Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.CCN(C(C)C)C(C)C.[NH2:18][C@@H:19]([CH3:35])[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[CH:27]=2)=[N:22]1>C(Cl)Cl>[Cl:34][C:28]1[CH:27]=[C:26]([C:23]2[CH:24]=[CH:25][N:21]([CH2:20][C@@H:19]([NH:18][C:6]([C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)=[O:8])[CH3:35])[N:22]=2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: O=C(O)c1cc[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc[nH]n1
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
To a mixture of 1H-pyrazole-3-carboxylic acid (89 mg, 0.767 mmol) in DCM (5 ml), was added DIPEA (0.40 ml, 2.30 mmol). O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniutnhexafluorophosphate (HBTU, 291.0 mg, 0.767 mmol) at RT. The mixture was stirred for 15 min and solid (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) was added. The reaction was stirred overnight at RT. The solvent was evaporated and water was added. The pH of the water phase was adjusted to 9-10 and the product was extracted to DCM. The organic layer was washed with water and brine, dried over Na2SO4 and evaporated. The crude product was purified with flash chromatography (DCM/EtOAc gradient) to give title compound 100 mg. 1H-NMR (400 MHz; d6-DMSO): δ 1.11 (d, 3H), 4.36 (m, 3H), 6.58 (t, 1H), 6.93 (d, 1H), 7.79 (m, 1H), 7.82 (d, 1H), 7.98 (d, 2H), 8.08 (bs, 1H), 8.25 (d, 1H), 13.20 (s, 1H).
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1.N.[NH2:22][C:23]([NH2:25])=[O:24]>C(OCC)(=O)C.C(#N)C.[Ag]OC#N.ClCCl>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=3)[CH2:11][O:24][C:23]([NH2:25])=[N:22]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NC(N)=O
Reactant: C=C(c1cccc(Br)c1)c1ccc(OC)c(C)c1
Agent: N#CO[Ag]
Agent: II
Agent: N
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C2(c3cccc(Br)c3)COC(N)=N2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A solution of iodine (1.92 g, 7.59 mmol) in ethyl acetate (50 mL) was added dropwise over 25 min to a mixture of 4-[1-(3-bromo-phenyl)-vinyl]-1-methoxy-2-methyl-benzene (2.1 g, 6.9 mmol) and silver cyanate (1.24 g, 8.28 mmol) in acetonitrile (19 mL) and ethyl acetate (9 mL), cooled in an ice bath. After complete addition, the reaction suspension was stirred for another 15 min at room temperature when TLC indicated the complete conversion of starting material. The reaction mixture was filtered, and the filtrate concentrated to give a dark grey oil. 50 mL of aqueous ammonia (25%) was added to the oil, and the mixture was stirred and warmed to 60° C. for 4 hours. LC-MS at this point indicated complete conversion of the intermediate urea to the desired aminoxazoline, dichloromethane (40 mL) was added to the crude and the two phases were separated. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Crude was purified by silica gel chromatography eluting with dichloromethane/methanol (gradient 0-2%) to give 1.0 g of the desired product as yellow gum (40%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:14](I)[CH3:15].[BH4-].