Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:21])[CH:13]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[CH:9]=[CH:8][CH:7]=1>[Ni].C(O)C>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:21])[CH2:13][CH:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)CCOc1cccc2oc(-c3nnn[nH]3)cc(=O)c12
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCOc1cccc2c1C(=O)CC(c1nnn[nH]1)O2
Reaction time: 8 h

Procedure:
To a solution of 1 part of 5-[5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]tetrazole in 50 parts of ethanol was added 5 parts of Raney nickel catalyst. The resulting mixture was hydrogenated at 20° C and 45 lbs/sq. in. pressure for 8 hours. The catalyst was filtered off and the filtrate was evaporated to give an oil which solidified on trituration with petroleum ether (b.p. 40°-60° C). This solid was crystallised from a mixture of ethyl acetate and petroluem ether (b.p. 40°-60° C) to give 0.2 parts of 5-[2,3-dihydro-5-(3-methylbutoxy)-4-oxo-4H-1-benzopyran-2-yl] tetrazole as a white solid, m.p. 134°-137° C. The structure of this product was confirmed by n.m.r. and m.s. measurements.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[CH:20]=O.C(O)(=O)C.[O:26]=[C:27]1[CH2:32][NH:31][CH2:30][CH2:29][NH:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[CH2:20][N:31]1[CH2:30][CH2:29][NH:28][C:27](=[O:26])[CH2:32]1
Reactant: O=C1CNCCN1
Reactant: O=Cc1c(-c2ccccc2)[nH]c2c([N+](=O)[O-])cc(Cl)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=C1CN(Cc2c(-c3ccccc3)[nH]c3c([N+](=O)[O-])cc(Cl)cc23)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
5-Chloro-3-formyl-7-nitro-2-phenyl-1H-indole (0.5 g, 1.66 mmol) prepared in Step A was dissolved in dichloroethane (20 mL). Acetic acid (0.10 g, 1.66 mmol), 2-oxopiperazine (0.3 g, 3.32 mmol) and sodium triacetoxyborohydride (0.71 g, 3.32 mmol) were added in drops thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction mixture was diluted with water, extracted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (0.55 g, Yield 86%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].N1C=CC=CC=1.[C:12]1([CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:20](=[O:21])[CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (1.1 g) and pyridine (1.82 mL) in dichloromethane (50 mL) was added 3-phenylpropionyl chloride (1.52 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.89 g).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[C:49]2[N:48]=[C:47]([Cl:50])[N:46]=[C:38]([NH:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C:37]=2[N:36]=[CH:35]1)(=O)C1C=CC=CC=1>N>[Cl:50][C:47]1[N:46]=[C:38]([NH:39][N:40]2[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)[C:37]2[N:36]=[CH:35][N:34]([C:49]=2[N:48]=1)[C@@H:11]1[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
The above 2',3',5'-tri-O-benzoyl-2-chloro-N-(1-piperidinyl)adenosine (19.2 g, 27.5 mmol) was dissolved in methanolic ammonia (150 ml) (previously saturated at -10° C.) and stirred at room temperature for 18 hours. The precipitated benzamide was removed by filtration, and the filtrate was evaporated to a fawn oil, which was triturated with diethyl ether to provide the title compound (6.0 g, 57%) as a white foam, 1H NMR (400 MHz, Me2SO-d6) δ3.55 (1H, m, H-5'a), 3.66 (1H, m, H-5'b), 3.94 (1H, q, H-4'), 4.12 (1H, m, H-3'), 4.50 (1H, q, H-2'), 5.82 (1H, d, H-1'), 8.40 (1H, s, H-8); HPLC retention time 26.57 (gradient elution, 5-25% acetonitrile/0.1M pH 3.3 ammonium sulphate buffer: 214 nm detector); purity 99%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[C:21]([C:25]([OH:27])=O)[CH:22]=[CH:23]3)=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.[CH2:46]([N:48](CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[C:21]([C:25](=[O:27])[NH:48][CH3:46])[CH:22]=[CH:23]3)=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[CH3:42])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(C(=O)O)ccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
The compound of step 6 (0.139 g, 0.24 mmol), methylamine hydrochloride (0.022 g, 0.32 mmol) and triethylamine (0.17 ml, 0.97 mmol) were dissolved in 2 ml of DMF and cooled to 0° C. TBTU (0.195 g, 0.61 mmol) was added and the solution was stirred at room temperature overnight. Water (8 ml) was then added and the mixture was extracted three times with EA. The combined organic phases were washed with 1 N hydrochloric acid, water, a saturated solution of sodium hydrogencarbonate and brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (DCM/MOH, 100:0, then 96:4) to give 0.065 g of the title compound as a beige solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:9]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33].[O:37]=[C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:47])[N-:39]1.[K+]>CN(C)C=O.C(OCC)(=O)C>[O:37]=[C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:47])[N:39]1[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:9]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)c1c(/C=C/CCCCCl)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Reactant: O=C1[N-]C(=O)c2ccccc21
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/CCCCN2C(=O)c3ccccc3C2=O)c2cc(F)ccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 160A (531 mg) and potassium 1,3-dioxoisoindolin-2-ide (213 mg) in N,N-dimethylformamide (10 ml) was heated at 80° C. for 8 hours. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and was concentrated. The residue was purified by flash chromatography, eluting with 0-100% ethyl acetate in dichloromethane to give (E)-ethyl 3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate. This ester was dissolved in a mixture of tetrahydrofuran and methanol and 5 equivalents of aqueous NaOH (10%) was added. The mixture was heated at 50° C. for 5 hours. The reaction mixture was concentrated and the residue was dissolved in dimethyl sulfoxide and trifluoroacetic acid-methanol (3:1), and purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 13.06 (s, 2H), 8.25 (t, J=5.52 Hz, 1H), 8.19 (dd, J=7.83, 1.38 Hz, 1H), 7.86 (dd, J=7.21, 1.99 Hz, 1H), 7.74 (dd, J=7.52, 1.38 Hz, 1H), 7.60-7.69 (m, 2H), 7.43-7.58 (m, 5H), 7.34-7.41 (m, 2H), 6.99-7.16 (m, 2H), 6.85 (d, J=7.36 Hz, 1H), 6.15-6.32 (m, 1H), 4.65-4.96 (m, 2H), 4.13 (t, J=5.68 Hz, 2H), 3.20-3.29 (m, 2H), 2.20-2.36 (m, 4H), 1.49-1.67 (m, 4H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.[S:6](Cl)([C:9]1[CH:17]=[CH:16][C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>O>[CH2:1]([NH:3][S:6]([C:9]1[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[CH:16][CH:17]=1)(=[O:7])=[O:8])[CH3:2]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CO
Product: CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 79 %

