Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Si:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:25]=1)[CH:21]=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[CH:25]=1)[CH:21]([OH:22])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C=O)cc(O[Si](C)(C)C(C)(C)C)c1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C(O)c2cc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c2)cc1
Yield: 81.3 %

Procedure:
Combining 4-bromoanisole (0.43 g) and aldehyde 9a (0.76 g) provided 3,5-di-(tert-butyldimethylsilyloxy)-4′-methoxybenzhydrol 15d as a faint yellow oil (0.80 g, 82%): EIMS m/z 474 (M+), 459, 417, 361, 343, 73; IR (KBr, cm−1) νmax 3420, 2932, 2859, 2361, 1591, 1451, 1252, 1163, 1026, 833; 1H-NMR δ 7.29 (2H, d, J=9.04 Hz), 6.89 (2H, d, J=9.0 Hz), 6.52 (2H, d, J=2.0 Hz), 6.28 (1H, t, J=2.0 Hz), 5.70 (1H, s), 3.83 (3H, s, OCH3), 1.00 (18H, s, C(CH3)3×2), 0.20 (12H s, Si(CH3)2×2); 13C-NMR (75.5 MHz) δ 159.0, 156.5, 146.1, 136.0, 127.9, 113.7, 111.5, 111.0, 75.5, 55.3, 25.7, 18.2, −4.4. Anal. (C26H42O4Si2) C, H.
Reaction SMILES: [CH2:1](N(CCCC)CCCC)CCC.CS(C)=O.O.[NH2:19][C:20]1[N:25]=[C:24]([CH:26]2[CH2:28][CH2:27]2)[N:23]=[C:22]([C:29]([OH:31])=[O:30])[C:21]=1[Cl:32].BrC>O>[NH2:19][C:20]1[N:25]=[C:24]([CH:26]2[CH2:28][CH2:27]2)[N:23]=[C:22]([C:29]([O:31][CH3:1])=[O:30])[C:21]=1[Cl:32]
Reactant: CCCCN(CCCC)CCCC
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Agent: CBr
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 5 °C
Yield: 80.8 %

Procedure:
A 200-mL reactor equipped with a 10-mL jacketed addition funnel below a cold-finger condenser at −10° C., a nitrogen inlet and overhead stirring was charged with tributylamine (20.4 g, 0.11 mol) and DMSO (45 mL). The mixture was stirred at 25° C., and 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid monohydrate (23.1 g, 0.1 mol) was added in portions. The reaction mixture was stirred at 30° C. while bromomethane (13.3 g, 8 mL, 0.14 mol) was condensed into the jacketed addition funnel and then added to the reaction mixture over 30 minutes. The mixture was stirred for an additional 3 h and then added over about 30 minutes to a reactor charged with water (200 mL) at 25° C. The resulting slurry was cooled to 5° C. and filtered. The filtered cake was washed with water (2×30 mL) and dried at 60° C. in a vacuum-oven for 16 h to give 18.4 g (81% yield) of the title compound as an off-white solid melting at 147-148° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].CCOC(C)=O.O.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:20]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1])#[N:21]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#N)c(O)c1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
A mixture of the iodide product from Step B (101 g, 0.36 mol) and zinc(II)cyanide (30 g, 0.25 mol) in 400 mL of dry DMF was degassed by bubbling argon through the solution for 20 minutes. Tetrakis(triphenylphosphine)palladium (8.5 g, 7.2 mmol) was added, and the solution was heated to 80° C. for 4 hours. The solution was cooled to room temperature, then stirred for an additional 36 hours. The reaction was poured into EtOAc water, and the organic layer was washed with brine (4×), dried (Na2SO4), and concentrated in vacuo to provide the crude product. Purification by column chromatography through silica gel (30%-50% EtOAc/hexane) provided the titled product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[CH3:24][O:25][C:26]([C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1)=[O:27]
Reactant: CC(C)(O)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2Cl)n1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2ccc(-n3cc(C(C)(C)O)nc3-c3ccccc3Cl)cc2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
To a 50 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 2-[1-(4-Bromo-phenyl)-2-(2-chloro-phenyl)-1H-imidazol-4-yl]-propan-2-ol (275 mg, 702 μmol), 3-methoxycarbonylphenyl boronic acid (164 mg, 913 μmol), PdCl2dppf (51 mg, 10 mol %), K2CO3 (290 mg, 2.11 mmol), 1,2-dimethoxyethane (13 mL) and H2O (1.5 mL). The reaction solution was allowed to stir at 70° C. for approximately 2 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a reparatory funnel and washed with aq NH4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 90% EtOAc to afford 122 mg (39% yield) of product MS (ES): 446.3, 448.3 [M+H]+.
Reaction SMILES: [I:1]I.[Si:3]([O:10][CH2:11][CH:12]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:13]O)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:6]([Si:3]([O:10][CH2:11][CH:12]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:13][I:1])([CH3:5])[CH3:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCC(CO)COc1ccc(OC(F)(F)F)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(CI)COc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.3 %