[Na+]>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH:12]=[CH:11][CH2:10][N:9]2[CH2:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Brc1ccc(-c2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCN1CC=CCC1c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a solution of 2-(4-bromophenyl)pyridine (2.7 g, 11.5 mmol) in DMF (50 mL) was added ethyl iodide (1.9 mL, 23.1 mmol) and the reaction mixture was heated to 80° C. for 16 h. The mixture was cooled then evaporated and the resultant residue dissolved in methanol (100 mL) before addition of sodium borohydride (1.5 g, 39.2 mmol) portionwise. The reaction mixture was stirred at ambient temperature for 1 h then evaporated and saturated aqueous sodium carbonate solution was added. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated then the residue was purified by flash chromatography (silica, Biotage 100 g column, 50% ethyl acetate in cyclohexane) to afford the title compound (0.9 g, 29%), which was used without further purification. 1H NMR (CDCl3, 300 MHz): 7.47-7.42 (m, 2H), 7.24-7.19 (m, 2H), 5.86-5.74 (m, 2H), 3.47-3.35 (m, 2H), 2.98-2.87 (m, 1H), 2.64-2.46 (m, 1H), 2.33-2.26 (m, 2H), 2.13-2.00 (m, 1H), 0.99 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][NH2:5].C[N:8](N=O)[C:9]([NH:11][N+:12]([O-:14])=[O:13])=N>CCO.O>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][NH:5][C:9]([NH:11][N+:12]([O-:14])=[O:13])=[NH:8]
Reactant: CC(C)=CCN
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: CC(C)=CCNC(=N)N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-methyl-2-butenylamine (3.0 g) is added dropwise at room temperature to a slurry of 1-methyl-3-nitro-1 -nitrosoguanidine (4.3 g) in 50 ml of EtOH/H2O (1/1). After stirring the mixture at room temperature for 18 hours, the precipitate which forms is removed by filtration. The solid is then slurred with dilute hydrochloric acid, collected by filtration and washed with ethanol/water (30/70). Recrystallization from ethanol gives a white solid with mp 134°-136° C.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](C(Cl)=O)=[CH:3][CH:2]=1.S(C1C=CC(S)=CC=1)C1C=CC(S)=CC=1.C(N(CC)CC)C.[O:40]1CCCC1>>[C:1]1(=[O:40])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Reactant: C1CCOC1
Agent: Sc1ccc(Sc2ccc(S)cc2)cc1
Solvent: CCN(CC)CC
Product: O=C1C=CC=C2C1=Cc1ccccc12
Reaction time: 0.5 h

Procedure:
A 10.0 g quantity of 9-fluorenone-4-carbonyl chloride (0.04 mole, obtained from Aldrich Chemicals Co, Milwaukee, Wis. 53201, USA) and 100 ml of tetrahydrofuran (obtained from Aldrich) were added to a 250 ml, 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was stirred for about ½ hour, and then 5.16 g of 4,4′-thiobisbenzenethiol (0.02 mole, obtained from Aldrich) in 50 ml of tetrahydrofuran were added, followed by the addition of 4.17 g of triethylamine (0.04 mole, obtained from Aldrich). The solution was refluxed for 6 hours, filtered hot to remove triethylamine hydrochloride salt byproduct and the filtrate was evaporated to dryness to obtain a first dimeric fluorenone derivative. The first dimeric fluorenone derivative was recrystallized from tetrahydrofuran/methanol with activated charcoal. The first dimeric fluorenone derivative was dried at 60° C. vacuum oven for 6 hours to yield a yellow solid (6.85 g, 50% yield).
