Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:5].[OH:19][CH2:20][CH2:21][O:22][C:23]1[C:30]([CH3:31])=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[CH3:32]>C(O)C.[Cu](Cl)Cl>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:17]([Cl:18])[CH:16]=[CH:15][CH:14]=3)[N:1]=[C:27]2[C:26]2[CH:29]=[C:30]([CH3:31])[C:23]([O:22][CH2:21][CH2:20][OH:19])=[C:24]([CH3:32])[CH:25]=2)=[CH:12][CH:11]=1
Reactant: Nc1c(Cl)cccc1C(=O)Nc1ccc(Br)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cl[Cu]Cl
Solvent: CCO
Product: Cc1cc(-c2nc3c(Cl)cccc3c(=O)n2-c2ccc(Br)cc2)cc(C)c1OCCO

Procedure:
To a solution of 2-amino-N-(4-bromophenyl)-3-chlorobenzamide (0.52 g, 1.60 mmol) and 4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde (0.31 g, 1.60 mmol) in anhydrous ethanol (20 mL), anhydrous copper (II) chloride (0.86 g, 6.40 mmol) was added and the reaction mixture was refluxed for 16 hours. The solvent was evaporated in vacuo, water (100 mL) was then added, and the product was extracted with ethyl acetate (200 mL). The organic phase was separated, washed with water (2×100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. The solvent was evaporated, and the crude compound was purified by the Simpliflash system (20-40% ethyl acetate in hexanes as eluent), to give the title compound as a white solid. Yield 0.37 g (46%). MP 185-186° C. 1H-NMR (400 MHz, CDCl3) 8.25 (d, J=8.20 Hz, 1H) 7.89 (d, J=7.42 Hz, 1H) 7.56-7.34 (m, 3H) 7.03 (t, J=4.29 Hz, 4H), 4.06-3.87 (m, 2H) 3.87-3.74 (m, 2H) 2.18 (s, 6H) 2.11-1.95 (m, 1H). MS (ES+) m/z: 499.36, 501.38 (100%), 503.33.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([SH:12])=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C.C(OCC)C.O.C(=O)(O)[O-]>[CH3:23][CH:22]([CH3:24])[CH2:21][CH:16]([S:12][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][N:10]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(Br)CC(C)C
Reactant: Sc1nnc(-c2ccccc2)[nH]1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)C(CC(C)C)Sc1nnc(-c2ccccc2)[nH]1
Reaction time: 0.5 h

Procedure:
5-Phenyl-4H-1,2,4-triazole-3-thiol (296 mg, 1.67 mmoles) in 5 mL of DMF was treated with sodium hydride (67 mg, 60% oil dispersion, 1.76 mmoles) and stirred for 30 minutes. Methyl 2-bromo-4-methylpentanoate (275 μL, 1.67 mmoles) was added in one portion and the reaction was stirred overnight. The reaction was diluted with diethyl ether, water and sat. aq. bicarbonate. The phases were separated and the organic phase was washed with 2 portions of 1.2 N hydrochloric acid and then brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a residue which was purified by flash chromatography to give methyl 4-methyl-2-[(5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]pentanoate.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:20]=[C:16]2[N:15]=[C:14]([CH3:26])[C:13]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C1(C2[O:41]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:20]=[C:16]2[N:15]=[C:14]([CH3:26])[C:13]=1[CH:27]([OH:41])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2nc(C)c(C(O)C(=O)OCC)c(Cl)n2n1
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a stirred solution of 0.9M KHMDS (40.9 mL, 36.8 mmol) in THF (100 mL) at −78° C. was added a THF (50 mL) solution of ethyl 7-chloro-6-(2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (10 g, 30.7 mmol, for synthesis see WO2013025584) was added over the course of 20 min. After 30 min, a THF (15 mL) solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (10.43 g, 39.9 mmol) was added to the red reaction mixture and stirring was continued for an additional 30 min at −78° C. Then, the resulting orange reaction mixture was quenched with sat. aq. NH4Cl (50 mL), diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a solid. This solid was triturated with small amount of ethyl acetate and solids were filtered, washed with hexanes and dried under high vacuum to afford ethyl 7-chloro-6-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5 g, 16.85 mmol, 43% yield, 90% pure) as light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 5.76 (s, 1H), 4.58-4.49 (m, 2H), 4.33 (dtt, J=10.7, 7.1, 3.7 Hz, 2H), 2.71-2.64 (s, 3H), 1.48 (t, J=7.2 Hz, 3H), 1.29-1.24 (m, 3H). LCMS (M+1)=342.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([NH:14]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34]>[Ni].O1CCOCC1.CO>[NH2:14][C:6]1[C:7](=[O:13])[N:8]([CH3:12])[C:9]2[C:4]([C:5]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2