Procedure:
A solution of iodine (2.89 g, 11.4 mmol) in anhydrous CH2Cl2 (6×10 mL, then 5mL+2 mL to rinse) was added dropwise (over 100 min) to a stirred mixture of alcohol 168 (3.28 g, 8.62 mmol), imidazole (1.50 g, 22.0 mmol) and triphenylphosphine (2.83 g, 10.8 mmol) in anhydrous CH2Cl2 (20 mL) under N2. After stirring at room temperature for 15 h, the resulting mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel. Elution with petroleum ether firstly gave foreruns, and then further elution with 5-20% CH2Cl2/petroleum ether gave tert-butyl(3-iodo-2-{[4-(trifluoromethoxy)phenoxy]methyl}propoxy)dimethylsilane (170) (3.90 g, 92%) as a pale brown oil; NMR (CDCl3) δ 7.13 (br dd, J=9.1, 0.7 Hz, 2H), 6.89 (dt, J=9.1, 3.0 Hz, 2H), 4.01 (dd, J=9.3, 5.7 Hz, 1H), 3.94 (dd, J=9.3, 6.2 Hz, 1H), 3.75 (dd, J=10.1, 5.6 Hz, 1H), 3.70 (dd, J=10.1, 5.6 Hz, 1H), 3.39 (dd, J=10.1, 5.9 Hz, 1H), 3.37 (dd, J=10.1, 6.0 Hz, 1H), 2.10 (sept, J=5.8 Hz, 1H), 0.89 (s, 9H), 0.07, 0.06 (2 s, 6H); HRCIMS calcd for C17H27F3IO3Si m/z [M+H]+ 491.0726. found 491.0721.
Reaction SMILES: CC(C)([O-])C.[K+].[P:7]([O-:24])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25](Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].Cl>CN(C=O)C.C1COCC1>[CH2:36]([P:7]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:24])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CCCCCCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of potassium t-butoxide (6.16 g, 55 mmol), in dry DMF (50 mL), under an argon atmosphere was added dropwise via syringe a solution of dibenzyl phosphite (13.1 g, 50 mmol) in dry DMF (5 mL), and the reaction mixture was stirred at room temperature for 20 min. Then a solution of lauryl bromide (18.6 g, 75 mmol) in dry THF (15 mL), was added dropwise under argon atmosphere, and the mixture was stirred at room temperature for an additional 1 h. After completion of the reaction, the mixture was neutralized with dilute HCl (40 mL) and extracted with ethyl acetate (200 mL), the organic phase was dried, concentrated, and purified by flash chromatography to afford the pure dibenzyl phosphate 14 as a colorless oil (Rf 0.46, silica, ethyl acetate and hexane, 1:2, 10.5 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23](Br)=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.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>[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:5]3[CH:10]=[CH:9][C:1]([O:2][CH2:3][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:7][CH:6]=3)=[CH:22][C:20]=2[N:21]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
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: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(OCc4ccccc4)cc3)cc2N=C(N)C1
Temperature: 100 °C
Yield: 36 %

Procedure:
(1E,4E)-2-Amino-8-(4-(benzyloxy)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (36%) was prepared as follows, substituting 4-(benzyloxy)phenylboronic acid for 4-(methoxycarbonyl)phenylboronic acid. (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. m/z (APCI-pos) M+1=468.2.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])(O)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[C:43]1([CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C>[C:43]1([CH:49]2[CH2:50][CH2:51][N:52]([C:1](=[O:2])[CH2:4][N:5]3[CH2:27][CH2:26][CH2:25][C@H:6]3[C:7]([N:9]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:53][CH2:54]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)N1CCC(c2ccccc2)CC1
Yield: 59 %

Procedure:
Using the procedure described above, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.124 g, 0.33 mmol, 1.0 eq), and N-methylmorpholine (43 uL, 40 mg, 0.40 mmol, 1.20 eq), in acetonitrile (3 mL) was treated with isobutyl chloroformate (45 uL, 47 mg, 0.35 mmol, 1.05 eq) followed by 4-phenylpiperidine (69 mg, 0.43 mmol, 1.3 eq). Workup as above provided 101 mg (59%) of L-isoleucine, N-[1-(2-(4-phenylpiperidyl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([NH2:17])[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]1>CCOC(C)=O>[Cl:9][C:4]1[N:3]=[C:2]([NH:16][CH:12]2[CH2:13][CH2:14][CH2:15][CH:10]([NH2:17])[CH2:11]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: NC1CCCC(N)C1
Reactant: Clc1cc(I)cc(Cl)n1
Solvent: CCOC(C)=O
Product: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 120 °C
Yield: 81.6 %