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH2:15])[CH2:9]2)(=[O:4])[CH3:3].Cl[C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)C>[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH:15][C:17]1[C:18]3[C:25]([CH3:26])=[CH:24][S:23][C:19]=3[N:20]=[CH:21][N:22]=1)[CH2:9]2)(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1ccc2c(c1)CC(N)C2
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)Oc1ccc2c(c1)CC(Nc1ncnc3scc(C)c13)C2
Yield: 26.3 %

Procedure:
Using 5-acetoxy-2-aminoindan hydrochloride (86 mg, 0.38 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (76 mg, 0.41 mmol), triethylamine (0.23 ml, 1.6 mmol), and ethanol (6 ml), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (34 mg, 0.10 mmol) having the following physical properties:
Reaction SMILES: [OH:1][C:2]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)([C:10]([OH:12])=[O:11])[CH2:3][C:4](=[N:8][OH:9])[C:5]([OH:7])=[O:6].Cl.O.[NH3:25]>C(O)C>[NH4+:8].[NH4+:25].[OH:1][C:2]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)([C:10]([O-:12])=[O:11])[CH2:3][C:4](=[N:8][OH:9])[C:5]([O-:7])=[O:6]
Reactant: N
Reactant: O=C(O)C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C([O-])C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)[O-])=NO
Product: [NH4+]
Reaction time: 72 h
Yield: 23 %

Procedure:
The above experiment in Example 2 was carried out on a 24-fold scale to prepare an aldol reaction mixture containing 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid. The resulting aldol reaction mixture was adjusted to pH 1.2 by addition of 12N hydrochloric acid and extracted twice with ethyl acetate (100 ml×2). The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, filtered to remove the magnesium sulfate, and concentrated with an evaporator to yield the residue. 28% Ammonia water (20 ml) was added, and then 200 ml of ethanol was added, and the mixture was preserved at 5° C. for 3 days. The precipitated crystals were collected by filtration and dried under reduced pressure to yield 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid diammonium salt (2.2 g)(purity 88%; yield 23%). The selectivity for the enantiomer was 44% ee for the 4R isomer.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1.CN1CCCC1=O>ClCCl>[Br:8][C:6]1[N:7]=[C:2]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cn1cc(Br)nc(Nc2ccc(CCO)cc2)c1=O
Temperature: 120 °C
Yield: 84.5 %

Procedure:
A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (2.0 g; 7.5 mmol), 2-(4-Amino-phenyl)-ethanol (1.0 g; 7.3 mmol), and 1-methyl-2-pyrrolidinone (1 mL) was heated at 120° C. for 1 hr. The mixture was cooled to room temperature, diluted with dichloromethane and filtered to give a dull brown oil. This was dissolved in CH2Cl2 and washed with 0.01N NaOH, and dried over solid sodium sulfate. After filtration and evaporation of the CH2Cl2 layer, the resulting brown solid was chromatographed on silica using methanol/CH2Cl2 (1:9) as eluent to provide 2.0 g of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (1) as a light tan solid. MS 324.23 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1.O=S(Cl)Cl.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])[N:10]=1
Reactant: O=C(O)c1csc(Oc2cccc(Cl)c2)n1
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1csc(Oc2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
1 g (3.75 mmol) 2-(3-chlorophenoxy)thiazole-4-carboxylic acid was added to 1 ml of SOCl2 and refluxed until the mixture gave a clear solution. Excess SOCl2 was evaporated in vacuo and the remaining acid chloride dissolved in 25 ml toluene. To this solution was added a solution of 0.34 g (3.65 mmol) aniline and 0.37 g triethylamine in 20 ml toluene. After stirring over night at room temperature the solution was washed with 20 ml dil. HCl, 20 ml water, 20 ml dil. NaOH and 20 ml water. The organic layer was dried with NaSO4 and evaporated to dryness to give 1.0 g (82.8%) 2-(3-chlorophenoxy)thiazole-4-carbanilide (m.p.:94°-95° C.).