Reactant: Cn1c(=O)c(NC(=O)OCc2ccc([N+](=O)[O-])cc2)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CO
Product: Cn1c(=O)c(N)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A mixture of 6-chloro-4-(2-chlorophenyl)-1,2-dihydro-1-methyl-3-(4-nitrobenzyloxycarbonylamino)-2-oxoquinoline (1.9 g, 3.8 mmol) and Raney nickel (1.9 g, 50% slurry in water) in 75 ml dioxane and 75 ml methanol was shaken under hydrogen (50 psi) in a Parr hydrogenation apparatus for 3 h. The catalyst was filtered and the filtrate was concentrated to dryness in vacuo. The residue was dissolved in 100 ml ethyl acetate and the solution was washed with 60 ml brine. The ethyl acetate solution was then dried (sodium sulfate) and concentrated in vacuo to a solid (1.2 g) which was purified by column chromatography on silica gel (150 g), eluting with 7:3 hexane/ethyl acetate to yield the title compound as an off-white solid (950 mg, 79% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:19])[C:11](=[O:18])[CH:12]=[CH:13][C:14]=2[C:15]([OH:17])=O)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH:43]1([CH2:46][O:47][NH2:48])[CH2:45][CH2:44]1.CCN(CC)CC>CC(N(C)C)=O.CCOC(C)=O>[CH:43]1([CH2:46][O:47][NH:48][C:15]([C:14]2[CH:13]=[CH:12][C:11](=[O:18])[N:10]([CH3:19])[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:20])=[O:17])[CH2:45][CH2:44]1
Reactant: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)ccc1=O
Reactant: NOCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)NOCC2CC2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A mixture of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.022 g, 0.064 mmol), EDCl (0.019 g, 0.097 mmol), and HOBt (0.019 g, 0.097 mmol) in DMA (1 mL) was stirred for 30 minutes at room temperature under N2. O-Cyclopropylmethyl-hydroxylamine (0.017 g, 0.19 mmol) was added followed by Et3N (0.022 mL, 0.016 g, 0.16 mmol). After the reaction mixture was stirred for 16 hours at room temperature, it was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and saturated NaCl. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/methanol, 20:1) gave 0.015 g (57%) pure desired product as a yellow solid. MS APCI (−) m/z 410, 411 (M−, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 11.4 (s, 1H), 9.81 (s, 1H), 7.58 (m, 2H), 7.28 (d, 1H), 6.82 (t, 1H), 6.17 (d, 1H), 3.46 (d, 2H), 3.22 (s, 3H), 0.99 (m, 1H), 0.48 (m, 2H), 0.18 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]3[CH2:29][CH2:30][C:31](=O)[C:32]=3[C:24]=2[N:23]=[C:22]1[CH3:34])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.O>[CH2:14]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]3[CH2:29][CH2:30][C:31](=[CH:5][C:3]#[N:4])[C:32]=3[C:24]=2[N:23]=[C:22]1[CH3:34])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a suspension of 60% sodium hydride (32 mg, 0.80 mmol) in tetrahydrofuran (5 mL) was added diethyl cyanomethylphosphonate (142 μL, 0.88 mmol), and the mixture was stirred at room temperature for 30 min. A solution of 3-benzyl-2-methyl-6,7-dihydroindeno[4,5-d]imidazol-8(3H)-one (73.4 mg, 0.27 mmol) in tetrahydrofuran (2 mL) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (53.3 mg, yield 67%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[C:6](=O)[C:5](=O)[C:4]=2[CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>C(O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4]([CH:3]=1)=[C:5]1[C:6](=[C:7]3[CH:8]=[C:9]([Br:16])[CH:10]=[CH:11][C:12]=23)[N:22]=[CH:19][CH:20]=[N:21]1
