Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:37][C@H:38]([C:56]([OH:58])=[O:57])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:55])[NH:44][S:45]([C:48]1[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=1)(=[O:47])=[O:46].[S:59]1[CH:63]=[CH:62][N:61]=[CH:60]1>>[CH2:1]([S:8]([NH:11][C@@H:12]([C:30]([NH:32][CH2:33][C:34]([NH:37][C@H:38]([C:56]([OH:58])=[O:57])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:55])[NH:44][S:45]([C:48]1[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=1)(=[O:47])=[O:46])=[O:35])=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:20])=[O:21])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[S:59]1[CH:63]=[CH:62][N:61]=[CH:60]1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)O)cc1
Agent: c1cscn1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)[C@@H](CCCNC(=N)NS(=O)(=O)c2ccc(C)cc2)NS(=O)(=O)Cc2ccccc2)C(=O)O)cc1
Yield: 63 %

Procedure:
A 100 mg portion of the compound of Example 11 was coupled with 0.19 mmol of H—Arg(Tos)—thiazole (prepared following the procedure of Example 5) following the procedure as described in Example 6. RP—HPLC purification gave the title compound (110 mg, 63% yield). FAB—MS (M+H)+917.8
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[C:10]2[C:11]([OH:14])=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.O[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:21][CH2:20]1.C(CP(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[C:10]2[C:11]([O:14][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:21][CH2:20]3)=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C1(CN2CCC(CO)CC2)CCOCC1
Reactant: Oc1noc2cccc(OCC(F)(F)F)c12
Agent: CCCC[PH](CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
A mixture of 4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-ol (230 mg, 1 mmol, EXAMPLE 1, step 2), methyl 4-{[4-(hydroxymethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate (270 mg, 1 mmol, EXAMPLE 1, step 4), and cyanomethyltributylphosphorane (400 mg, 1.5 mmol) in toluene (1.0 mL) was stirred at 100° C. for 16 h. After cooling, the mixture was concentrated in vacuo to give a dark brown oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 2:1) to give 250 mg (51%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([NH:18]C=O)[S:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:5])[CH3:2].Cl.C(O)C>O1CCCC1>[CH2:1]([O:3][C:4]([CH2:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
A mixture of 2-ethoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (7.2 g.), conc. hydrochloric acid (10 ml.), ethanol (70 ml.) and tetrahydrofuran (20 ml.) was stirred for 2 hours at ambient temperature. After removing the solvent from the reaction mixture in vacuo, water was added thereto and the mixture was adjusted to pH 3.3 with an aqueous solution of sodium bicarbonate under ice-cooling. Precipitates were collected by filtration and dried to give 2-ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (4.6 g.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:22]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=O)=[C:21]([CH3:29])[C:20](Br)=[CH:19][N:18]=2)=[CH:11][CH:10]=1)#[N:2].C(O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:26]1([C:24]2[N:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][CH:11]=3)[C:17]3=[N:18][CH:19]=[CH:20][C:21]([CH3:29])=[C:22]3[N:23]=2)[CH2:28][CH2:27]1
Reactant: Cc1c(Br)cnc(NCc2ccc(-c3ccccc3C#N)cc2)c1NC(=O)C1CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=CO
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Yield: 83 %

Procedure:
Toluene (30 ml) was added to 2.0 g (4.3 mmol) of 2-(2'-cyanobiphenyl-4-yl)methylamino-3-cyclopropanecarboxamido-5-bromo-4-methyl-pyridine, 1.0 g (21.7 mmol) of formic acid, 3.5 g (34.6 mmol) of triethylamine and 10% Pd--C (300 mg), followed by heating under reflux for 6 hours. After the reaction liquid was brought to room temperature and filtered to remove the catalyst, vacuum concentration was effected. Chloroform (100 ml) and water (50 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 1.3 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine (yield 82%).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:11]>>[CH2:8]([O:7][C:5]([C:4]1[N:11]([CH2:10][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=[N:2][N:1]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: CCOC(=O)C#N
Product: CCOC(=O)Cn1nnnc1C(=O)OCC
Yield: 97.5 %

