Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[N:32]1[O:36][N:35]=[C:34]2[C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=[CH:40][C:33]=12>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:37]4[C:34]5=[N:35][O:36][N:32]=[C:33]5[CH:40]=[CH:39][CH:38]=4)(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc5nonc45)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and benzo[1,2,5]oxadiazole-4-sulfonyl chloride. Purity (ELSD, based on MW=603.6)=95%.
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:29])[C@H:12]([CH3:28])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2C(OC(C)(C)C)=O)[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[ClH:30].O1CCOCC1>>[ClH:30].[CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:29])[C@H:12]([CH3:28])[C@@H:13]([O:14][CH3:15])[C@@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7]1
Reactant: CO[C@H]([C@@H](C)C(=O)NCCC1C=CC=CC=C1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)NCCC1C=CC=CC=C1
Reaction time: 1 h

Procedure:
Intermediate #63 (400 mg, 0.989 mmol, 1 eq.) was treated with a 4 M solution of hydrochloric acid in dioxane (10 mL, 40 mmol, 40 eq.). After 1 hour, the reaction mixture was concentrated in vacuo and the residue was taken up in dichloromethane and washed with 1 M sodium hydroxide solution. The aqueous layer was back-extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide #64 (301 mg, quantitative) as a brown oil, which slowly began to solidify upon standing. LC-MS: m/z 305.3 [M+H+], retention time=0.54 minutes; HPLC (Protocol G): retention time=4.848 minutes; 1H NMR (400 MHz, CDCl3), characteristic signals: δ 6.64-6.67 (m, 2H), 6.16-6.22 (m, 2H), 6.08-6.14 (br m, 1H), 5.16-5.22 (m, 2H), 3.44 (s, 3H), 3.31 (dd, J=6.3, 4.5 Hz, 1H), 2.98-3.04 (m, 1H), 2.94 (ddd, J=10.5, 7.2, 5.6 Hz, 1H), 2.81 (ddd, J=10.5, 7.7, 6.7 Hz, 1H), 2.57 (qd, J=7.1, 4.5 Hz, 1H), 1.90-1.97 (m, 2H), 1.49-1.55 (m, 1H), 1.18 (d, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]1[CH:42]=[CH:41][C:11]([C:12]([NH:14][C:15]2[C:16]3[CH:29]=[C:28]([C:30]([NH:32][N:33]([CH3:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[S:27][C:17]=3[N:18](C(OC(C)(C)C)=O)[N:19]=2)=[O:13])=[CH:10][CH:9]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:40][N:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:30]([C:28]1[S:27][C:17]2[NH:18][N:19]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[CH:41]=[CH:42][C:8]([CH2:7][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[C:16]=2[CH:29]=1)=[O:31]
Reactant: C1CCNC1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide and then 93 μL (1.11 mmol) of pyrrolidine are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 25 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-pyrrolidin-1-ylmethylbenzamide are thus obtained in the form of a yellow powder melting from 172 to 178° C. LC-MS-DAD-ELSD: 475(+)=(M+H)(+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[NH:5]2.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[N:5]2[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC1Nc2cc(Br)ccc2-n2cccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N2c3cc(Br)ccc3-n3cccc3C2C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
