Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:27]=[CH:26][C:15]2[C:16]3[N:17]=[C:18]([CH2:24][OH:25])[S:19][C:20]=3[CH2:21][CH2:22][O:23][C:14]=2[CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:27]=[CH:26][C:15]2[C:16]3[N:17]=[C:18]([CH:24]=[O:25])[S:19][C:20]=3[CH2:21][CH2:22][O:23][C:14]=2[CH:13]=1
Reactant: OCc1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
Oxalyl chloride (0.24 mL, 2.9 mmol) was added dropwise to a solution of methyl sulfoxide (0.20 mL, 2.9 mmol) in dry dichloromethane (5 mL) and the resulting mixture was stirred 5 min. A solution of (8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-methanol (0.60 g, 1.9 mmol) in dichloromethane (5 mL) was added portion-wise to the mixture and followed immediately by triethylamine (0.8 mL, 5.8 mmol). The reaction mixture was stirred and monitored by the disappearance of the starting alcohol. The reaction was quenched by the addition of water and EtOAc. The aqueous layer was extracted with EtOAc, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (0-50% EtOAc/heptane) to provide 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbaldehyde (0.41 g, 69% yield). 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.39 (dd, J=8.5, 6.8, 1H), 7.37-7.15 (m, 2H), 4.38 (m, 2H), 4.12 (d, J=9.5, 1H)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7](=[O:10])[NH:8][CH:9]=1.Br[CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>CN(C)C=O>[C:13]12([CH2:12][N:8]3[CH:9]=[C:4]([Br:3])[CH:5]=[CH:6][C:7]3=[O:10])[CH2:14][CH:15]3[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]3)[CH2:22]1)[CH2:20]2
Reactant: O=c1ccc(Br)c[nH]1
Reactant: BrCC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(Br)cn1CC12CC3CC(CC(C3)C1)C2
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
To an ambient suspension of NaH (185 mg, 4.63 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide (30 mL) was added 5-bromopyridin-2(1H)-one (700 mg, 4.02 mmol). The reaction mixture was stirred for 15 minutes, and 1-(bromomethyl)adamantane (968 mg 4.22 mmol) was added. The mixture was heated to 120° C. overnight, cooled to room temperature, and quenched by the addition of water and ether. The layers were separated, and the aqueous extracted with additional ether (twice). The combined organics were washed with brine, dried over Na2SO4, and filtered. Chromatography on silica gel, eluting with a gradient of 5 to 30% ethyl acetate in hexanes, provided the title compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)=[N:11][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1cc(-n2cncn2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 36 h
Yield: 87.3 %

Procedure:
A mixture of 1.00 g (2.05 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide and 1.42 g (2.05 mmol) 1,2,4-triazole was stirred at 130° C. for 36 h. After cooling to room temperature the crude mixture was purified by flash chromatography to give 0.93 g (87%) of the title compound as a white solid. MS m/e (%): 520 (M+H+, 100).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH:16]=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:18].[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(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>[O:18]=[C:7]1[N:6]([CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)[CH:3]=2)[C:11]2[CH:12]=[C:13]([CH:16]=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: O=Cc1ccc2c(c1)N(Cc1cccc(I)c1)C(=O)CO2
Reactant: OB(O)c1ccncc1
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: CN(C)C=O
Solvent: O
Product: O=Cc1ccc2c(c1)N(Cc1cccc(-c3ccncc3)c1)C(=O)CO2

Procedure:
To a solution of 4-(3-iodo-benzyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.100 g, 0.254 mmol) and Pd(PPh3)4 (0.015 g, 0.01 mmol) in DMF (20.0 mL) was added pyridine-4-boronic acid (0.034 g, 0.279 mmol) followed by the addition of Na2CO3 (2 mL, 2.0 M solution). The solution was heated to reflux overnight with good stirring. The heat was turned off, the solution was poured into H2O (30 mL), and the organic phase was extracted with CH2Cl2 (3×40 mL). The organic phase was than dried over MgSO4, filtered, and concentrated down under reduced pressure. The product was chromatographed with CH2Cl2/MeOH (9:1).