Procedure:
A mixture of ethyl azidoacetate (13.1 grams, 98.5 percent pure, 0.1 mole) and ethyl cyanoformate (20.0 grams, distilled, 0.2 mole) was heated in an oil bath at 110°-111°C. for 24 hours. Removal of excess ethyl cyanoformate in vacuo gave 22.25 grams (98% of theoretical yield) of ethyl 5-(ethoxycarbonyl)-1-H-tetrazole-1-acetate which was shown to be 91% pure by nuclear magnetic resonance.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:15]([O:17]N1C(=O)CCC1=O)=O)[CH2:3][CH2:4][C:5](=[O:14])[O:6]CC1C=CC=CC=1.[NH2:32][C@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34].Cl.C(N(CC)CC)C>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C@H:2]([C:15]([NH:32][C@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[O:17])[CH2:3][CH2:4][C:5](=[O:14])[OH:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Boc-L-Glu(OBzl)OSu (Bachem), 434 mg (1 mmol) is reacted with L-Ala-OtBu. HCl, 182 mg (1 mmol) in 10 mL DMF containing triethylamine (202 mg). After stirring for 16 hours at room temperature, the reaction mixture is rotary evaporated to dryness and the residue is redissolved in methylene chloride, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is redissolved in methanol, 50 mL, and transferred to a Parr flask. 10% Pd/C catalyst (Aldrich), 50 mg, is added and the flask is charged with 40 psi hydrogen gas on a Parr shaker. The mixture is shaken for 2 hours at room temperature or until no further consumption of hydrogen is noted. The Parr flask is evacuated and charged with argon gas. The mixture is filtered through Celite, and the filtrate is rotary evaporated to give crude Boc-L-Glu-L-Ala-OtBu.
Reaction SMILES: S([O-])([O:4][CH2:5][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:7])(=O)=O.[Na+].[CH2:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:7])[C:5]([O:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCO
Reactant: CCCCCCOC(C)(COS(=O)(=O)[O-])OCCCCCC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)C(C)(OCCCCCC)OCCCCCC
Yield: 84 %

Procedure:
To a solution of methyl pyruvate 1 (10.0 g, 98.0 mmol) in toluene (100 mL) is added 1-hexanol 2 (40.1 g, 392 mmol) and p-Ts0H (186 mg, 0.98 mmol). The mixture is heated to reflux for 10 hours with azeotropic removal of water from the reaction mixture. The reaction is quenched with saturated NaHCO3 (100 mL), and the reaction mixture is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give hexyl 2,2-bis(hexyloxy)propanoate 3 (29.5 g, 84%) as a colorless oil: Rf (15% EtOAc/hexane)=0.53; IR (thin film, cm−1) 2956, 2930, 2860, 1746 (C═O), 1467, 1280, 1137, 1062. 1H NMR (600 MHz, CDCl3) δ 4.14 (t, J=7.2 Hz, 2H), 3.48 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 3.35 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 1.65-1.63 (m, 2H), 1.59-1.54 (m, 4H), 1.49 (s, 3H), 1.35-1.24 (m, 18H), 0.86 (t, J=7.2 Hz, 9H); 13C NMR (150 MHz, CDCl3) δ 170.2, 99.5, 65.4, 62.6, 31.7, 31.3, 29.7, 28.5, 25.8, 25.5, 22.6, 22.5, 21.9, 14.0, 13.9.
Reaction SMILES: [CH3:1][C:2]1[N+:10]([O-:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH2:27]([N:29](CC)[CH2:30][CH3:31])[CH3:28].N1CCCC1>ClCCl>[N:29]1([C:4]([C:3]2[C:2]([CH3:1])=[N+:10]([O-:11])[CH:9]=[CH:8][CH:7]=2)=[O:6])[CH2:30][CH2:31][CH2:28][CH2:27]1
Reactant: Cc1c(C(=O)O)ccc[n+]1[O-]
Reactant: CCN(CC)CC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1CCNC1
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCCC2)ccc[n+]1[O-]
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a suspension of 2-methylnicotinic acid-1-oxide (0.701 g) and N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.243 g) in dichloromethane (30 ml) was added dropwise a solution of triethylamine (0.570 g) in dichloromethane (5 ml) and followed a solution of pyrrolidine (0.407 g) in dichloromethane (5 ml) under stirring at cooling in an ice-bath. After completion of the addition, the mixture was allowed to stand to room temperature overnight. The reaction mixture was washed with water and dried over sodium sulfate. Removal of the solvent gave a crude product. The crude product was purified by column chromatography on silica gel with a mixture of chloroform and methanol (50:1) as an elunet to give 3-(1-pyrrolidinylcarbonyl)-2-methylpyridine-1-oxide (0.530 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:18]1([CH2:24][C:25]2[S:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.NC1N=CC(C2SC(CN3CCCCC3)=CC=2)=CC=1C(NC1C=CN=CC=1)=O>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:28]2[S:29][C:25]([CH2:24][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:26][CH:27]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[O:9]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncn1
Agent: Nc1ncc(-c2ccc(CN3CCCCC3)s2)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccc(CN3CCOCC3)s2)cc1C(=O)Nc1ccncn1