A solution of 7-bromo-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (225 mg, 0.86 mmol) in methylene chloride (4 mL), under nitrogen, was treated with m-anisoyl chloride (219 mg, 1.28 mmol) followed by triethyl amine (0.24 mL, 1.72 mmol). The reaction was stirred at 25° C. for 15 h, after which time the reaction was washed with a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was concentrated in vacuo. The product was purified via Biotage Horizon® (25S, silica, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane) to yield 287 mg (84%) of 7-bromo-5-(3-methoxybenzoyl)-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline as a white foam. MS (ESI) m/z 397/399 ([M+H]+); HRMS: calcd for C20H17BrN2O2, 396.0473; found (ESI+), 397.05389.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:23]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:22]=[CH:21][CH:20]=4)[CH:17]=3)[C:12]([CH2:30][CH3:31])=[N:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]2[C:19]([C:16]3[CH:17]=[C:18]4[C:13]([C:12]([CH2:30][CH3:31])=[N:11][N:10]4[CH:5]4[CH2:9][CH2:8][CH2:7][CH2:6]4)=[CH:14][CH:15]=3)=[CH:20][CH:21]=[N:22]2)[CH2:25][CH2:26]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCc1nn(C2CCCC2)c2cc(-c3ccnn3C3CCNCC3)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nn(C2CCCC2)c2cc(-c3ccnn3C3CCN(C(C)=O)CC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
Acetyl chloride (7.8 μL, 0.11 mmol) was slowly added to a mixture of 1-cyclopentyl-3-ethyl-6-(1-piperidin-4-yl-1H-pyrazol-5-yl)-1H-indazole (20 mg, 0.055 mmol), triethylamine (15 μL, 0.11 mmol) in methylene chloride (2 mL), and the reaction was stirred for 16 hours at room temperature. Methylene chloride was added and the organic layer was washed with saturated sodium bicarbonate, water, then brine, dried, filtered and concentrated. The residue was dissolved in ethyl acetate and purified by silica gel column chromatography using 100% ethyl acetate as the eluent to afford 18 mg (81%) of 6-[1-(1-acetylpiperidin-4-yl)-1H-pyrazol-5-yl]-1-cyclopentyl-3-ethyl-1H-indazole. LC/MS (EI) tR 4.29 (Method C), m/z 406.3 (M++1).
Reaction SMILES: C(OC([NH:8][C:9]1[C:49]([CH3:50])=[CH:48][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:29][C:30](=O)[CH2:31][O:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH:40]4[S:44][C:43](=[O:45])[NH:42][C:41]4=[O:46])=[CH:35][CH:34]=3)=[C:18]([N:20]([CH3:28])C(=O)OC(C)(C)C)[CH:19]=2)=[CH:11][C:10]=1[CH3:51])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C:9]1[C:49]([CH3:50])=[CH:48][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[N:29]=[C:30]([CH2:31][O:32][C:33]4[CH:34]=[CH:35][C:36]([CH2:39][CH:40]5[S:44][C:43](=[O:45])[NH:42][C:41]5=[O:46])=[CH:37][CH:38]=4)[N:20]([CH3:28])[C:18]=3[CH:19]=2)=[CH:11][C:10]=1[CH3:51]
Reactant: Cc1cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1N
Temperature: 25 °C
Reaction time: 23 h
Yield: 19.8 %

Procedure:
A mixture of t-butyl N-[5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)-2-[4-(2,4dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate (1.88 g) and 4N hydrogen chloride in 1,4-dioxane (20 ml) was stirred at room temperature for 23 hours. The reaction mixture was concentrated and water added to the residue. The mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1 as the eluant to afford the desired compound (0.26 g, mp 209-211° C.).