Reactant: NCCN
Reactant: O=C1C(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Solvent: CCO
Product: Brc1ccc2c3ccc(Br)cc3c3nccnc3c2c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A mixture of 2,7-dibromophenanthrene-9,10-dione (1.0 g, 2.7 mmol), ethylenediamine (1.8 mL, 26.9 mmol) and ethanol (20 mL) was heated to 85° C. After 3 hours, the reaction was cooled to room temperature and the solids were filtered and thoroughly washed methanol to yield 6,11-dibromodibenzo[f,h]quinoxaline (360 mg, 34%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[SH:33].[H-].[Na+]>O>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1cn2nc(-c3ccnc(F)c3)ccc2n1
Reactant: Fc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cn2nc(-c3ccnc(Sc4ccccc4F)c3)ccc2n1
Temperature: 110 °C
Reaction time: 42 h

Procedure:
To a 10-mL, round-bottomed flask was added N-(6-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 3) (0.034 g, 0.13 mmol), DMF (2.0 mL), 2-fluorothiophenol (0.045 mL, 0.42 mmol, Aldrich, St. Louis, Mo.), and sodium hydride (17 mg, 0.45 mmol, 60% dispersion in mineral oil, Aldrich, St. Louis, Mo.). The mixture was stirred at 110° C. for 42 h. The mixture was poured into water and extracted with EtOAc (3×30 mL). The combined extracts were washed with water (2×30 mL) and brine (30 mL) then dried (Na2SO4), and concentrated onto silica. Purification by silica gel chromatography (0 to 3.5% MeOH (2 M in NH3)/CH2Cl2), followed by further purification by preparative HPLC (Phenomenex Synergi 4μ MAX-RP 150×21.2 mm, 2 to 100% CH3CN/H2O, 0.1% TFA, over 15 min) (Phenomenex, Torrance, Calif.) and conversion to the free base by elution of the isolated material through an SCX cartridge (Radleys Discovery Technologies, Essex, UK) with MeOH (2 M in NH3)/CH2Cl2 afforded the title compound as a yellow solid. MS (ESI positive ion) m/z: 380 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.99 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.28 (s, 1H), 8.13 (d, J=9.5 Hz, 1H), 7.82-7.84 (m, 3H), 7.71 (t, J=7.3 Hz, 1H), 7.62 (q, J=6.7 Hz, 1H), 7.43 (t, J=8.8 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 2.11 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CC#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:6]2[N:7]=[CH:2][C:3]([NH2:8])=[N:4][CH:5]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1nccnc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Temperature: 60 °C
Yield: 88 %

Procedure:
Bromopyrazin-2-amine (2.0 g, 11.49 mmol), (4-methylsulfonylphenyl)boronic acid (2.758 g, 13.79 mmol) and K3PO4 (4.878 g, 22.98 mmol) were combined in MeCN (40 mL)/Water (10 mL) and Pd[P(tBu)3]2 (216 mg, 0.4227 mmol) was added. The reaction was heated at 60° C. for 1 hour. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with water, then Et2O then dried in vacuo to give the sub-title compound as a beige solid which was used without further purification (2.53 g, 88% Yield). 1H NMR (400.0 MHz, DMSO) δ 3.20 (s, 3H), 6.80 (br s, 2H), 7.94 (d, 2H), 8.00 (d, 1H), 8.17 (d, 2H) and 8.64 (d, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13]C(=O)C)=[CH:4][CH:3]=1.[C:19]([C:23]([CH2:25][C:26](OCC)=[O:27])=O)([F:22])([F:21])[F:20].O.[OH-].[Na+]>C1(C)C=CC=CC=1.OS(O)(=O)=O>[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:5]1[CH:17]=[C:18]2[C:2](=[CH:3][CH:4]=1)[NH:1][C:26](=[O:27])[CH:25]=[C:23]2[C:19]([F:22])([F:21])[F:20]
Reactant: CC(=O)Nc1ccccc1Cc1ccc(N)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccccc1Cc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 45.5 %

Procedure:
