Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27](Cl)=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O1CCCCC1[O:40][C@H:41]([CH3:44])[CH2:42][OH:43].[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27]([O:43][CH2:42][C@H:41]([OH:40])[CH3:44])=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: O=C(Nc1nc2cc(-c3ccc(C(F)(F)F)c(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Reactant: C[C@H](CO)OC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](O)COc1ccc2nc(C(=O)Nc3nc4cc(-c5ccc(C(F)(F)F)c(Cl)c5)ccc4[nH]3)cn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (80 mg) and (R)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol (100 μL) in dry DMF (1 mL) was added NaH (40 mg, dispersion in mineral oil) and the mixture was stirred at room temperature for 1 h. Then, water (10 mL) was added and the reaction mixture stirred for 10 minutes. The precipitated solid was filtered and dissolved in 1:1 mixture of methanol and DCM (5 mL). To this was added 2 M solution of hydrochloric acid in methanol (1 mL) and stirred at room temperature for 2 h. After air drying, the product was purified by column chromatography (12 g pre-packed silica gel column cartridge) using DCM and 2N ammonia in methanol to afford 6-((R)-2-hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (37 mg). LCMS (m/z): 532. 1H NMR (400 MHz, DMSO-d6): δ 12.5 and 11.5 (1H, brs) 8.85 (1H, s) 8.15 (1H, d) 7.92 (1H, brs) 7.87-7.93 (3H, m) 7.55-7.63 (2H, m) 7.08 (1H, d) 5.01 (1H, d) 4.17 (2H, d) 4.03-4.07 (1H, m) 1.18 (3H, d).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH:6]1[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].O1[CH2:27][CH2:26][CH2:25][CH2:24]1>CC1C=C(N=C=O)C=CC=1.C(#N)C>[C:10]([NH:9][C:7](=[O:8])[CH:6]1[CH2:14][CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:5]1[C:3](=[O:4])[CH2:2][NH:1][C:3]([NH:5][C:6]1[CH:14]=[CH:27][CH:26]=[C:25]([CH3:24])[CH:7]=1)=[O:4])([CH3:13])([CH3:12])[CH3:11]
Reactant: C1CCOC1
Reactant: CC(C)(C)NC(=O)C1CCC(c2ccccc2)N1C(=O)CN
Agent: Cc1cccc(N=C=O)c1
Solvent: CC#N
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)NC(C)(C)C)CCC2c2ccccc2)c1

Procedure:
By proceeding in a fashion similar to that described in Example 2, but starting from 1.9 g of (2RS,5SR)-1-(2-aminoacetyl)-5-phenyl-N-tert-butylprolinamide in solution in 20 cm3 of anhydrous tetrahydrofuran and 0.82 cm3 of 3-methylphenyl isocyanate, after recrystallistion in acetonitrile, 0.7 g of (2RS,5SR)-N-tert-butyl-1-[3-(3-methylphenyl)ureidoacetyl]-5-phenylprolinamide, melting at 169° C., is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+].[Na+].[Cl-]>O>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][S:11]([O-:14])(=[O:13])=[O:12])=[CH:4][CH:5]=1)#[N:10].[Na+:15]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=S([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(CS(=O)(=O)[O-])cc1

Procedure:
A mixture of α-bromo-p-tolunitrile (24.5 g; 125 mmol) and sodium sulfite (17.0 g; 135 mmol) in 50 ml of water was heated to reflux and refluxed for 18 hours. The mixture was poured, while still hot, into 100 ml of saturated aqueous NaCl. The resulting heavy white precipitate was thoroughly chilled, collected by suction filtration, and washed with two portions of saturated aqueous NaCl and three portions of Et2O. After drying in vacuo over CaSO4, the sodium p-cyanophenylmethylsulfonate was obtained in essentially quantitative yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[CH2:7][O:8][CH2:9][CH2:10][N:11]=[N+:12]=[N-:13])[CH3:2].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.N1C=CC=CC=1>CCO>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:6](=[O:14])[CH2:7][O:8][CH2:9][CH2:10][N:11]=[N+:12]=[N-:13])=[CH:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[CH3:2]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)COCCN=[N+]=[N-]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN=[N+]=[N-]
Temperature: 60 °C
Yield: 42.5 %