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)[CH3:2].[CH3:10][S:11]([O:14]S(C)(=O)=O)(=[O:13])=[O:12].O[CH2:20][C:21]1[N:22]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[N:50]([C:51]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[N:49]=[N:48][N:47]=3)=[CH:36][CH:35]=2)[C:23]([C:30]([O-:32])=[O:31])=[C:24]([C:26]([OH:29])([CH3:28])[CH3:27])[N:25]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:29][C:26]([C:24]1[N:25]=[C:21]([CH2:20][O:14][S:11]([CH3:10])(=[O:13])=[O:12])[N:22]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[N:50]([C:51]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[N:49]=[N:48][N:47]=3)=[CH:38][CH:39]=2)[C:23]=1[C:30]([O:32][CH2:1][CH3:2])=[O:31])([CH3:27])[CH3:28]
Reactant: CC(C)(O)c1nc(CO)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1C(=O)[O-]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCN(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(C)(C)O)nc(COS(C)(=O)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
0.371 ml of N,N-diisopropyl-N-ethylamine and then 0.371 g of methanesulfonic anhydride were added, under a nitrogen atmosphere, to a solution of 500 mg of ethyl, 2-hydroxymethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (b) above] in 10 ml of tetrahydrofuran. The mixture was then stirred at room temperature for 1.5 hours, after which it was mixed with ethyl acetate and an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 610 mg of the title compound as an amorphous powder. The compound was employed in the subsequent reactions without any further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17]I.[Na+].[Cl-]>CN(C=O)C.O>[Cl:14][CH2:15][CH2:16][CH2:17][O:11][C:7]1[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:10]=[N:9][CH:8]=1
Reactant: ClCCCI
Reactant: CC(C)Oc1cncc(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cncc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-isopropoxypyridin-3-ol (1.04 g, 6.80 mmol) in DMF (10 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.25 g of an 80% dispersion in mineral oil, 8.33 mmol) in DMF (15 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (1.67 g, 8.16 mmol), and the resulting dark brown mixture was stirred at ambient temperature for 4 h. Cold water (25 mL) was carefully added, followed by saturated NaCl solution (25 mL). The resulting mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation producing a dark-brown oil (0.92 g, 59.0%).
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]([N:18]([C:20]2[C:21]([Cl:41])=[C:22]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:23][O:24][C:25]2[C:33]3[N:32]=[C:31]([O:34][CH3:35])[N:30]([CH3:36])[C:29]=3[CH:28]=[CH:27][CH:26]=2)[CH3:19])=[O:17])=[O:13])=[CH:6][CH:5]=1)([OH:3])=O.[NH2:42][C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:41][C:21]1[C:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]2[CH:8]=[N:9][C:4]([C:1](=[O:3])[NH:42][C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)=[CH:5][CH:6]=2)=[CH:39][CH:38]=[C:37]([Cl:40])[C:22]=1[CH2:23][O:24][C:25]1[C:33]2[N:32]=[C:31]([O:34][CH3:35])[N:30]([CH3:36])[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)cccc2n1C
Reactant: Nc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)Nc5ccncc5)nc4)c3Cl)cccc2n1C
Temperature: 50 °C
Reaction time: 24 h
Yield: 7.7 %

Procedure:
To a solution of 4-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (90 mg) and 4-aminopyridine (14.3 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.7 mg) and 1-hydroxybenzotriazole (26.4 mg) at ambient temperature, and after standing for 1 day, the mixture was stirred for 8 hours at 50° C. To the mixture was added water, and extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 12:1, v/v) to give 4-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(4-pyridylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (7.8 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:42]([N:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51]([CH2:58][CH2:59][NH2:60])=[CH:50]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([N:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51]([CH2:58][CH2:59][NH:60][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=2)[C:30]([OH:32])=[O:31])=[CH:50]1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCCc1cn(Cc2ccccc2)c2ccccc12
