Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-])=O.C(O)C.O.O.[Sn](Cl)Cl>C(=O)(O)[O-].[Na+]>[CH2:11]1[C:12]2[NH:13][C:14]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=3)[C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2[nH]c3c(c2c1)CCCC3
Temperature: 70 °C
Yield: 95.3 %

Procedure:
6-Nitro-2,3,4,9-tetrahydro-1H-carbazole (0.100 g, 0.462 mmol) was dissolved in a 40 mL scintillation vial containing a magnetic stir bar and 2 mL of ethanol. Tin (II) chloride dihydrate (1.04 g, 4.62 mmol) was added to the reaction mixture and the resulting suspension was heated at 70° C. for 16 h. The crude reaction mixture was then diluted with 15 mL of a saturated aqueous solution of sodium bicarbonate and extracted three times with an equivalent volume of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate, and evaporated to dryness to yield 2,3,4,9-tetrahydro-1H-carbazol-6-amine (82 mg, 95%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][N:14]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:18])=[CH:15][N:14]=1
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1OC

Procedure:
6-Chloro-N-(3,4-dimethoxy-phenyl)-nicotinamide was prepared from 3,4-dimethoxy aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C14H13N2O3Cl [M+H]+: 293.0688. Found: 293.0687.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].NCC1CCN(CC2C=CC(Cl)=C(Cl)C=2)C1.[NH2:31][CH2:32][C@@H:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:40]=2[Cl:46])[CH2:34]1>>[Cl:46][C:40]1[C:41]([Cl:45])=[CH:42][CH:43]=[CH:44][C:39]=1[CH2:38][N:35]1[CH2:36][CH2:37][C@@H:33]([CH2:32][NH:31][C:12](=[O:14])[CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH2:34]1
Reactant: CC(=O)Nc1cccc(CC(=O)O)c1
Reactant: NC[C@@H]1CCN(Cc2cccc(Cl)c2Cl)C1
Agent: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Product: CC(=O)Nc1cccc(CC(=O)NC[C@@H]2CCN(Cc3cccc(Cl)c3Cl)C2)c1

Procedure:
Proceeding as described above but substituting 4-(2,5-dimethylphenyl)-4-oxobutyric acid with 2-(3-acetylaminophenyl)acetic acid and 3-aminomethyl-1-(3,4-dichlorobenzyl)pyrrolidine with 3-(S)-aminomethyl-1-(2,3-dichlorobenzyl)pyrrolidine gave N-[1-(2,3-dichlorobenzyl)pyrrolidin-3-(S)-ylmethyl]-2-(3-acetylaminophenyl)-acetamide.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20](O)=[O:21])=[C:13]([O:23][CH3:24])[CH:12]=3)[CH2:4][CH3:5])[CH3:2].[CH3:25][N:26](C)[CH:27]=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.CNC>O>[CH2:4]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20]([N:26]([CH3:27])[CH3:25])=[O:21])=[C:13]([O:23][CH3:24])[CH:12]=3)[CH2:1][CH3:2])[CH3:5]
Reactant: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(=O)O)c(OC)cc3n12
Reactant: CN(C)C=O
Agent: CNC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(=O)N(C)C)c(OC)cc3n12
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
1-(1-Ethylpropyl)-8-methoxy-4-oxo-4,5-dihydroimidazo[1,5-a]-quinoxaline-7-carboxylic acid as synthesized in above Example 32, 329 mg, N,N-dimethylformamide 5 mL and 1,1′-carbonyldiimidazole 275 mg were mixed and stirred for an hour at room temperature in nitrogen atmosphere. Dimethylamine hydrochloride 816 mg was added, followed by 5.5 hours' stirring. The reaction mixture was diluted with water, extracted with ethyl acetate and washed with saturated saline. The extract was dried over anhydrous sodium sulfate, and from which the solvent was distilled off. To the residue tert-butyl methyl ether was added, heated under stirring, and the precipitate was recovered by filtration, followed by washing with tert-butyl methyl ether. The product was dried in flowing air (40° C.) to provide 223 mg of the title compound.