A solution of N-[2-(4-nitrobenzyl)phenyl]acetamide (6.80 g, 25.2 mmol) in EtOAc (700 mL) was treated with Pd (10% on C, 0.53 g, 0.5 mmol). The mixture was stirred under a H2 atmosphere for 5 h. The reaction mixture was filtered through Celite, before being concentrated to yield N-[2-(4-aminobenzyl)phenyl]acetamide (6.00 g, 99%): δH ((CD3)2SO)=2.00 (s, 3H), 3.75 (s, 2H), 4.80 (s, 2H), 6.45 (d, 2H), 6.80 (d, 2H), 7.00–7.15 (m, 3H), 7.35 (d, 1H), 9.20 (s, 1H). A PhMe (75 mL) suspension of this aniline (5.00 g, 20.8 mmol) was treated with a solution of CF3COCH2CO2Et (3.83 g, 20.8 mmol) in PhMe (50 mL), before being heated under reflux for 1.5 h. The PhMe was evaporated off under reduced pressure, then the residue was dissolved in EtOAc (400 mL), before being washed with 0.2 M HCl (50 mL) & brine (50 mL). After drying (MgSO4), the EtOAc solution was filtered & concentrated to give a foam that was dissolved in H2SO4 (40 mL). The mixture was heated at 90° C. for 1.5 h, before being cooled & poured onto crushed ice. H2O was added to adjust the volume to 400 mL, then the off-white precipitate produced was collected by filtration & air-dried. The precipitate was treated with AcOH (8 mL) & 12 M HCl (40 mL), & the resulting suspension was heated under reflux. The solid gradually dissolved & heating was stopped after 4 h. The cooled reaction mixture was poured onto crushed ice (50 g), then H2O (200 mL) was added. The aqueous phase was basicified with solid NaOH, then the mixture was extracted with EtOAc (200 mL). The EtOAc layer was dried (MgSO4), filtered, & concentrated to provide the title compound (3.01 g, 45%): δH ((CD3)2SO)=3.85 (s, 2H), 4.85 (s, 2H), 6.50 (t, 1H), 6.60 (d, 1H), 6.85 (d, 1H), 6.90–7.00 (m, 2H), 7.35 (d, 1H), 7.50 (d, 1H), 7.55 (s, 1H); m/z (ES+)=360.3
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:13](=[O:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O>C(OCC)(=O)C.C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C@H:13]([OH:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)CCl)OCc1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1cccc2ccccc12)[C@H](O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
(3S)-3-Benzyloxycarbonylamino-1-chloro-4-naphthyl-2-butanone (190.1 mg, 0.5 mmol) and a formic acid/triethylamnine azeotropic mixture (0.1 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.34 mg, 0.0005 mmol, s/c=1000) in ethyl acetate (0.5 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, purification by silica gel column chromatography gave a desired compound, (2S,3S)-3-benzyloxycarbonylamino-1-chloro-2-hydroxy-4-naphthylbutane (179.0 mg; yield: 93.3%). As a result of HPLC analysis, the production ratio of the desired (2S,3S)-form to the isomeric (2R,3S)-form, (2S,3S):(2R,3S), was 10.9:1. The results of elementary analysis were as follows.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]=[C:4]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[NH:3]1.[CH2:17]([NH:19][C:20](=[O:34])[NH:21][C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[C:23]=1[C:31](O)=[O:32])[CH3:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH2:17]([NH:19][C:20](=[O:34])[NH:21][C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[C:23]=1[C:31]([N:9]1[CH2:8][CH2:7][C:6]2([N:5]=[C:4]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[NH:3][C:2]2=[O:1])[CH2:11][CH2:10]1)=[O:32])[CH3:18]
Reactant: CC(=O)NCC1=NC2(CCNCC2)C(=O)N1
Reactant: CCNC(=O)Nc1sc2ccccc2c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCNC(=O)Nc1sc2ccccc2c1C(=O)N1CCC2(CC1)N=C(CNC(C)=O)NC2=O
Reaction time: 12 h

Procedure:
Solutions each of 2B (1.0 equivalent), 2-(3-ethylureido)benzo[b]thiophene-3-carboxylic acid (2C, 1.25 equivalents), DMF (0.14 M), EDC (1.25 equivalents), and HOBT (1.25 equivalents) is added triethylamine (1.0 equivalent) at room temperature. After stirring for 12 hr, the reaction is complete as determined by LCMS analysis. The reaction mixture is then partitioned between ethyl acetate and water and the separated organics is dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory LCMS provides N-((8-(2-(3-ethylureido)benzo[b]thiophene-3-carbonyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-2-yl)methyl)acetamide (2), respectively.
