuo to afford 5,6-diamino-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione (2.34 g, 96%); LRMS for C11H11FN4O2 (M+H)+ at m/z=251.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Br)ccc43)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Yield: 47.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 92 (0.4 g, 0.66 mmol) was reacted with diisopropylethylamine (0.43 g, 3.3 mmol), diphenylphosphinic chloride (0.31 g, 1.3 mmol), then reacted with methyl 4-amino-3-methoxybenzoate (Ark Pharm) (0.18 g, 0.99 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield 0.21 g, 48%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C(OCC)C>[CH3:16][Si:15]([CH3:18])([CH3:17])[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(c1ccccc1)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
Step 1—To a stirring solution of N-methylaniline (80 g, 0.75 mol) in diethyl ether (600 ml) cooled at −78° C. was added n-butyl lithium (2.4 M in hexanes, 342 ml, 0.82 mol) keeping the temperature below −60° C. The resulting slurry was stirred for 1 hour then chlorotrimethylsilane (114 ml, 0.90 mol) was added while keeping the temperature below −70° C. The reaction was allowed to warm to room temperature overnight then filtered to remove the precipitated white solid. The filtrates were concentrated in vacuo then distilled under high-vac to yield the N-trimethylsilyl-N-methylaniline (126 g, 94%) as a colorless/straw colored liquid: b.p. 48° C./0.6 mmHg; 1H NMR (CDCl3) 0.33 (s, 9H), 2.95 (s, 3H), 6.85 (t, 1H, 7 Hz), 6.94 (d, 2H, 8 Hz), 7.27 (t, 2H, 9 Hz).
Reaction SMILES: C([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1)C.Br>C(O)(=O)C.O.ClCCl>[NH2:11][C:9]1[S:10][C:6]2[CH:5]=[C:4]([OH:3])[CH:13]=[CH:12][C:7]=2[N:8]=1
Reactant: CCOc1ccc2nc(N)sc2c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc2ccc(O)cc2s1
Yield: 88.5 %

Procedure:
To a solution of 7 g of 6-ethoxy-1,3-benzothiazol-2-amine (commercial) in 65 cm3 of glacial acetic acid are added 130 cm3 of a 48% solution of hydrobromic acid in water. The solution is refluxed for about 20 hours. After concentrating to dryness under reduced pressure (13 kPa), the residue is taken up in 50 cm3 of water and the pH of the solution is brought to about 8 by addition of solid sodium hydrogen carbonate. The mixture is extracted with four times 250 cm3 of ethyl acetate and the combined organic phases are washed with three times 20 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The solid obtained is taken up in 20 cm3 of dichloromethane, filtered off by suction, washed with three times 10 cm3 of dichloromethane and then three times 20 cm3 of diethyl ether, and dried under reduced pressure (13 kPa) over phosphorus pentoxide. 5.3 g of 2-amino-1,3-benzothiazol-6-ol are thus obtained in the form of a pink powder, the characteristics of which are as follows:
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1.[CH3:25][C:26]1[N:31]=[C:30]2[NH:32][C:33]([CH2:35][CH3:36])=[N:34][C:29]2=[C:28]([CH3:37])[CH:27]=1>>[CH2:21]([O:20][C:18](=[O:19])[CH:17]=[C:7]1[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:32]3[C:30]4=[N:31][C:26]([CH3:25])=[CH:27][C:28]([CH3:37])=[C:29]4[N:34]=[C:33]3[CH2:35][CH3:36])=[CH:4][C:5]=2[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:8]1=2)[CH3:22]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: CCOC(=O)C=C1c2ccc(CBr)cc2C=Cc2ccc(F)cc21
Product: CCOC(=O)C=C1c2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)cc2C=Cc2ccc(F)cc21
Yield: 14 %