Procedure:
A mixture of 4-(2-azido-ethoxy)-3-oxo-butyric acid ethyl ester (3 g, 13.94 mmol), 2-chlorobenzaldehyde (3 g, 21.34 mmol) and pyridine (1.5 mL, 1.47 g, 18.55 mmol) in EtOH (14 mL) was heated to 60° C. and maintained at this temperature for 3 h. The mixture was concentrated in vacuo. The concentrate was taken up in EtOAc (100 mL), washed successively with 1N HCl (25 mL) and brine (25 mL), dried (Na2SO4), filtered, concentrated in vacuo. The crude product was purified by chromatography using the ISCO Combiflash SQ16× (120 gram Redisep silica gel column, 0 to 60% EtOAc in hexanes for 30 min at 40 mL/min) to afford 2.00 g of 2-[2-(2-azido-ethoxy)-acetyl]-3-(2-chloro-phenyl)-acrylic acid ethyl ester (mixture of E/Z isomers) and 1.01 g of recovered starting material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:22])([CH2:19][CH:20]=[CH2:21])[CH2:9][N:10]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[C:11]2Cl)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:19]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[O:22][C:11]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:10]2[CH2:9]1)[CH:20]=[CH2:21]
Reactant: C=CCC(O)(Cn1cc([N+](=O)[O-])nc1Cl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCC1(c2ccc(Br)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of crude 2-(4-Bromo-phenyl)-1-(2-chloro-4-nitro-imidazol-1-yl)-pent-4-en-2-ol in DMF (48 mL) was added Cs2CO3 (2.84 g, 8.7 mmol) and stirred for 2 h at 50° C. The reaction mixture was cooled to rt, quenched with water, diluted with EtOAC and washed with brine and water. The organic layers were separated, dried (MgSO4) and concentrated. The concentrates were recrystallized with EuOAc to provide 270 mg of white solid. 1H NMR (400 MHz, DMSO-d) 68.11 (s, 1H), 7.64 (m, 2H), 7.38 (m, 2H), 5.80 (m, 2H), 5.12 (m, 2H), 4.62 (d, J=11.2 Hz, 1H), 4.01 (d, J=11.2 Hz, 1H), 2.96 (m, 2H); ESI MS m/z 352 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)=[O:12])[C:3]1=[O:15]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Cn1ccc(N)n1
Solvent: Brc1ccccc1
Product: Cc1cc(O)c(C(=O)Nc2ccn(C)n2)c(=O)n1C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 62.8 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 79 mg of 3-amino-1-methylpyrazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 6.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 134 mg of 1,6-dimethyl-4-hydroxy-N-(1-methylpyrazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 25) represented by the formula:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]Cl)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4].[I-:28].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][I:28])[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4]
Reactant: [I-]
Reactant: COC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1

Procedure:
A solution of 106.2 g (0.250 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester and 56.2 g (0.375 mole) of sodium iodide in 2200 ml of acetone is refluxed for 40 minutes. The reaction mixture is thereupon concentrated in vacuo. Water is added to the residue, and extraction is performed twice with methylene chloride. The organic phase is washed twice with diluted aqueous sodium bisulphite solution and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is dissolved in the minimum amount of methylene chloride, and 400 ml of ether is slowly added with stirring, whereupon the reaction product crystallises out. After filtration with suction and drying in vacuum, there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 125°-128°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[I-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:17][CH:16]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)CNc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CN(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 80 °C
Yield: 51.2 %

Procedure:
N-phenylglycine ethyl ester (781 mg, 4.3 mmol), 4-chlorobenzyl chloride (690 mg, 4.3 mmol) and sodium iodide (64 mg) were dissolved in toluene (7 mL) under argon. The reaction was heated in a graphite bath at 80° C. for 24 h. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with 1M HCl followed by brine. The solution was dried over MgSO4, filtered, and concentrated in vacuo. Purification of the resultant oil by flash chromatography (10:1 hexanes/EtOAc) afforded the title compound as a green oil (669 mg, 51%). MS (ES+) m/z 304 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][CH:10]=1)([O-])=O.[N+](C1C=CSC=1C1C=CC=CC=1)([O-])=O>>[NH2:1][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccsc1-c1ccc(Cl)cc1
Agent: O=[N+]([O-])c1ccsc1-c1ccccc1
Product: Nc1ccsc1-c1ccccc1
Yield: 81 %

Procedure:
The same procedures as described in Example 3 were carried out except that 3-nitro-2-(4-chlorophenyl)thiophene was replaced by 3-nitro-2-phenylthiophene. The yield was 81%. 1H-NMR(CDCl3, δ value):3.82(2H, brs), 6.66(1H, d, J=5.1), 7.12(1H, d, J=5.1), 7.22-7.29(1H, m), 7.42(2H, dt, J=1.5, 7.3), 7.52(2H, dd, J=1.5, 7.3)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)N)=[CH:6][CH:5]=1.CC[O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[C:27]3[CH:26]([CH2:25][C:23]([OH:24])=[O:22])[CH2:31][CH2:30][CH2:29][C:28]=3[C:16]3[C:11]2=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)=[CH:6][CH:5]=1
Reactant: COc1ccc(CN(N)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: COc1ccc(Cn2c3c(c4cc(F)ccc42)CCCC3CC(=O)O)cc1