Reaction SMILES: CN(C=O)C.[C:6]([NH2:9])(=[O:8])[CH3:7].[Cl:10][C:11]1[CH:12]=[C:13]([F:18])[C:14](F)=[N:15][CH:16]=1.Cl>C1COCC1>[C:6]([NH:9][C:14]1[C:13]([F:18])=[CH:12][C:11]([Cl:10])=[CH:16][N:15]=1)(=[O:8])[CH3:7]
Reactant: Fc1cc(Cl)cnc1F
Reactant: CC(N)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Cl)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
Under a nitrogen atmosphere, DMF (200 mL) and THF (830 mL) were added to acetamide (94.8 g, 1.61 mol), and the mixture was warmed to 50° C. A 40 wt % sodium hexamethyldisilazide THF solution (629 g, 1.37 mol) was added dropwise thereto, and the mixture was stirred for 2 hours at the same temperature. 5-Chloro-2,3-difluoropyridine (100.0 g, 0.67 mol) was then added, THF (20 mL) was further added, and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was cooled to 0° C., 2.8 M HCl (500 mL) was added, the mixture was warmed to room temperature, and the organic layer was separated. The organic layer was washed with a 20 wt % sodium chloride aqueous solution (500 mL), and the solvent was distilled off under reduced pressure. THF (500 mL) was added to the residue, and the mixture was heated to 70° C. to dissolve the residue. After cooling to room temperature and confirming the precipitation of solids, n-heptane (1500 mL) was added, and the mixture was further cooled to 0° C. and stirred for 3 hours at that temperature. The precipitated crystals were collected by filtration, washed with a mixed solvent of THF (100 mL) and n-heptane (500 mL), and dried under reduced pressure to obtain the title compound (91.2 g).
Reaction SMILES: C(OC([NH:8][C@:9]([CH3:27])([CH:19]=[CH:20][C:21]1[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1)[CH2:10][O:11][C:12](=[O:18])CCCCC)=O)(C)(C)C.[OH-].[Na+].CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1.CO.C(Cl)Cl.O>[CH3:27][C@@:9]1([CH:19]=[CH:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[CH2:10][O:11][C:12](=[O:18])[NH:8]1
Reactant: CCCCCC(=O)OC[C@@](C)(C=Cc1cccn1C)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cccc1C=C[C@]1(C)COC(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
(2R)-2-t-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(1-methylpyrrol-2-yl)-3-butene (37.0 g, 97.8 mmol) obtained in Reference example 1 (1d) was dissolved in a mixture of tetrahydrofuran (100 mL) and methanol (100 mL) and a 2N aqueous sodium hydroxide solution (100 mL) was added thereto, followed by stirring of the mixture at room temperature for 1 hour. Water and methylene chloride were added to the reaction mixture to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain a crude product (28.8 g, yield: quantitative). A solution of potassium t-butoxide (13.2 g, 117 mmol) in tetrahydrofuran (80 mL) was added to a solution of the crude product in tetrahydrofuran (320 mL) under ice-cooling over 10 minutes and the mixture was stirred at the same temperature for 20 minutes. Acetic acid (6.7 mL, 117 mmol) was added to the reaction mixture to neutralize it and the mixture was concentrated under reduced pressure. Water and ethyl acetate were added thereto to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 1:1-1:2) to obtain the title compound (20.3 g, yield: quantitative).
Reaction SMILES: [F:1][CH2:2][C:3]([OH:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N1C=CN=C1.CN(C)C=O.[CH3:22][Si:23]([CH3:26])([CH3:25])Cl>CCCCCC>[F:1][CH2:2][C:3]([O:11][Si:23]([CH3:26])([CH3:25])[CH3:22])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6]
Reactant: C#CCC(O)(CF)CCCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(CF)(CCCC)O[Si](C)(C)C
Temperature: 0 °C

Procedure:
To a solution of 4.38 g. of 4-fluoromethyl-4-hydroxy-1-octyne and 4.8 g. of imidazole in 19 ml. of dimethylformamide, cooled in an ice bath under nitrogen, is added 4.5 ml. of trimethylchlorosilane via a syringe during a few minutes. The mixture is stirred in the ice bath for 30 minutes and then at room temperature under nitrogen overnight. The solution is poured into hexane, washed with saturated aqueous sodium bicarbonate, water, then brine and dried over anhydrous sodium sulfate. The solvents are removed in vacuo giving the product as a colorless liquid.