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCc1cn(Cc2ccccc2)c2ccccc12
Yield: 48.4 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (73 mg, 0.13 mmol) and 2-(1-benzyl-1H-indol-3-yl)ethylamine hydrochloride (45 mg, 0.16 mmol) according to Method C to give the title compound (48 mg). 1H-NMR (400 MHz, CD3OD) d 7.56 (d, J=7.6 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 5.28 (s, 2H), 4.69 (s, 2H), 4.48 (m, 1H), 4.22 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 3.52 (m, 1H), 3.38 (m, 1H), 2.98 (m, 2H), 2.86 (m, 3H), 2.72 (dd, J=9.3 Hz, J=13.8 Hz, 1H), 1.33 (s, 9H); HRMS m/z 762.3292 (calc. of monoisotopic mass for C43H46N4O9 gives 762.3265).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].FC(F)(F)S(OCC(F)(F)F)(=O)=O>C1COCC1>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:3][C:2]([F:7])([F:6])[F:1])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CC(F)(F)F)CC3)cc1OCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.9 %

Procedure:
A suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoro acetate (250 mg, 0.51 mmol) in THF (5 mL) was treated with TEA and the mixture flushed with argon. 2,2,2-trifluoroethyl trifluoromethane sulfonate (0.15 mL, 1.02 mmol) was added and the mixture stirred at RT for 72 h. The reaction mixture was partitioned between DCM and water, the organic layer washed with saturated aqueous sodium hydrogen carbonate followed by brine and then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was dissolved in 1.25 M HCl in methanol then concentrated in vacuo to give a solid which was triturated in IPA then diethyl ether. The resultant solid was subjected to RPHPLC (C18 column, gradient 10 to 98% methanol in water+0.1% HCO2H) to give 361 as a white solid (49 mg, 23%). LCMS: RT=4.59 min, [M+H]+=461. 1H NMR 400 MHz (DMSO-d6) δ: 8.33 (1H, d, J=8.29 Hz), 7.91-7.91 (2H, m), 7.08 (1H, dd, J=8.36, 1.79 Hz), 6.92 (1H, m), 5.91-5.90 (1H, m), 4.51 (4H, q, J=5.90 Hz), 3.21 (2H, q, J=10.30 Hz), 3.03 (2H, d, J=11.25 Hz), 2.45 (3H, m), 1.76 (2H, m), 1.69-1.67 (2H, m), 1.49 (6H, d, J=6.60 Hz)
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:25]([OH:27])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.O[N:36]1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.C(N(C(C)C)C(C)C)C.[C:63]([C:66]1[CH:74]=[CH:73][C:69]([C:70]([OH:72])=O)=[CH:68][CH:67]=1)(=[O:65])[CH3:64]>CN1CCCC1=O.ClCCl>[C:63]([C:66]1[CH:67]=[CH:68][C:69]([C:70]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH2:1])[C:25](=[O:27])[NH2:36])=[O:72])=[CH:73][CH:74]=1)(=[O:65])[CH3:64]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(C(=O)NCCCC[C@H](N)C(N)=O)cc1
Reaction time: 0.33 h

Procedure:
Rink-amide-resin (loading: 0.43 mmol/g, 6.66 g, 2.86 mmol) was swelled with dichloromethane (50 ml). The solvent was removed. A 20% solution of piperidine in N-methylpyrrolidinone was added (50 ml). The reactor was shaken for 20 min. The liquid was removed. The resin was washed with N-methylpyrrolidinone (3×50 ml) and dichloromethane (5×50 ml). A solution of BOC-Lys(FMOC)-OH (5.37 g, 11.5 mmol) in N-methylpyrrolidinone (50 ml) and a solution of 1-hydroxybenzotriazole (1.75 g, 11.5 mmol) in N-methylpyrrolidinone (20 ml) were added successively. Diisopropylcarbodiimide (1.79 ml, 11.5 mmol) and ethyldiisopropylamine (1.96 ml, 11.5 mmol) were added. The reactor was shaken at room temperature for 16 h. The liquid was removed. The resin was washed with N-methylpyrrolidinone (3×50 ml) and dichloromethane (3×50 ml). A solution of 4-acetylbenzoic acid (2.82 g, 11.5 mmol) in N-methylpyrrolidinone (50 ml) and a solution of 1-hydroxybenzotriazole (1.75 g, 11.5 mmol) in N-methylpyrrolidinone (20 ml) were added successively. Diisopropylcarbodiimide (1.79 ml, 11.5 mmol) and ethyldiisopropylamine (1.96 ml, 11.5 mmol) were added. The reactor was shaken at room temperature for 16 h. The resin was washed with N-methylpyrrolidinone (3×50 ml) and dichloromethane (3×50 ml). A solution of 50% of trifluoroacetic acid and 10% triisopropylsilane in dichloromethane (50 ml) was added to the resin. The reaction vessel was shaken for 1 h at room temperature. The liquid was collected. The solvent was removed in vacuo. The residue was redissolved in toluene (50 ml). The solvent was removed in vacuo.