Procedure:
The same procedure as in Step D of Example 1 was repeated using 0.34 g of Compound 4-b and 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine to give 60 mg (14%) of the product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2=[N:14][C:15]3[C:20]([N:21]=[C:12]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=[CH:19][CH:18]=[CH:17][CH:16]=3.[C:22]1(=O)[O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23]1>>[C:22]1(=[O:28])[N:1]([CH2:2][CH2:3][CH2:4][N:5]2[C:13]3=[N:14][C:15]4[C:20]([N:21]=[C:12]3[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:26](=[O:27])[CH2:25][CH2:24][CH2:23]1
Reactant: O=C1CCCC(=O)O1
Reactant: NCCCn1c2ccccc2c2nc3ccccc3nc21
Product: O=C1CCCC(=O)N1CCCn1c2ccccc2c2nc3ccccc3nc21

Procedure:
6-(3-aminopropyl)-6H-indolo(2,3-b)quinoxaline (2.77 g, 0.01 mole) is heated (3 hours, 170° C.) with glutaric acid anhydride (1.14 g, 0.01 mole) and then the melt is allowed to cool and recrystallization from acetonitrile is carried out. Yield: 3,43, (92%) mp. 312°-314° C.
Reaction SMILES: [CH2:1]([C:8]([CH2:10][CH3:11])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([CH2:15]Cl)=[CH2:14]>>[CH3:14][C:13]([CH2:15][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8](=[O:9])[CH2:10][CH3:11])=[CH2:12]
Reactant: C=C(C)CCl
Reactant: CCC(=O)Cc1ccccc1
Product: C=C(C)CC(C(=O)CC)c1ccccc1

Procedure:
If ethyl benzyl ketone is reacted with β-methallyl chloride according to the foregoing details, then there is obtained 2-methyl-4-phenyl-hept-1-en-5-one of boiling point 93° C./3 mmHg; nD20 =1.5094.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]#[C:10][C:11]1[N:12]=[C:13]2[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]2=[N:15][CH:16]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O.[Cu](I)I>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[C:11]([CH:16]=[N:15][C:14]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])[CH:18]=[CH:19][C:13]=32)=[CH:10][CH:9]=1
Reactant: CC1CCCCN1CC#Cc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Agent: I[Cu]I
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC1CCCCN1c1ccc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 130 °C
Reaction time: 3 h
Yield: 19.5 %

Procedure:
To a flask containing (+/−)-2-[3-(2-methyl-piperidin-1-yl)-prop-1-ynyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (185 mg, 0.48 mmol) was added copper iodide (37 mg, 0.19 mmol), and DBU (0.34 mL, 2.28 mmol) in dry dimethyl acetamide (1 mL). The mixture was vacuum degassed and heated to 130° C. and stirred for 3 hours. The mixture was cooled to ambient and quenched via the addition of water (30 ml) and ethyl acetate (30 ml).The material was shaken in a reparatory funnel, and the ethyl acetate phase was collected. The aqueous phases were back extracted with ethyl acetate (2×25 ml), the organics combined, dried (MgSO4), filtered and stripped. The remainder was purified by preparative TLC using 25% ethyl acetate in hexanes as eluant. The product band was collected to provide 36 mg of (+/−)-8-(2-methyl-piperidin-1-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-3,4,8a-triaza-as-indacene as a brown-black oil. Note that starting material (90 mg) was also recovered. This material was subjected to the identical reaction conditions as above (but over-night heating), to provide an extra 12 mg of product. MS (M+H)+=385.
Reaction SMILES: [OH:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([OH:11])([CH2:10][CH:4]([CH:5]3[NH:13]C(=O)C)[CH2:3]1)[CH2:9]2.Cl>>[NH2:13][CH:5]1[CH:4]2[CH2:3][C:2]3([OH:1])[CH2:9][C:8]([OH:11])([CH2:7][CH:6]1[CH2:12]3)[CH2:10]2
Reactant: CC(=O)NC1C2CC3(O)CC1CC(O)(C2)C3
Agent: Cl
Product: NC1C2CC3(O)CC1CC(O)(C2)C3
Temperature: 80 °C
Yield: 55.8 %