Reaction SMILES: [H-].[Na+].C[CH:4](C)[C@H:5]([C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)[C:6](=[O:12])[CH2:7]P(=O)(O)O.P(=O)(O)O.[CH:25]([C@H:27]1[C@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][C@H:32]2[C@@H:28]1[CH2:29][C:30](=[O:44])[O:31]2)=O>COCCOC>[O:12]=[C:6]([C@@H:5]([C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)[CH3:4])/[CH:7]=[CH:25]/[C@H:27]1[C@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][C@H:32]2[C@@H:28]1[CH2:29][C:30](=[O:44])[O:31]2
Reactant: Cc1cccc([C@H](C(=O)CP(=O)(O)O)C(C)C)c1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: O=[PH](O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc([C@@H](C)C(=O)/C=C/[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2OC(=O)c2ccccc2)c1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Sodium hydride (55%) (8.75 g) was dispersed in 1,2-dimethoxyethane (DME) (300 mL) and the mixture was ice-cooled. A solution of phosphonate {dimethyl (3R)-2-oxo-3-(m-tolyl)butylphosphonate} (54.7 g) synthesized in Example 2 in DME (50 mL) was added, and the mixture was stirred for 1 hr. To the above-mentioned solution was added a solution of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one (50.0 g) in DME (400 mL), and the mixture was stirred for 1 hr. The reaction was quenched with 350 mL of 10% brine, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the residue was concentrated under reduced pressure. The concentrated crude product was recrystallized from t-butyl methyl ether to give the title compound (64.7 g). The structural property was as described below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: COc1cccc(C(=O)Nc2nc(C)c(C(=O)NCc3ccccc3)s2)c1
Yield: 34 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-methoxybenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 34% yield; m.p. 75-77° C.; 1H NMR (CDCl3, 300 MHz) δ 7.43-7.31 (m, 8H), 7.12 (td, J=2.4, 6.7 Hz, 1H), 5.97 (t, J=5.6 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 3.82 (s, 3H), 2.47 (s, 3H); MS (ES+) m/z 382.1 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-])=O)[C:6]1=[O:18].CO>>[NH2:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]2=[O:18]
Reactant: COCCn1ccc2c([N+](=O)[O-])cccc2c1=O
Solvent: CO
Product: COCCn1ccc2c(N)cccc2c1=O
Reaction time: 2 h

Procedure:
Into a 250 ml round bottom flask was combined 2-(2-methoxyethyl)-5-nitroisoquinolin-1(2H)-one (1.23 g, 0.00495 mol) palladium/C (0.05 g, 0.0005 mol) and methanol (50 mL, 1 mol). The flask was purged and evacuated with hydrogen twice and the mixture was allowed to stirr under an atmosphere of hydrogen (1 atm) for two hours. The mixture was filtered over Celite and the filtrate reduced in vacuo to yield the title compound as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14]C(OCC2C=CC=CC=2)=O)[C@H:10]([OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](O)C1

Procedure:
To a stirred solution of (±)-cis-4-benzyloxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.365 mmol, 0.128 g)) in methanol (3 mL) was added 10% palladium on carbon (0.07 g, wet). The resultant reaction mixture was subjected to hydrogenation using a balloon full of hydrogen for 2 h. The catalyst was filtered through a pad of celite. The pad was washed with methanol (10 mL), and the combined filtrate was concentrated under reduced pressure to get (±)-cis-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([C:18]1[C:26]([F:27])=[CH:25][C:21]2[S:22][CH:23]=[CH:24][C:20]=2[CH:19]=1)[OH:17].Cl>C(Cl)Cl.C(OCC)C.C(OCC)(=O)C.O.C(N(CC)CC)C>[Cl:11][CH2:12][CH2:13][O:14][CH2:15][C:16]([C:18]1[C:26]([F:27])=[CH:25][C:21]2[S:22][CH:23]=[CH:24][C:20]=2[CH:19]=1)=[O:17]
Reactant: OC(COCCCl)c1cc2ccsc2cc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: O=C(COCCCl)c1cc2ccsc2cc1F
Reaction time: 0.5 h

Procedure:
To a solution of 8.73 ml of oxalyl chloride in 90 ml of methylene chloride is dropwise added 14.2 ml of dimethyl sulfoxide at -70° C. over 30 minutes. The solution is stirred at the same temperature for ten minutes, after which a solution of 11 g of 2-(2-chloroethoxy)-1-(6-fluorobenzo[b]thiophen-5-yl)ethanol in 90 ml of methylene chloride is dropwise added thereto at the same temperature over 30 minutes. The resulting mixture is stirred at the same temperature for 30 minutes, and then, 50.2 ml of triethylamine is dropwise added thereto. The temperature of the resulting mixture is elevated to room temperature, and thereafter, 200 ml of diethyl ether is added thereto. Then, insolubles are removed from the diethyl ether-added mixture by filtration. Then, the solvent is removed from the resulting filtrate by distillation under reduced pressure. To the residue obtained are added 200 ml of water and 200 ml of ethyl acetate, and then, the pH is adjusted to 1 with 1N hydrochloric acid. Thereafter, the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is removed from the thus dried layer by distillation under reduced pressure. To the residue obtained is added 50 ml of diethyl ether, after which insolubles are collected by filtration, to obtain 9.5 g of colorless, solid 2-(2-chloroethoxy)-1-(6-fluorobenzo[b]thiophen-5-yl)ethanone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[Br:11]
Reactant: Oc1ccccc1Br
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cccc(Oc2ccccc2Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
To a stirred solution of 3-fluorophenylboronic acid (2.10 g, 15 mmol), 2-bromophenol (1.77 g, 10 mmol) and Cu(OAc)2 (0.93 g, 5 mmol) in anhydrous CH2Cl2 (25 mL) was added activated 4 Å molecular sieves (˜0.1 g), followed by anhydrous Et3N (3.5 mL, 25 mmol). The resulting dark green solution was stirred at rt for 48 h. The mixture was evaporated under reduced pressure and the residue was washed several times with Et2O (˜150 mL). The Et2O solution was washed with sat'd aq NH4Cl, and 1 N aq HCl. The organic layer was evaporated and the crude product was purified by flash column chromatography to give 1-(3-fluorophenoxy)-2-bromobenzene (1.28 g, 48%) as clear oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][NH2:11])=O)=[CH:3][CH:2]=1.Cl[C:13]1[N:14]=[N:15][C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][CH:18]=1>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[N:14]3[N:15]=[C:16]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH:17]=[CH:18][C:13]3=[N:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: Clc1ccc(-c2cccs2)nn1
Reactant: NNC(=O)Cc1ccncc1
Product: c1csc(-c2ccc3nnc(Cc4ccncc4)n3n2)c1

Procedure:
The title compound was prepared as described in Example 17 from 4-pyridineacetic acid hydrazide (1.81 mmol) and 3-chloro-6-thiophen-2-yl-pyridazine (0.58 mmol) as a pale yellow solid. 1H NMR (CD3OD) δ 8.50 (2H dd, J=4.6 Hz, 1.4 Hz), 8.22 (1H d, J=9.6 Hz), 7.94 (1H, dd, J=3.8 Hz, 1.2 Hz), 7.93 (1H, d, J=9.8 Hz), 7.74 (1H, dd, J=5.0 Hz, 1.0 Hz), 7.52 (2H, m), 7.23 (1H, dd, J=5.3 Hz, 3.8 Hz), 4.69 (2H, s). ESI-MS (m/z): Calcd for C15H11N5S: 293.1; found 294.2 (M+H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C:26](O)=[O:27])[C:20]4=[N:19][N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:44][C@@H:45]([CH2:48][CH3:49])[CH2:46][OH:47].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[OH:47][CH2:46][C@@H:45]([NH:44][C:26]([C:25]1[C:20]2[N:21]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:13]=3)=[N:18][N:19]=2)[CH:22]=[CH:23][CH:24]=1)=[O:27])[CH2:48][CH3:49]
Reactant: O=C(Cc1ccccc1)Nc1ccc(-c2nnc3c(C(=O)O)cccn23)cc1
Reactant: CC[C@H](N)CO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@@H](CO)NC(=O)c1cccn2c(-c3ccc(NC(=O)Cc4ccccc4)cc3)nnc12
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