Reaction SMILES: [O:1]=[C:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:20][C:2]1([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[O:23][CH2:22][CH2:21][O:1]1
Reactant: OCCO
Reactant: CC(=O)CCCCCCN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(CCCCCCN2C(=O)c3ccccc3C2=O)OCCO1

Procedure:
A mixture of 142.0 g (0.52 mole) of N-(7-oxooctyl)phthalimide, 60 ml of ethylene glycol, 5.80 g of p-toluenesulfonic acid and 290 ml of benzene was refluxed overnight using a Dean-Stark trap to collect the azeotrope. The reaction was cooled, treated with 2 N NaOH solution, the organic layer separated, dried over anhydrous potassium carbonate, filtered and stripped to give 125.25 g of orange oil, 76% pure by gc (SE-30, 90°-280°@16°/min).
Reaction SMILES: CNCCNC.[F:7][C:8]([F:23])([F:22])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[N:19][NH:18][C:17](=[O:21])[CH:16]=2)=[CH:11][CH:10]=1.Br[C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])=[C:27]([O:37][CH3:38])[CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(Cl)Cl.[Cu]I>[OH:33][C:31]([CH3:34])([CH3:32])[CH2:30][O:29][C:28]1[CH:35]=[CH:36][C:25]([N:18]2[C:17](=[O:21])[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:8]([F:7])([F:22])[F:23])=[CH:10][CH:11]=3)[CH:20]=[N:19]2)=[CH:26][C:27]=1[O:37][CH3:38]
Reactant: COc1cc(Br)ccc1OCC(C)(C)O
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cn[nH]1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-n2ncc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 110 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
N1,N2-dimethylethane-1,2-diamine (10 μL, 0.09 mmol) was added to a mixture of 5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)-one Part A (15 mg, 0.06 mmol), 1-(4-bromo-2-methoxyphenoxy)-2-methylpropan-2-ol Part B of Procedure 1 (20.6 mg, 0.08 mmol), potassium phosphate tribasic (39.8 mg, 0.19 mmol), and copper (I) iodide (17.8 mg, 0.09 mmol) in DMF (0.8 mL). After stirring at 110° C. overnight, the reaction mixture was diluted with CH2Cl2, filtered, washed with sat NaHCO3, brine, dried (MgSO4), and concentrated. The crude product was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product 2-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-5-(4-(trifluoromethyl)-phenyl)pyridazin-3(2H)-one L-1 (11.7 mg, 0.03 mmol, 41.0% yield) as a yellow solid. LC/MS 435 (M+H)+, tR 0.94 min (method 5). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.20 (1H, d, J=2.01 Hz), 7.73-7.87 (4H, m), 7.17-7.26 (3H, m), 7.02 (1H, d, J=8.28 Hz), 3.91 (3H, s), 3.89 (2H, s), 1.38 (6H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[C:10]#[N:11].[N-:12]=[N+:13]=[N-:14].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]=[N+:13]=[N-:14])=[CH:4][C:3]=1[C:10]#[N:11]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(CBr)ccc1Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(CN=[N+]=[N-])ccc1Cl
Reaction time: 18 h
Yield: 97.8 %

Procedure:
A stirred mixture of 4-chloro-3-cyanobenzyl bromide (3.0 g, 13 mmol) and sodium azide (1.26 g, 19.4 mmol) was refluxed 5 hours in absolute ethanol (30 mL). The mixture was kept 18 hours at ambient temperature, filtered, and the filtrate was evaporated under vacuum. The residue was triturated with diethyl ether, filtered, and evaporated to provide 2.45 g (98%) liquid 4-chloro-3-cyanobenzyl azide; I.R. (neat): 2240, 2100 cm1.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@@H:9]([CH3:11])[OH:10])=[O:6])[CH2:3][OH:4].FC(C(O)=O)(F)F.[CH3:29][CH:30]([CH2:32][C@H:33]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:34](OC1C=CC([N+]([O-])=O)=CC=1)=[O:35])[CH3:31].C(N(CC)CC)C.C(O)(=O)C>CN(C)C=O.C(OCC)(=O)C>[NH:46]([C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[C@H:33]([C:34]([NH:1][C@H:2]([C:5]([NH:7][C@H:8]([C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C@@H:9]([CH3:11])[OH:10])=[O:6])[CH2:3][OH:4])=[O:35])[CH2:32][CH:30]([CH3:31])[CH3:29]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H](NC(=O)[C@@H](N)CO)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