Procedure:
To N-(5,7-dihydroxy-2-adamantyl)acetamide (110 mg, 0.489 mmol) was added 4N aq HCl (3 mL) slowly. The reaction mixture was heated to 80° C. overnight. The mixture was cooled to rt and concentrated. The residue was treated with satd aq NaHCO3. The water was removed under reduced pressure, and the solid was triturated with methanol. The mixture was filtered, and the solids were washed with methanol. The filtrate was concentrated give to 6-aminoadamantane-1,3-diol (50 mg, 56%). 1H-NMR (400 MHz, D2O): δ=1.45 (m, 2H), 1.63 (m, 6H), 1.73 (m, 4H), 2.12 (m, 2H), 3.27 (m, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([F:18])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29]OS1(=O)=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:16]([O:15][C:13]([C:10]1[N:11]([CH2:29][CH2:30][NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([F:18])=[CH:5][C:4]=2[Br:3])=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cc2cc(F)cc(Br)c2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)cc(Br)c2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To a stirred mixture of sodium hydride [disp. 55-65%] (175 mg, 4.37 mmol) in DMF (5.6 ml) was added drop wise at room temperature under argon atmosphere a solution of commercially available ethyl 7-bromo-5-fluoro-1H-indole-2-carboxylate [CAS No. 396076-60-1] (1.04 g, 3.64 mmol) in DMF (2.8 ml). Afterwards the mixture was allowed to stir for 5 min at room temperature, then commercially available 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester [CAS No. 459817-82-4] (975 mg, 4.37 mmol) was added and the solution was allowed to stir at room temperature for 15 h. The solution was cooled in an ice bath, and citric acid (10%, 62 ml) was added drop wise. The mixture was allowed to stir at room temperature for 1 h, and was afterwards extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with brine (80 ml), dried (MgSO4) and evaporated. The crude material (2.04 g) was purified by flash chromatography on silica gel (heptan/ethyl acetate 0-80%) to yield 7-bromo-1-(2-tert-butoxycarbonylamino-ethyl)-5-fluoro-1H-indole-2-carboxylic acid ethyl ester as a light yellow oil (1.37 g, 88%), MS (ISN) m/z=431.2 [(M+H)+].
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].CC(O)=O>ClC(Cl)C>[CH3:4][O:3][C:1]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[N:15]/[NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(/C=N/NC(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 4-carbomethoxy benzaldehyde (5.0 g, 36.46 mmol) in dichloroethane (40 mL) was added tert-butyl carbazate (4.03 g, 30.46 mmol) followed by AcOH (1.74 mL, 30.46 mmol). After 1.5 hours, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3, solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. This material was used without any further purification in the next step. 1H NMR (CDCl3, 500 MHz): 8.03 (d, J=8.5 Hz, 3H), 7.93 (bs, 1H), 7.8 (d, J=8.2 Hz, 2H), 3.96 (s, 3H), 1.58 (s, 9H). LC-MS=3.1; (M+H−56)=223.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH:6]=[CH:5]2.C([Li])CCC.CN(C)[CH:24]=[O:25].O>O1CCCC1>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:24]=[O:25])[CH:3]=2)[N:8]=1
Reactant: CN(C)C=O
Reactant: COC(OC)c1ccc2cc(Br)ccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)c1ccc2cc(C=O)ccc2n1
Reaction time: 0.17 h
Yield: 37.8 %

Procedure:
To a solution of 6-bromo-2-(dimethoxymethyl)quinoline (1.11 g, 3.94 mmol) in tetrahydrofuran (20 mL) were added n-butyllithium (1.6 mol/L; 3.7 mL, 5.9 mmol) and dimethylformamide (0.61 mL, 7.9 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (3:1 hexane/ethyl acetate) to afford 2-dimethoxymethyl-6-quinolinecarboxaldehyde (344 mg, 38%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(Cl)CCl.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]=[C:22]([CH2:26][CH2:27][C:28](O)=[O:29])[C:21]1=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:28](=[O:29])[CH2:27][CH2:26][C:22]1[C:21](=[O:31])[N:20]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:24][CH:23]=1
Reactant: O=C(O)CCC1=CCCN(Cc2ccccc2)C1=O
Reactant: Nc1ccccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC(=O)CCC1=CCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 91 %