Procedure:
6.2 “A27” is prepared from 2-amino-5-bromo-N-pyrimidin-4-yl-pyridine-3-carboxamide and 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester according to step 2 of the synthesis of “A1”;
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][O:15][C:16](=[O:35])[C:17]1[CH:22]=[C:21]([S:23](=[O:33])(=[O:32])[NH:24][C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:14][O:15][C:16](=[O:35])[C:17]1[CH:22]=[C:21]([S:23](=[O:33])(=[O:32])[NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:8]3[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=3)=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]=1[CH3:34]
Reactant: COC(=O)c1cc(S(=O)(=O)Nc2ccc(Br)cc2)ccc1C
Reactant: CCCCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Fe]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCCCc1ccc(-c2ccc(NS(=O)(=O)c3ccc(C)c(C(=O)OC)c3)cc2)cc1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
A mixture of 4-butylbenzeneboronic acid (174 mg, 0.975 mmol), 5-(4-bromo-phenylsulfamoyl)-2-methyl-benzoic acid methyl ester (150 mg, 0.39 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (16 mg, 0.019 mmol), 1,1′-bis(diphenylphosphino)ferrocene (11 mg, 0.019 mmol) and potassium carbonate (0.39 ml of a 2M aqueous solution, 0.78 mmol) in 15 ml 1,4-dioxane was heated at reflux under nitrogen for 20 hr. The reaction mixture was cooled to room temperature, diluted with 80 ml water and extracted with 2×70 ml ethyl acetate. The combined ethyl acetate extracts were washed with 60 ml brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 15 g), eluting with 6:1 hexane/ethyl acetate to yield the title compound as a white solid (109 mg, 64% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[C:19](=[O:37])[NH:20][C:21](=[O:36])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][OH:35])[CH:24]=2)[C:12]2[O:16][CH:15]=[CH:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>O1CCCC1.C(OCC)(=O)C>[CH3:45][S:46]([O:35][CH2:34][CH2:33][CH2:32][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:22]2[C:21](=[O:36])[NH:20][C:19](=[O:37])[C:18]=2[C:11]2[C:12]3[O:16][CH:15]=[CH:14][C:13]=3[CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:24]1)(=[O:48])=[O:47]
Reactant: O=C1NC(=O)C(c2cc(OCc3ccccc3)cc3ccoc23)=C1c1cn(CCCO)c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCCn1cc(C2=C(c3cc(OCc4ccccc4)cc4ccoc34)C(=O)NC2=O)c2ccccc21
Yield: 100.1 %

Procedure:
Dissolve 3-(5-Benzyloxybenzofur-7-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione (380 mg, 0.77 mmol) and triethylamine (0.43 ml, 3.1 mmol) in tetrahydrofuran (15 ml) and cool in an ice bath. Add methanesulfonyl chloride (0.066 ml, 0.85 mmol) dropwise, and stir for four hours. Dilute the reaction in ethyl acetate, wash with water and brine, dry with magnesium sulfate, and concentrate to give the title compound (440 mg, 100%). MS(ES+): 571.14.
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[C:8]([CH3:30])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>C1COCC1.O>[CH3:30][C:8]1[N:9]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]=[C:6]([Sn:35]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:31][CH2:32][CH2:33][CH3:34])[N:7]=1
Reactant: Cc1nc(I)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Reaction time: 2 h
Yield: 117.3 %

Procedure:
3 M Ethyl magnesium bromide in THF (6.0 ml, 18.0 mmol) was added dropwise to a solution of 4-iodo-2-methyl-1-trityl-1H-imidazole (5.30 g, 11.8 mmol) in THF (100 ml) at −78° C. After stirring for 2 h, tributyltin chloride (5.0 ml, 18.4 mmol) was added. After stirring for an additional 2 h, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 8.49 g of impure 2-methyl-4-(tributylstannyl)-1-trityl-1H-imidazole as a orange liquid. Method [7] Retention time 11.32 min by HPLC (MH+ 615).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:22])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A slurry of 4-acetoxybenzoic acid (100 g, 555.1 mmol) in CH2Cl2 (50 mL) was treated with a catalytic amount of DMF (0.5 mL) and cooled in ice bath. The reaction was stirred as neat oxalyl chloride (51 mL, 582.82 mmol, 1.05 equiv.) was added dropwise. The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give 4-(chlorocarbonyl)phenyl acetate (110 g, 100% th.; 110% pract.), which was used in the next step without further purification; 1H NMR (CDCl3) δ 8.09 (d, 2H), 7.20 (d, 2H), 2.28 (s, 3H) ppm.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:14])=[C:12]([Br:15])[S:11][C:10]=2[CH:16]=1)(=[O:5])[CH3:4]>CCOCC.O1CCOCC1.O>[Br:15][C:12]1[S:11][C:10]2[CH:16]=[C:6]([C:3](=[O:5])[CH2:4][Br:1])[CH:7]=[CH:8][C:9]=2[C:13]=1[CH3:14]
Reactant: CC(=O)c1ccc2c(C)c(Br)sc2c1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: Cc1c(Br)sc2cc(C(=O)CBr)ccc12
Reaction time: 0.75 h
Yield: 85.1 %