Reaction SMILES: [CH2:1]([Si:3]([CH2:15][CH3:16])([CH2:13][CH3:14])[O:4][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6]#[CH:7])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:29]([SnH:33]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>>[CH2:38]([Sn:33]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:34][CH2:35][CH2:36][CH3:37])/[CH:7]=[CH:6]/[CH:5]([O:4][Si:3]([CH2:13][CH3:14])([CH2:1][CH3:2])[CH2:15][CH3:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:39][CH2:40][CH3:41]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(CCCCC)O[Si](CC)(CC)CC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](CC)(CC)CC
Temperature: 25 °C

Procedure:
A solution of 20 g of 3-triethylsilyloxy-1-octyne, 150 mg of azobisisobutyronitrile, and 30 ml of tri-n-butyltin hydride is magnetically stirred un er an argon atmosphere at 140° C. for 2 hours, (EXOTHERMIC), then cooled to ambient temperature. The excess tin hydride is removed by distillation (~70°/1.0 mm). The residue is purified by distillation to provide 36.5 g of the oil (bp 165° C. at 0.05 mm).
Reaction SMILES: N1C=CC=CC=1N1CCN(C[C:14]2[N:18]=[C:17]([NH:19][C@H:20]([C:25]([N:27]3[CH2:34][CH2:33][CH2:32][C@H:28]3[C:29]([OH:31])=[O:30])=[O:26])[CH2:21][CH:22]([CH3:24])C)[S:16][N:15]=2)CC1.[CH3:35][O:36]C1N=C(NC(CC[C@H](C)[C@@H](C([N-]CCC(C)C)=O)N)=O)SN=1.[CH3:59]OC1N=C(NC(CC(C)C[C@@H](C([N-]CCC(C)C)=O)N)=O)SN=1>>[CH3:35][O:36][C:14]1[N:18]=[C:17]([NH:19][C@H:20]([C:25]([N:27]2[CH2:34][CH2:33][CH2:32][C@H:28]2[C:29]([OH:31])=[O:30])=[O:26])[C@H:21]([CH2:22][CH3:24])[CH3:59])[S:16][N:15]=1
Reactant: COc1nsc(NC(=O)CC[C@H](C)[C@H](N)C(=O)[N-]CCC(C)C)n1
Reactant: COc1nsc(NC(=O)CC(C)C[C@H](N)C(=O)[N-]CCC(C)C)n1
Reactant: CC(C)C[C@H](Nc1nc(CN2CCN(c3ccccn3)CC2)ns1)C(=O)N1CCC[C@H]1C(=O)O
Product: CC[C@H](C)[C@H](Nc1nc(OC)ns1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
which has the following chemical formula: ##STR19## {3-[4-(2-pyridyl)piperazinylmethyl]-1,2,4-thiadiazol-5-yl}-leucyl-proline, which has the following chemical formula: ##STR20## 5-{3-methoxy-1,2,4-thiadiazolyl}carbamoyl-leucyl isoamylamide 5-{3-methoxy-1,2,4-thiadiazolyl}carbamoyl-isoleucyl isoamylamide
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[CH:17](O)=[O:18]>CCOCC>[CH:17]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)=[O:18]
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Reactant: O=CO
Solvent: CCOCC
Product: Nc1nc2c(ncn2COCCOC=O)c(=O)[nH]1

Procedure:
A solution of 9-(2-hydroxyethoxymethyl)guanine (4.73 g) in 97% formic acid (24 ml) was stirred at room temperature overnight. The amber solution was diluted with about 200 ml of dry ether and chilled. The resulting white precipitate was filtered, dried and recrystallized from dry dimethylformamide to give 9-(2-formyloxyethoxymethyl)guanine (3.6 g, m.p. 225°-227° C.).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:5]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 37.6 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), tert-butyl 2-aminoacetate (18.29 mg, 0.139 mmol), HATU (45.9 mg, 0.121 mmol), and 4-methylmorpholine (37.6 mg, 0.372 mmol) were added to DMF (1 mL). It was stirred for 20 min and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 15 min, 20 mL/min, 220 nM, product retention=16.4 min) to provide (R/S)-tert-butyl 2-(2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)acetate (20 mg, 0.035 mmol, 37.9% yield): LCMS=488.1 [M+H−C4H9]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.12 (2 H, d, J=8.35 Hz), 7.50-7.75 (7 H, m), 5.17 (1 H, s), 3.90 (2 H, s), 1.44 (9 H, s); HPLC peak RT=9.1 min (Method A).