Procedure:
40 mg of 1,2-phenylenediamine (0.37 mmol), 77 mg of EDC (0.4 mmol) and 1 mg of DMAP (3 M %) were added to reaction solution dissolving 3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid prepared by above Example 8 in 1 ml of methylene chloride under Argon atmosphere. After the mixture was stirred for 13 hrs at room temperature, the resulting mixture was diluted with ethyl acetate and washed with 10% NaOH solution (10 ml). Then the residue was extracted with 50 ml of chloroform, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:20) as an eluant to give 96 mg of N-(2-amino-phenyl)-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide (g2) (yield: 91%).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([NH2:14])=[O:13])[CH:8]=[C:7]1[CH:15]([CH3:17])[CH3:16])[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.[CH2:27]([O:30]N1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O)C=C>>[CH2:1]([O:4][N:5]1[C:27](=[O:30])[N:10]2[CH2:11][C@H:6]1[C:7]([CH:15]([CH3:17])[CH3:16])=[CH:8][C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCON[C@H]1CN[C@H](C(N)=O)C=C1C(C)C
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C(C(C)C)=C[C@H]2C(N)=O

Procedure:
The title compound was prepared from (2S,5R)-5-(allyloxyamino)-4-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (0.0981 g, 0.41 mmol) and N,N-diisopropylethylamine (Intermediate 42, 0.286 mL, 1.64 mmol) following the procedure described for Intermediate 16. The desired product was obtained as a light yellow oil (69 mg, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])[CH:15]=[N:14][C:13]=3[N:12]([CH3:25])[C:11](=[O:26])[CH:10]=2)=[C:4]([F:27])[CH:3]=1.C1C(=O)N([Cl:35])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])[CH:15]=[N:14][C:13]=3[N:12]([CH3:25])[C:11](=[O:26])[C:10]=2[Cl:35])=[C:4]([F:27])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(=O)cc(Nc2ccc(Br)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Solvent: ClCCl
Product: Cn1c(=O)c(Cl)c(Nc2ccc(Br)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 20C (60 mg, 0.136 mmol) was dissolved in 2 mL DCM. NCS (22 mg, 0.165 mmol) was added. The mixture was stirred at room temperature overnight. Example 29 (35.3 mg, 54%) was isolated by preparative HPLC separation. 1H NMR (400 MHz, MeOD) δ 8.50 (s, 1H) 7.45 (d, J=8.0 Hz, 1H) 7.38 (d, J=8.0 Hz, 1H) 7.10 (t, J=8.0 Hz, 1H) 4.51 (m, 1H) 4.03 (m, 1H) 3.88 (m, 1H), 3.82 (s, 3H) 3.68 (d, J=4 Hz, 2H). [M+H] calc'd for C17H15BrClFN4O4, 475; found, 475.
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:5]([NH:10][C:11](=[O:29])[CH2:12][C:13]2[CH2:14][CH2:15][N:16](C(OCC3C=CC=CC=3)=O)[CH2:17][CH:18]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.C[Si](C)(C)CCOCCl>C1COCC1>[NH:16]1[CH2:17][CH2:18][C:13]2([C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:11](=[O:29])[CH2:12]2)[CH2:14][CH2:15]1
Reactant: O=C(CC1=CCN(C(=O)OCc2ccccc2)CC1)Nc1ncccc1Br
Agent: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC2(CCNCC2)c2cccnc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 117 mg, 4.88 mol) was added in portions over 10 min to a solution of benzyl 4-{2-[(3-bromopyridin-2-yl)amino]-2-oxoethyl}-3,6-dihydropyridine-1(2H)-carboxylate (1.91 g, 4.43 mol) in THF (15 mL) at 0° C. After 0.5 h, 2-(trimethylsilyl)ethoxymethyl chloride (0.861 mL, 4.88 mol) was then added slowly, keeping the temperature of the reaction mixture below 10° C. After 4 h, sodium hydride (60 mg) and 2-(trimethylsilyl)ethoxymethyl chloride (0.45 ml) were added and the reaction allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 40 to 70% ethyl acetate:hexanes to give the title compound (1.51 g). MS: m/z=560.2 (M+1).