Procedure:
Bromine (1.67 g.) was added dropwise to a stirred solution of 6-acetyl-2-bromo-3-methylbenzo[b]-thiophene (2.50 g.) in a mixture of ether (15 ml.) and dioxan (15 ml.). The solution was stirred for 45 minutes and then diluted with water (100 ml.). The layers were separated and the aqueous layer was washed several times with ethyl acetate. The combined organic layer and extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was chromatographed on silica gel. Elution with chloroform gave 2-bromo-6-bromoacetyl-3-methylbenzo[b]thiophene (2.75 g.) pure enough for further reaction. A sample crystallized from ethyl acetate/petrol (b.p. 60°-80°) had m.p. 126°-128° C.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:26](O)=[O:27])[N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>>[C:1]([NH:5][C:26]([C:15]1[N:16]([CH3:25])[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=2)[N:14]=1)=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Reactant: CC(C)(C)N
Product: Cc1ccc(-c2nc(C(=O)NC(C)(C)C)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using t-butylamine (0.022 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[N:1]1([C:6]2[N:11]=[C:10]([C:12]([NH:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)=[O:14])[CH:9]=[N:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cncc(N2CCCC2)n1
Reactant: Nc1nnn[nH]1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCCC2)n1

Procedure:
To a suspension of 2.90 g of 6-(1-pyrrolidinyl) pyrazine-2-carboxylic acid in 45 ml of tetrahydrofuran, 2.30 ml of triethylamine and 2.00 ml of pivaloyl chloride were added dropwise successively at 0 ° C. under stirring. After stirring for 1 hour at 0 ° C., 1.40 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 1 hour at room temperature, and then refluxed for 12 hours, The reaction mixture was evaporated, and water was added to the residue. The precipitate was collected by filtration, and recrystalized from dimethylsulfoxide affording 1.63 g of the desired compound as yellow needles. The obtained crystal was consistent with that of (a)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+]>C(O)C.C(=O)(O)[O-].[Fe]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Br:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCO
Product: COC(=O)c1cc(Br)cc(N)c1C
Temperature: 80 °C
Yield: 85 %

Procedure:
To stirred solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (290 g, 1060 mmol) in ethanol (1.5 L) was added aqueous ammonium chloride (283 g, 5290 mmol dissolved in 1.5 L water). The resulting mixture was stirred and heated at 80° C. followed by addition of iron powder (472 g, 8450 mmol) in portions at 80° C. The resulting reaction mixture was heated at 80° C. for 12 h. After completion, the reaction mixture was hot filtered over celite and the celite bed was washed with methanol (5 L) followed by washing with 30% MeOH in DCM (5 L). The combined filtrate was concentrated in-vacuo, the residue obtained was diluted with aqueous bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the title compound as brown solid (220 g, 89% yield).
Reaction SMILES: [O:1]1C=CC=[C:2]1[C:6]1[N:10]([C:11]2[N:16]=[C:15]([CH2:17][NH:18][C:19](=[O:30])[C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:31]([F:34])([F:33])[F:32])[CH:7]=1.C(Cl)(Cl)(Cl)Cl.I([O-])(=O)(=O)=[O:41].[Na+].C(O)(C)C>C(#N)C.O.[Ru](Cl)(Cl)Cl>[C:25]([O:24][C:23]([NH:22][C@@H:20]([CH3:21])[C:19]([NH:18][CH2:17][C:15]1[N:16]=[C:11]([N:10]2[C:6]([C:2]([OH:1])=[O:41])=[CH:7][C:8]([C:31]([F:33])([F:32])[F:34])=[N:9]2)[CH:12]=[CH:13][CH:14]=1)=[O:30])=[O:29])([CH3:26])([CH3:28])[CH3:27]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC#N
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cccc(-n2nc(C(F)(F)F)cc2C(=O)O)n1
Reaction time: 18 h
Yield: 100.6 %

Procedure:
To a stirred solution of 48 (40 mg, 0.083 mmol) in acetonitrile (0.24 mL) at 23° C. was added carbon tetrachloride (0.238 mL) followed by ruthenium chloride (1.9 mg, 8.3 pmol). A solution of sodium periodate (80 mg, 0.375 mmol) in water (0.36 mL) was added and the resulting suspension was allowed to stir for 18 h. Isopropanol was added and after 10 min, the suspension was filtered through celite. A 1N HCl solution and saturated sodium thiosulfate aqueous solution were added and the mixture extracted with EtOAc, dried over Na2SO4 and then evaporated to dryness. The crude was used without any further purification. The title product 49 (38.2 mg, 100% yield) was isolated as a brown oil. LRMS (ESI): calc. 457.4; found 458.5 (MH)+.