A suspension of 3-(4-(2-phenylacetamido)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (59A) (14 mg, 0.038 mmol), EDC (9 mg, 0.047 mmol) and HOBt (6.4 mg, 0.047 mmol) in a mixed solvent of DMF (0.5 mL) and DCM (0.5 mL) was stirred for 5 min, and then (S)-2-aminobutan-1-ol hydrochloride salt (5.6 mg, 0.045 mmol) and triethylamine (7.6 mg, 0.075 mmol) were added. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The crude product was purified by preparative HPLC using CH3CN/H2O/TFA solvent system to yield the title compound (8.3 mg, 50%). HPLC/MS (Method C): retention time 1.75, [M+H]+=444.5. 1H NMR (500 MHz, DMSO-d6): δ 10.50 (s, 1H), 9.58 (d, J=8.25 Hz, 1H), 8.71 (d, J=7.15 Hz, 1H), 8.14 (d, J=6.05 Hz, 1H), 7.80-7.92 (m, 4H), 7.30-7.43 (m, 4H), 7.26 (t, J=6.60 Hz, 1H), 7.19 (t, J=6.87 Hz, 1H), 3.93-4.07 (m, 1H), 3.71 (s, 2H), 3.54-3.63 (m, 1H), 3.50 (dd, J=11.0 Hz, 4.95 Hz, 1H), 1.68-1.78 (m, 1H), 1.54-1.65 (m, 1H), 0.87-1.06 (m, 3H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9](=[O:12])[CH:10]=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23]>CO>[CH2:1]([C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9](=[O:12])[CH2:10][CH2:11][N:22]([CH3:23])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: C=CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Product: CN(C)CCC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared according to Scheme 1 in an analogous manner as intermediate III with the one additional step; step B involving Michael addition using dimethyl amine (vida infra). Step A: To a solution of N-Boc-phenylalanine-Weinreb amide (10.0 g, 32.4 mmol) in 200 mL THF cooled to −40° C. was added vinyl magnesium bromide (97.0 mL, 97.0 mmol, 1.0 M in THF) dropwise. After stirring at −40 to −20° C. for 5 h. The reaction mixture was poured onto cold 3N HCl (600 mL), extracted with EtOAc (3×200 mL), the organic layers combined and washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford crude tert-butyl (1S)-1-benzyl-2-oxobut-3-enylcarbamate which was used as is in the following Michael addition reaction. Step B: In a flask containing tert-butyl (1S)-1-benzyl-2-oxobut-3-enylcarbamate (0.75 g, 2.72 mmol) in MeOH (10 mL) was added dimethyl amine (2.73 mL, 2.0 M MeOH, 5.45 mmol). The mixture was stirred at rt for 1 h. The mixture was concentrated to dryness to give tert-butyl (1S)-1-benzyl-4-(dimethylamino)-2-oxobutylcarbamate which was used in the next reaction without further purification. Step C: In a 50 mL flask containing ketone (825 mg, 2.57 mmol) from step B in 25 mL of EtOH at room temperature was added NaBH4 (92 mg, 2.57 mmol) in two portions. The mixture was stirred overnight and lmL of H2O added. The reaction was concentrated to dryness and partitioned between EtOAc and H2O. The layers were separated and the aqueous layer extracted once again. The combined organic layers were washed with brine, dried over Na4SO4 and concentrated to dryness to give crude tert-butyl (1S,2RS)-1-benzyl-4-(dimethylamino)-2-hydroxybutylcarbamate. 1H NMR indicated a mixture of alpha and beta diastereomers. The crude material was deprotected in step D below without further purification. Step D: A scintillation vial containing tert-butyl (1S,2RS)-1-benzyl-4-(dimethylamino)-2-hydroxybutylcarbamate (250 mg, 0.78 mmol) in EtOAc was cooled to 0° C. HCl (g) was gently bubbled into the mixture for ca. 1 min. The vial was sealed with a cap and allowed to warm to rt. After 30 min. the mixture was concentrated with N2 and then concentrated further via rotorary evaporation to give an off-white solid intermediate XII, N-(2S,3RS)-2-amino-5-(dimethylamino)-1-phenylpentan-3-ol as hydrochloride salt: (2:1 ratio of diastereomers, major isomer reported) 1H NMR (400 MHz, MeOD) δ 7.28 (m, 5H), 3.91 (dt, J=6.9 Hz, 3.6 Hz, 1H), 3.61 (m, 1H), 3.35 (m, 2H) 3.22 (m, 2H), 2.9-3.0 (overlapping m, 2H), 2.89 (s, 6H); ES MS (M+H)=223.3.