Reaction SMILES: CC1C(CN2C=C(C(N=[N+]=[N-])=O)C=N2)=C(C)ON=1.[N:19]([C:22]1[CH:23]=[N:24][N:25]([CH2:27][C:28]2[C:29]([CH3:34])=[N:30][O:31][C:32]=2[CH3:33])[CH:26]=1)=[C:20]=[O:21].Cl.[NH2:36][C:37]([CH3:44])([CH3:43])[C:38](OCC)=[O:39]>C1(C)C=CC=CC=1>[CH3:34][C:29]1[C:28]([CH2:27][N:25]2[CH:26]=[C:22]([N:19]3[C:38](=[O:39])[C:37]([CH3:44])([CH3:43])[NH:36][C:20]3=[O:21])[CH:23]=[N:24]2)=[C:32]([CH3:33])[O:31][N:30]=1
Reactant: CCOC(=O)C(C)(C)N
Reactant: Cc1noc(C)c1Cn1cc(N=C=O)cn1
Agent: Cc1noc(C)c1Cn1cc(C(=O)N=[N+]=[N-])cn1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbonyl azide (Example 10-1a) (10 g, 41.0 mmol) is stirred under nitrogen in dry toluene (150 mL) along with molecular sieves at reflux until no emission of nitrogen was observed, which indicates complete conversion of 1-((3, 5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbonyl azide into 4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole. The solution was cooled down to 50° C. and ethyl 2-amino-2-methylpropanoate hydrochloride (5.30 g, 41.0 mmol) was added in one portion. Stirring continued for 3 hours at 50° C. followed by reflux for 12 hours. The mixture was filtered over a pad of celite. The filtrate was concentrated on the rotovap and the residue was purified over silica gel using 25% ethyl acetate in hexanes. Yield 65% (8.00 g), white solid. 1H NMR (DMSO-d6, 400 MHz): . s, 6H), 2.15 (s, 3H), 2.41 (s, 3H), 5.18 (s, 2H), 7.78 (d, J=0.4 Hz, 1H), 8.16 (d, J=0.4 Hz, 1H), 8.59 (br s, 1H). MS 304 (MH+). This compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 2.27 μM.
Reaction SMILES: [C:1]([C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>C(O)(=O)C.[Pd]>[CH2:1]([C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC#Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1c[nH]cn1
Reaction time: 16 h
Yield: 89.7 %

Procedure:
Twenty percent Pd/C (1 g) was added to a solution of 4-(1-dodecynyl)-1-(triphenylmethyl) imidazole (2.39 g, 5 mmol) in glacial acetic acid (100 mL), along with 50 psi of hydrogen gas. Stirred for 16 hours and concentrated in vacuo. The residue was made basic with saturated Na2CO3, neutralized with 1N HCl, and extracted with ether. The ether layer was dried over MgSO4, filtered, and concentrated to give an oily white solid. Recrystallized from hexanes to give the title compound as a white solid (1.06 g, 90%); mp 69°-71° C.
Reaction SMILES: [NH2:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12.[CH3:28][CH2:29][C:30](Cl)=[S:31].[OH-].[Na+]>C(=O)(O)[O-].[Na+].CC(C)=O>[CH3:28][CH2:29][C:30]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:19][N:20]=[N:21][N:22]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[S:31]
Reactant: CS(=O)(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CCC(=S)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(=S)N[C@@H]1C(=O)N2C(C(=O)O)=C(C(CCNS(C)(=O)=O)Sc3nnn[nH]3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (-20°) solution of 11.32 g (0.026 mol) of 7-amino-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 220 ml of 3% sodium bicarbonate and 220 ml of acetone is added dropwise a solution of 3.66 g (0.029 mol) of methylthioacetyl chloride in 52 ml of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml of ethyl acetate is added and the slurry is acidified with 3N hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]([CH2:30][CH2:31][NH2:32])[CH2:27][CH2:28][NH2:29]>>[NH2:29][CH2:28][CH2:27][O:26][CH2:30][CH2:31][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: NCCOCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCOCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2′-oxydiethanamine. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 (dd, J=1.2, 7.6 Hz, 1 H), 7.92 (s, 1 H), 7.83 (d, J=7.2 Hz, 1 H), 7.70-7.67 (m, 2 H), 7.59-7.55 (m, 2 H), 5.96 (s, 1 H), 5.28 (s, 2 H), 4.49 (s, 2 H), 3.81 (t, J=5.2 Hz, 2 H), 3.72-3.68 (m, 6 H), 3.13 (t, J=4.8 Hz, 2 H), 2.45 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@:10]([OH:18])([CH:15]([CH3:17])[CH3:16])[CH2:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH3:19][C@H](N)C1C=CC=CC=1>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C@@:10]([OH:18])([CH:15]([CH3:16])[CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[C:6]([CH3:19])[CH:7]=1
Reactant: CC(C)[C@@](O)(CCc1ccc(F)cc1)CC(=O)O
Reactant: C[C@H](N)c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1CC[C@](O)(CC(=O)O)C(C)C
Temperature: 25 °C

Procedure:
Compound G-16 (enriched—62% (S)-enantiomer/38% (R) enantiomer) (11.1 g, 41.5 mmol) was dissolved in 120 mL EtOAc and treated with (S)-α-methylbenzylamine (6.52 g, 53.79 mmol). The resulting suspension was heated to reflux until all solids dissolved, at which time the solution was allowed to cool to room temperature overnight. The reaction flask was cooled to 0° C. for 1 hour. The resulting solids were filtered off and washed with cold Et2O. HPLC analysis of isolated solid (as the free acid): (AS chiralpak column, 0.8 mL/min., 98% Hexanes/2% IPA/+0.1% Formic acid).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:14])[N:3]=1.O.[CH3:35][N:36](C=O)C>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>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([C:35]#[N:36])=[N:3][C:4]([C@@H:13]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][N:20]3[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH3:14])=[CH:5]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C#N)n4)ncnc32)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ((S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (1.5 g, 3.1 mmol, 1.0 eq) and tetrakis(triphenylphosphine)palladium (181 mg, 0.16 mmol, 0.05 eq) in DMF (50 mL) at RT, dicyanozine (476 mg, 4.06 mmol, 1.3 eq) was added and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was poured into water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbonitrile 29.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C.CCCCCC.CCOCC>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)C(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-fluorophenyl glyoxylic acid (100 mg, 0.595 mmol) in ethyl ether (5 ml) was added trimethylsilyl diazomethane (2 M/hexane, 1 ml) at 0° C. TLC showed reaction was complete after 1 h. The ether was evaporated to leave a yellow oil. Chromatography with hexane/ether (95:5) gave methyl 4-fluorophenylglyoxalate as a pale yellow oil (75 mg). 500 MHz 13C NMR (CDCl3): δ 184.11; 167.85; 165.79; 163.59; 133.04; 132.96; 128.97; 116.33; 116.16; 115.90; 115.72; 52.85.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:37])=[C:15]([C@:17]23[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]2[C:21](=[O:27])[N:20]([CH3:28])[C:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:18]3)[CH:16]=1.[CH3:38][O:39][C:40]1[N:41]=[CH:42][C:43]([C:46](O)=[O:47])=[N:44][CH:45]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:37][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:46]([C:43]2[CH:42]=[N:41][C:40]([O:39][CH3:38])=[CH:45][N:44]=2)=[O:47])=[CH:16][C:15]=1[C@:17]12[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]1[C:21](=[O:27])[N:20]([CH3:28])[C:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[N:18]2
Reactant: COc1cnc(C(=O)O)cn1
Reactant: C[C@H]1OC[C@]2(c3cc(N)ccc3F)N=C(NC(=O)OC(C)(C)C)N(C)C(=O)[C@H]12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C)[C@H]3C(=O)N(C)C(NC(=O)OC(C)(C)C)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
N-Ethyl-N-(propan-2-yl)propan-2-amine (0.33 mL, 1.9 mmol) was added to a stirred mixture of tert-butyl ((4aS,5R,7aS)-7a-(5-amino-2-fluorophenyl)-3,5-dimethyl-4-oxo-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (150 mg, 0.38 mmol), 5-methoxypyrazine-2-carboxylic acid (89 mg, 0.57 mmol) and (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (300 mg, 0.57 mmol) in dry DCM (2 mL). The mixture was stirred at RT overnight. The reaction mixture was partitioned between DCM and NaHCO3 (aq). The aqueous layer was extracted with DCM (×2). The combined extracts were dried by passing through a hydrophobic frit and then evaporated. The residue was purified by column chromatography (normal phase, 10 g, Biotage SNAP cartridge KP-Sil, 12 mL per min, gradient 5% to 30% EtOAc in n-hexane) to give the title compound (213 mg, foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.52 (d, J=6.06 Hz, 3H) 1.56 (s, 9H) 3.31 (s, 3H) 3.44 (dd, J=9.09, 1.77 Hz, 1H) 4.08 (s, 3H) 4.31 (d, J=9.85 Hz, 1H) 4.37-4.47 (m, 2H) 7.16 (dd, J=10.74, 8.97 Hz, 1H) 7.54 (dd, J=6.82, 2.53 Hz, 1H) 7.84 (ddd, J=8.78, 4.23, 2.65 Hz, 1H) 8.15 (d, J=1.26 Hz, 1H) 9.01 (d, J=1.26 Hz, 1H) 9.49 (s, 1H) 10.60 (s, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[N+:2]=[N-:3].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1>[N+:10]([C:6]1[CH:5]=[C:4]([N:1]2[CH:18]=[C:17]([Si:14]([CH3:16])([CH3:15])[CH3:13])[N:3]=[N:2]2)[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: [N-]=[N+]=Nc1cccc([N+](=O)[O-])c1
Reactant: C#C[Si](C)(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cn(-c2cccc([N+](=O)[O-])c2)nn1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
Azido-3-nitro-benzene (CAS:1516-59-2, 11.8 g, 72 mmol) were dissolved in 20 ml THF and 30 ml trimethylsilylacetylene. The reaction mixture was stirred at 60° C. for 3 days. The solvents were evaporated off and the title compound was obtained as a brown solid (16.9 g, 90%), mp 75-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1.P(Br)(Br)[Br:20]>C1COCC1.CCOC(C)=O>[Br:20][CH2:14][C:13]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:10][O:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: BrP(Br)Br
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CBr

Procedure:
To a solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-yl]-methanol (1.14 g, 4 mmol) in THF (20 mL) is added PBr3 (0.76 mL, 8 mmol). The reaction mixture is stirred at reflux for 30 minutes. The reaction mixture is diluted with EtOAc and is washed with 0.2 N HCl. The organic layer is separated, dried (MgSO4), filtered, and concentrated to give the title compound as an oil.