52.5 g of H-Ser-Thr-OBzl.TFA are dissolved in 145 ml of dimethylformamide and mixed at 0° C. with a solution of 48.0 g of BOC-Leu-ONP. 21 ml of triethylamine and 0.75 ml of glacial acetic acid are then added. The reaction mixture is stirred for 3 hours at 0° C. and overnight at room temperature. After adding 2.1 liters of ethyl acetate the solution is extracted by shaking twice with water, twice with 0.1 N hydrochloric acid, twice with 10% strength sodium chloride solution, eight times with 20% strength potassium carbonate solution, twice with 10% strength sodium chloride solution and once with 30% strength sodium chloride solution. After drying over sodium sulphate the solution is concentrated to about 1.4 liters. The protected tripeptide of melting point 114°-116° C. crystallises overnight in the refrigerator; [α]D -14° (c = 2 in dimethylformamide); Rf2 = 0.25 (on silica gel).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[F:32][C:33]([F:38])([F:37])[C:34](=O)[CH3:35].CO>C(Cl)(Cl)Cl>[F:32][C:33]([F:38])([F:37])[CH:34]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH3:35]
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: CC(=O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 40 mg (0.098 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 1 mL chloroform was treated with 1 mL (large excess) trifluoracetone and 62 mg (0.29 mmol) NaBH3(CN), followed by addition of 1 mL methanol. The mixture was stirred at ambient temperature for 15 h when it was quenched before complete conversion to product. The reaction mixture was diluted with 20 mL DCM, washed with 20 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a mixture of diasteriomers (9:1 by HPLC). MS (ES+): 508 (M+H)+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:7][C@H:6]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:26])[CH2:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[N:10]=[CH:9]2)[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][C@@H:4]1[CH2:5][C@H:6]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:26])[CH2:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[N:10]=[CH:9]2)[CH2:7]1
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](n2cnc(NC(=O)Cc3cccc4ccccc34)c2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1C[C@@H](n2cnc(NC(=O)Cc3cccc4ccccc34)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
N-[1-(cis-3-azido-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide (Preparation 4, Step 4; 330 mg, 0.95 mmol) was treated with triphenylphosphine (301 mg, 1.15 mmol) in tetrahydrofuran (10 mL) and water (1 mL) at 23° C. The solution was stirred at room temperature for 18 h. The solvent was removed in vacuo and the resulting residue was purified by silica gel chromatography (20:1:0.5 chloroform-methanol-ammonium hydroxide) to afford 289 mg (95% yield) of N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide; 1H NMR (400 MHz, CD3OD) δ 8.05 (d, J=7.5 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.45 (m, 5H), 7.35 (s, 1H), 4.26 (m, 1H), 4.16 (s, 2 H), 3.29 (m, 2H), 3.16 (m, 1H), 2.75 (m, 2H), 2.1 (m, 2H); MS (AP/CI): 321.3 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[C@@H:8](I)[C@H:4]([C@@H:5]([C:18]([O:20][CH3:21])=[O:19])[N:6]2[C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:3]1.O.[F-:23].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.C(OCC)(=O)C>[F:23][C@@H:8]1[C@H:4]2[CH2:3][C@@H:2]([OH:1])[C@@H:7]1[N:6]([C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C@@H:5]2[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H]([C@H]2I)N1[C@H](C)c1ccccc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H]([C@@H]2F)N1[C@H](C)c1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of methyl (1S,3S,4S,6R,7S)-6-hydroxy-7-iodo-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (100 mg) in acetonitrile (8 mL), was added tetrabutylammonium fluoride hydrate (102 mg). The mixture was stirred at 80° C. for 30 minutes. The resulting mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound (59.5 mg)