Procedure:
A mixture of 2,6-dichloro-4-iodopyridine (2.500 g, 9.13 mmol) and cyclohexane-1,3-diamine (4.44 mL, 36.5 mmol) was heated at 120° C. in a capped vial for 2 hours. While warm, the reaction mixture was treated with EtOAc and washed with water (3×). The organic layer was dried and concentrated to give 2.62 g of the crude title compound. This material was carried into the next step without further purification.
Reaction SMILES: [O-][CH2:2]C.[Na+].C(O[CH:8]([C:14]([O:16]CC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])C.Cl.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[NH:26])=[CH:23][CH:22]=1>C(O)C>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]2[NH:27][C:14](=[O:16])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2][N:26]=2)=[CH:23][CH:22]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: CC[O-]
Reactant: CCOC(=O)C(OCC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccc(Cl)cc2)[nH]c1=O

Procedure:
Sodium ethoxide (11.12 ml, 2 equiv) as a 21% w/v solution in ethanol was added dropwise to a suspension of diethyl ethoxymalonate (3.03 ml, 1 equiv) and 4-chlorobenzamidine hydrochloride (4.23 g, 1 equiv) in ethanol (30 ml), then the mixture was heated to reflux for 4 hours. After cooling, the solvent was removed in vacuo and the residue was triturated with ether. The solid was filtered off, then resuspended in water and acidified to pH 2. The product was filtered off, washed with water and dried; yield 2.94 g. 1H-NMR (d6-DMSO) δ 1.29 (3H, t), 4.26 (2H, q), 7.65 (2H, m), 8.18 (2H, m), 8.65 (1H, s); MS (APCI−) found (M−1)=277/279; C13H11ClN2O3 requires 278/280.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][N:6]=[C:7]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][CH2:11][Cl:12].[C-:20]#[N:21].[Na+]>CS(C)=O>[ClH:12].[NH2:2][CH2:3][CH2:4][O:5][N:6]=[C:7]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:20]#[N:21]
Reactant: [C-]#N
Reactant: NCCON=C(CCCCCl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCCC(=NOCCN)c1ccc(Cl)cc1

Procedure:
10 mmol (3.3 gr) of 4',5-dichlorovalerophenone O-(2-amino ethyl)oxime hydrochloride, melting point 140° -141.5° C, were dissolved in 10 ml of dimethylsulphoxide. 25 mmol (1.2 gr) of sodium cyanide were added to said solution.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[N:6][CH:7]=1.[OH-].[K+].Br[CH2:16][CH2:17][OH:18]>C(O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH2:16][CH2:17][OH:18])[N:12]=2)=[N:6][CH:7]=1
Reactant: Brc1ccc(-c2nn[nH]n2)nc1
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: OCCn1nnc(-c2ccc(Br)cn2)n1
Temperature: 80 °C
Yield: 26.4 %

Procedure:
5-Bromo-2-(2H-tetrazol-5-yl)pyridine (WO 0194342 A1) (1.2 g, 5.3 mmol) was dissolved/suspended in 1-propanol (15 ml), a solution of potassium hydroxide (250 mg, 4.5 mmol) in 1-propanol (15 ml) was added and it was heated at 80° C. for 1 hour. 2-Bromoethanol (0.344 ml, 4.8 mmol) was added and it was refluxed for one day. Further potassium hydroxide (270 mg) and 2-bromoethanol (0.35 ml) were added and the mixture was heated for another 4 hours at reflux. Further potassium hydroxide and 2-bromoethanol were added once more and the mixture was refluxed for 14 hours. The reaction mixture was filtered through a 0.45 μM membrane and the filter cake was washed with ethanol and dichloromethane. Chromatography on silica gel with hexanes/ethyl acetate 1:1 to ethyl actetate gave 0.342 g of the title compound (24%), together with 0.225 g of the corresponding 1H-tetrazole regioisomer.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH:16]=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39][C:40](Br)(Br)[Br:41]>C(Cl)Cl>[BrH:39].[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH:16]=[C:40]([Br:41])[Br:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C=O)ncn2-c2cccc(Cl)c2C1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Br
Product: CN1Cc2c(C=C(Br)Br)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3.0 g (10.9 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde and 5.7 g (21.7 mmol) of triphenylphosphine were dissolved in 80 ml of methylene chloride at room temperature. Thereafter, the mixture was cooled with an ice-bath to 0° and at this temperature there was added dropwise thereto a solution of 4.0 g (12.0 mmol) of tetrabromomethane in 15 ml of methylene chloride. Thereafter, the mixture was stirred at room temperature for a further 6 hours and subsequently evaporated in a vacuum. The residue was suspended in ethyl acetate and heated under reflux for 30 minutes, cooled to 10° while stirring, suction filtered and dried. The crystalline crude product was recrystallized from alcohol and there was obtained 7-chloro-3-(2,2-dibromovinyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrobromide as white crystals of melting point 215°-217°.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(Cl)cccc1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(Cl)cccc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), benzylamine (0.065 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-7-chloro-2,3-dihydro-isoindol-1-one (0.126 g, 99%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.22 (s, 2H), 4.76 (s, 2H) 7.28-7.46 (m, 8H). GC-MS: m/z 257 (M)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:22]=[CH:21][C:8]2[O:9][C:10]3[C:16]([NH:17][C:18](=[O:20])[CH3:19])=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].N1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)C=CC=1>[Cu]I.O.C(Cl)Cl>[C:1]([N:4]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:5]1[CH:22]=[CH:21][C:8]2[O:9][C:10]3[C:16]([N:17]([C:18](=[O:20])[CH3:19])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)Oc1cccc(NC(C)=O)c1O2
Reactant: c1ccc2ncccc2c1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N(c1ccccc1)c1ccc2c(c1)Oc1cccc(N(C(C)=O)c3ccccc3)c1O2
Temperature: 170 °C
Reaction time: 48 h