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][C:9]([NH:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+]>CO>[C:29]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][C:9]([NH:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])=[O:10])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)CCNC(=O)CNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)CNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1.7 Grams of ethyl 3-(2-{(3,3,3-triphenylpropanoyl)amino}acetylamino)propionate was dissolved in a mixed liquid consisting of 70 ml of tetrahydrofuran and 20 ml of methanol. To the solution 5.0 ml of 4N aqueous sodium hydroxide solution was added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was distilled off under reduced pressure, and the residue was rendered acidic by addition of 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated saline solution and dried over anhydrous magnesium sulfate. Upon distilling the solvent off under reduced pressure, 1.10 g of the title compound was obtained.
Reaction SMILES: N1C=CC=C(CN)C=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16].FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[CH3:41][C:42]1[N:43]=[C:44]([N:50]2[CH2:54][C@@H:53]([CH3:55])[N:52]([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=3)[C:51]2=[O:67])[S:45][C:46]=1[C:47](O)=[O:48]>>[CH3:41][C:42]1[N:43]=[C:44]([N:50]2[CH2:54][C@@H:53]([CH3:55])[N:52]([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:64])([F:66])[F:65])=[CH:59][CH:58]=3)[C:51]2=[O:67])[S:45][C:46]=1[C:47]([NH:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)=[O:48]
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccccn1
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccn1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with pyridin-2-ylmethanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-4-methyl-2-(4-methyl-2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a solid (61%): mp 136-137° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.55-8.49 (m, 2H), 7.79-7.71 (m, 3H), 7.56 (d, J=8.1 Hz, 2H), 7.31-7.24 (m, 2H), 4.67 (d, J=16.1 Hz, 1H), 4.49-4.43 (m, 3H), 4.22 (dd, J=10.1, 9.1 Hz, 1H), 3.84-3.77 (m, 1H), 3.56 (dd, J=10.1, 6.8 Hz, 1H), 2.49 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 489.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][NH:13][C:12](=[O:19])[CH:11]=1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]([CH3:22])[C:12](=[O:19])[CH:11]=1
Reactant: CI
Reactant: O=c1cc(Nc2ccc(I)cc2F)c([N+](=O)[O-])c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc([N+](=O)[O-])c(Nc2ccc(I)cc2F)cc1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
4-(2-Fluoro-4-iodophenylamino)-5-nitropyridin-2(1H)-one (1.28 g, 3.41 mmol) was dissolved in dry DMF (20 mL) and cooled to 0° C. under an ice-bath. To the solution was added NaH (60% in oil) (168 mg, 4.2 mmol) portion-wise. The resulted mixture was stirred at 0° C. for 1 hour, followed by the addition of methyl iodide (260 uL, 4.17 mmol) drop-wise through a syringe. The solution was allowed to warm to room temperature and stirred for 16 hours. Water (20 mL) was added slowly and stirring was continued for 30 minutes. The resulted yellow precipitate was filtered, dried under vacuum at 40° C. for 5 hours, and used for the next reaction without further purification. (1.017 g, 77% yield)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:30])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>N1C=CC=CC=1.O1CCOCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:15]2[C:10]([C:8]([C:6]3[N:7]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[CH:3]=[CH:4][CH:5]=3)=[O:9])=[N:11][CH:12]=[C:13]([Cl:30])[CH:14]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(N)n2)cc1
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
N-[2-(6-amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (52 mg, 0.1 mmol) in pyridine/1,4-dioxane (1:1, 4 mL) was treated with acetyl chloride (100 mg) and then stirred at 60° C. for 2 h. After evaporation of solvent under reduced pressure, to the mixture was added THF (5 mL), followed by NaOH (2 N, 2 mL) and stirred at room temperature for another 2 h. The mixture was diluted with EtOAc and the organics were washed with 1 N HCl, NaHCO3 (saturated), and brine; dried over MgSO4, concentrated under reduced pressure, and purified through automated normal-phase chromatography to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 10.80 (s, 1H), 8.37 (d, 1H), 8.22 (m, 2H), 8.14 (s, 1H), 7.80 (m, 3H), 7.46 (m, 3H), 2.20 (s, 3H), 1.23 (s, 9H); MS (ES) (M+H)+ expected 487.1. found 487.1.