Procedure:
Following the procedure of Example 1, but using 1-(4-methoxybenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: CC(C)(OC(N[C@H](C([N:14]1[CH2:31][CH2:30][CH2:29][C@H:15]1[C:16]([NH:18][CH:19]([CH:26]([CH3:28])[CH3:27])[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[O:17])=O)C(C)C)=O)C.[ClH:33]>>[ClH:33].[NH2:18][C@H:19]([C:20]([N:18]([CH:19]([CH:26]([CH3:27])[CH3:28])[C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])[C:16](=[O:17])[C@@H:15]1[CH2:29][CH2:30][CH2:31][NH:14]1)=[O:25])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)C(F)(F)F
Agent: Cl
Product: CC(C)C(C(=O)C(F)(F)F)N(C(=O)[C@@H]1CCCN1)C(=O)[C@@H](N)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A stirred solution of 50 (1.19 g, 2.56 mmol) is cooled to 0° C. and treated with HCl gas until saturation. The mixture is stirred at 0° C. for 30 min and the solvent is removed in vacuo to give 51 (1.0 g, 97%, mixture of 2 diastereomers of ketone form and 2 diastereomers of hydrate form, 3:1 ratio of diastereomers and 4:1 ratio of hydrate to ketone) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OB(O)O)=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-].[Na+].[Na+].C(O)C.Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:24]=1
Reactant: O=Cc1ccc(OB(O)O)cc1
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cccnc2)cc1
Yield: 25.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.65 g, 0.56 mmol), 4-formylphenylboric acid (2.81 g, 18.7 mmol), 2M aqueous sodium carbonate (18.7 ml, 37.4 mmol) and ethanol were added to the nitrogen-saturated solution of 3-bromopyridine (2.66 g, 16.8 mmol) in toluene and refluxed under nitrogen for 8 hrs. Water was added to the solution and extracted with ethyl acetate, washed with water and brine and dried. Solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/1.5) to give 4-(3-pyridyl)benzaldehyde (0.78 g, 25%).
Reaction SMILES: [C:1]([C:3]1(O)[C:12]2([CH3:13])[C:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH2:5][CH:4]1[CH3:16])#[CH:2].[OH-:18].[Na+]>CC1C=CC=CC=1C>[CH3:16][C:4]1[CH2:5][CH:6]=[C:7]2[C:12]([CH3:13])([CH2:11][CH2:10][CH2:9][C:8]2([CH3:15])[CH3:14])[C:3]=1[CH2:1][CH:2]=[O:18]
Reactant: [OH-]
Reactant: C#CC1(O)C(C)CC=C2C(C)(C)CCCC21C
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC1=C(CC=O)C2(C)CCCC(C)(C)C2=CC1
Temperature: 145 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
A solution of 1-ethynyl-2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a-octahydro-1-naphthalenol (4.00 g; 17.2 mmol) in o-xylene (60 ml) was treated with [V2O6SiPh2]n (400 mg) [Tetrahedron Lett. 1976, 17, 2981] and heated at reflux (145° C.). After 17 hours, the rearrangement was complete. The reaction mixture was poured into 5% aquous NaOH. The product was extracted twice with Et2O and washed successively with H2O and twice with satured aqueous NaCl, dried (Na2SO4) and evaporated. Bulb-to-bulb distillation (125° C. (oven temp.)/0.04 mbar) afforded 97% pure (2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)acetaldehyde (3.42 g; yield=83%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Br:40][C:41]1[CH:42]=[C:43]([NH2:48])[C:44]([NH2:47])=[CH:45][CH:46]=1>C(Cl)Cl.O>[NH2:47][C:44]1[CH:45]=[CH:46][C:41]([Br:40])=[CH:42][C:43]=1[NH:48][C:14](=[O:16])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:13])[CH3:17]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Br)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-[(benzyloxy)carbonyl]-2-methylalanine (Preparation 56, 35 g, 0.15 mmol) in DCM (600 mL) was added HOBt (25 g, 0.18 mmol) followed by EDCI.HCl (35.5 g, 0.18 mmol) and the reaction stirred at room temperature for 30 minutes. 4-Bromobenzene-1,2-diamine (30.7 g, 0.16 mmol) was added and the reaction heated to reflux for 24 hours. The reaction was cooled and poured into water (500 mL). The organic layer was separated, washed with water (200 mL), brine (100 mL) dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford the title compound as a brown solid that was taken directly on to the next step (80 g, 66%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:17])[C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5].[Br:18]Br>C(O)(=O)C>[Br:18][C:10]1[C:9]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=2[O:7][C:6]=1[C:4]([N:3]([O:2][CH3:1])[CH3:17])=[O:5]
Reactant: BrBr
Reactant: COc1ccc2oc(C(=O)N(C)OC)cc2c1
Solvent: CC(=O)O
Product: COc1ccc2oc(C(=O)N(C)OC)c(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution (100 mL) of N,5-dimethoxy-N-methyl-1-benzofuran-2-carboxamide (9.24 g) synthesized above in acetic acid was added dropwise bromine (2.21 mL), and the mixture was stirred overnight at room temperature. The resulting precipitate was collected by filtration and washed with diisopropyl ether to give the title object compound (9.48 g, 77%) as an orange solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:13]([NH2:15])=[O:14])=[N:4][C:5]([C:9]([OH:12])([CH3:11])[CH3:10])=[C:6]([Cl:8])[N:7]=1.[NH2:16][C:17]1[CH:18]=[N:19][N:20]([CH2:22][CH2:23][OH:24])[CH:21]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>O1CCOCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:16][C:17]2[CH:18]=[N:19][N:20]([CH2:22][CH2:23][OH:24])[CH:21]=2)[C:3]([C:13]([NH2:15])=[O:14])=[N:4][C:5]=1[C:9]([OH:12])([CH3:11])[CH3:10]
Reactant: Nc1cnn(CCO)c1
Reactant: CC(C)(O)c1nc(C(N)=O)c(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1Cl
Yield: 62 %