Procedure:
A slurry prepared from 34.3 g (0.115 mole) of N,N′-diacetyl-2,6-diaminodibenzodioxin, 96.4 g (0.576 mole) of iodobenzene, 48.2 g (0.253 mole) of copper (I) iodide, 63.6 g (0.460 mole) of potassium carbonate, and 1500 ml of quinoline was heated with stirring at 170° C. for 48 hours. The slurry was cooled to room temperature, 500 ml of methylene chloride and 500 ml of water were added, and a precipitate was filtered off. To the filtrate was added 500 ml of water and the organic layer was separated from the aqueous layer. The organic layer was concentrated and dried under reduced pressure to give 79.4 g of a crude product. The product was used without purification in the next reaction.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:65][CH2:66][CH2:67][CH2:68][NH2:69])[C:3](=[O:64])[NH:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:63])[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]([NH:39][CH2:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:62])[C@@H:55]([NH2:61])[CH2:56][CH2:57][CH2:58][CH2:59][NH2:60])=[O:38].[C:70](Cl)(=[O:84])[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83].C(N([CH2:91][CH3:92])CC)C>ClCCl>[O:64]=[C:3]([C@H:2]([NH:1][C:70](=[O:84])[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:91][CH3:92])[CH2:65][CH2:66][CH2:67][CH2:68][NH:69][C:70](=[O:84])[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[NH:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:63])[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]([NH:39][CH2:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:62])[C@H:55]([NH:61][C:70](=[O:84])[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:70](=[O:84])[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])=[O:38]
Reactant: NCCCC[C@H](N)C(=O)NCCCOCCOCCOCCCNC(=O)CCOCCOCCOCCOCCOCCC(=O)NCCCOCCOCCOCCCNC(=O)[C@@H](N)CCCCN
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)NCCCC[C@@H](NC(=O)CCCCCCCCCCCCC)C(=O)NCCCOCCOCCOCCCNC(=O)CCOCCOCCOCCOCCOCCC(=O)NCCCOCCOCCOCCCNC(=O)[C@@H](CCCCNC(=O)CCCCCCCCCCCCC)NC(=O)CCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N1,N19-bis((S)-16,20-diamino-15-oxo-4,7,10-trioxa-14-azaicosyl)-4,7,10,13,16-pentaoxanonadecane-1,19-diamide (synthesis previously described) was dissolved in dichloromethane and placed in an ice-bath. Myristoyl chloride was added followed by triethylamine. The ice-bath was removed and the reaction was allowed to stir overnight at room temperature under a blanket of inert gas. Next day, diluted with dichloromethane to 100 mL and washed with 1M HCl (75 mL), H2O (75 mL), saturated bicarbonate solution (75 mL) and saturated brine solution (75 mL). Back extracted all aqueous washes with dichloromethane (25 mL). Dried organics with MgSO4, filtered and concentrated. Purification by silica gel chromatography with a dichloromethane/methanol gradient yielded N1,N19-bis((R)-15,22-dioxo-16-tetradecanamido-4,7,10-trioxa-14,21-diaza-penta-triacontyl)-4,7,10,13,16-pentaoxanonadecane-1,19-diamide (410 mg). LCMS ESI+: m/z 1841 (M+H).