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[O:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:10][C:9]=2[CH:8]=[CH:7]1>CCOCC>[Cl:4][C:7]1[O:6][C:13]2[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:10][C:9]=2[CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1cc2occc2[nH]1
Solvent: CCOCC
Product: CCOC(=O)c1cc2oc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
Under a N2 atmosphere, sulfuryl chloride (0.15 mL, 1.85 mmol) was added dropwise over 10 min to a stirring solution of ethyl 4H-furo[3,2-b]pyrrole-5-carboxylate (300 mg, 1.67 mmol) in ether (7.5 mL). The reaction was stirred at rt for 4 h. The solvent was removed in vacuo. The residue was taken up in DCM and washed with H2O (1×) and brine (1×), then dried with Na2SO4, filtered and concentrated. Purification by HPLC gave 160 mg of ethyl 2-chloro-4H-furo[3,2-b]pyrrole-5-carboxylate. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.98 (s, 1H), 6.76 (s, 1H), 6.34 (s, 1H), 4.35 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.CCN(C(C)C)C(C)C.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34].CO>CN(C=O)C>[CH3:31][N:32]([CH3:36])[C:33]([N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)=[O:34]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine hydrochloride (253.6 mg, 0.809 mmol, 1 eq) in DMF (6 mL), DIPEA (0.7 mL, 4 mmol, 5 eq) was added at rt. The solution was cooled to 0° C. and N,N-dimethylcarbamoyl chloride (107.7 mg, 1.002 mmol, 1.2 eq) in DMF (1 mL) was added. The reaction was stirred from 0° C.→rt for 30 min. MeOH was added and all organic solvent was concentrated in vacuo to dryness. The residue was dissolved in CH2Cl2, washed with water (1×) and brine (1×), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, giving 292.5 mg (98%, 0.798 mmol) of the title compound, as a waxy white solid that had solidified upon drying. 1H NMR (400 MHz, CDCl3): δ=1.32 (s, 12H), 1.94-2.07 (m, 2H), 2.16 (dd, J=12.3, 2.4 Hz, 2H), 2.85 (s, 6H), 2.87-2.95 (m, 2H), 3.78 (d, J=13.4 Hz, 2H), 4.24-4.34 (m, 1H), 7.76 (s, 1H), 7.80 (s, 1H). MS (AP+): m/z=349.13 (100) [MH+]. HPLC: tR=2.91 min (ZQ3, polar—5 min).
Reaction SMILES: [NH:1]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:39]([NH:41][NH2:42])=[O:40])[CH2:37][OH:38])=[O:34])[CH2:29][C:30](=[O:32])[NH2:31])=[O:26])[C@@H:22]([CH3:24])[OH:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].Cl.O1CCOCC1.[N:57]([O-])=O.C(N(C(C)C)CC)(C)C>CS(C)=O.CN(C=O)C>[NH:1]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:39]([N:41]=[N+:42]=[N-:57])=[O:40])[CH2:37][OH:38])=[O:34])[CH2:29][C:30](=[O:32])[NH2:31])=[O:26])[C@@H:22]([CH3:24])[OH:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: O=N[O-]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)NN)[C@@H](C)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N=[N+]=[N-])[C@@H](C)O
Temperature: -25 °C
Reaction time: 1 h

Procedure:
5.94 g (8.55 mM) of Boc-Ile-Phe-Thr-Asn-Ser-NH-NH2 are dissolved in 27 ml of DMSO plus 37 ml of DMF. After cooling to -25° C., 6.1 ml of a 5.6 N HCl/dioxane solution then 1.23 ml of tertiobutyl nitrite (1.2 equiv.) prediluted in 5 ml of DMF precooled to -20° C., are added. After 1 hr. 15 mins. of stirring between -20° and -25° C., 6.1 ml of diisopropylethylamine (DIPEA) are added to take the pH to around 6, then 3 ml of DMF are added to take the volume to 85 ml and this solution is conserved at -25° C.