Procedure:
A mixture of 3,5-dichloro-6-(2-hydroxypropan-2-yl)pyrazine-2-carboxamide (2.0 g), 2-(4-amino-1H-pyrazol-1-yl)ethan-1-ol (1.12 g), diisopropylethylamine (2.79 mL), and dioxane (20 mL) was heated and refluxed for 2 hours. The reactant was cooled, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with a mixture of chloroform:methanol (10:1). The organic phase was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=99:1-90:10) to obtain 5-chloro-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-(2-hydroxypropan-2-yl)pyrazine-2-carboxamide (1.69 g) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][NH:41]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCCl.C(N(CC)CC)C>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]2[CH2:11][C@@H:10]([C:37]([N:41]3[CH2:42][CH2:43][C:44]4[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:40]3)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCc3ccccc3C2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (97 mg), 1,2,3,4-tetrahydroisoquinoline (67 μl), HOBt (19 mg) and triethylamine (104 μl) were dissolved in 1,2-dichloroethane (5 ml), WSC.HCl (107 mg) was added, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, and diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-1:1) was concentrated under reduced pressure to give the object compound (102 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:45])[N:10]([CH2:33][CH:34]([N:42]=[N+]=[N-])[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.O=[Pt]=O>[CH2:1]([O:8][C:9](=[O:45])[N:10]([CH2:33][CH:34]([NH2:42])[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(N=[N+]=[N-])c1ccc(Cl)cc1)C(=O)OCc1ccccc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(N)c1ccc(Cl)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl[2-azido-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (30 mg, 0.05 mmol) in THF (1 mL) was added PtO2 (8 mg) and the reaction was stirred at room temperature under hydrogen for 1 hour. The catalyst was removed by filtration through a plug of Celite with 100% EtOAc and the filtrate was concentrated to afford crude benzyl[2-amino-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.66 (25% EtOAc/hexanes). LCMS=611.3 (M+1)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([C:19](OCC)=[O:20])[CH2:16][C:15]=3[CH:24]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:25]([NH2:28])[CH:26]=[CH2:27]>C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([C:19]([NH:28][CH2:25][CH:26]=[CH2:27])=[O:20])[CH2:16][C:15]=3[CH:24]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C=CCN
Reactant: CCOC(=O)C1Cc2cc(-c3ccc(NC(C)=O)cc3)ccc2O1
Solvent: CCO
Product: C=CCNC(=O)C1Cc2cc(-c3ccc(NC(C)=O)cc3)ccc2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 ml of ethanol was added to a mixture of 1.6 g of 7D and 20 ml of 2-propenylamine. The mixture was stirred for 3 hours at room temperature. The solid which formed was collected, washed with ethanol, then ether and dried under reduced pressure to give 7, mp: 244°-247° C.