Procedure:
To a 40-mL vial with magnetic stir bar at 25° C. was added the Ethylamine solution (0.91 g, 20 mmol, 1.3 mL, 70% w/v in water, 4.5 eq.) and methanol (5 mL). The reaction vial was cooled to 0° C. The Nosyl chloride (1.0 g, 4.5 mmol, 1 eq.) was added portion-wise keeping the temperature between 0-5° C. and stirring continued ×15 min. after addition was complete. Water (10 mL) was then added. A precipitate began to form immediately. Stirring was continued at 0° C.×30 minutes. The material was collected by filtration, rinsed with water, and dried thoroughly in vacuo to afford 827 mg (79% yield). LCMS (ESI) 231 (M+H); 229 (M−H).
Reaction SMILES: [Cl-].[Li+].[CH3:3][C:4]1([CH3:25])S[C@@H:7]2[C@H:9]([NH:12][C:13]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:14])[C:10](=[O:11])[N:6]2[C@H:5]1[C:22]([OH:24])=[O:23]>CO.C(O)(C)(C)C>[CH2:15]([O:24][C:22]([C:5]([N:6]1[C:10](=[O:11])[C@@H:9]2[C@H:7]1[O:14][C:13]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[N:12]2)=[C:4]([CH3:25])[CH3:3])=[O:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: CC(C)(C)O
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)[C@H]2N=C(Cc3ccccc3)O[C@H]21
Yield: 88 %

Procedure:
A 6.2 mg quantity of lithium chloride was dissolved in a mixture of 2 ml of methanol and 0.5 ml of tert-butyl alcohol. To the solution was added 62.4 mg of benzyl ester of penicillin G to prepare an electrolyte. The electrolyte was subjected to electrolysis under the same conditions as in Example 1. The isolation and purification gives 50 mg of contemplated compound in 88% yield.
Reaction SMILES: ClC1C=C(C(Cl)=O)C=C(Cl)C=1.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([N:22]=[C:23]=[S:24])=[O:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([N:22]=[C:23]=[S:24])=[O:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:41][CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C(N=C=S)c1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(Cl)cc(Cl)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
3,5-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,5-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3,5-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 79%). Mass spectrometry value (ESI-MS, m/z): 529 (M++1)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:25][CH:24]1[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1Cc1ccccc1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC1Cc1ccccc1

Procedure:
Intermediate 1 was coupled with 2-Benzyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 479.
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[F:31])[C:8]([NH:10][C:11]1[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[F:31])[C:8]([NH:10][C:11]1[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])#[N:2]
Reactant: N#C[Cu]
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(F)c(Br)c2)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(F)c(C#N)c2)cc1
Temperature: 200 °C
Reaction time: 20 h
Yield: 30.7 %

Procedure:
CuCN (606 mg, 6.77 mmol) was dissolved in NMP (25 mL) and the solution was heated to 200° C. for 45 min. To this stirring solution was added N1-(3-bromo-4-fluorobenzoyl)-N2-(4-methoxybenzoyl)-1,2-benzenediamine (700 mg, 2.26 mmol) and stirring continued for 20 h. The solution was then cooled to room temperature, diluted with ethyl acetate and washed once with 1 N ammonium hydroxide, twice with 1 N HCl and once with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed with 10% ethyl acetate/dichloromethane to give 270 mg (44%) of off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[C:33](B(O)O)=[C:32]([CH3:37])[O:31][N:30]=1>>[CH3:28][C:29]1[C:33]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:24])[CH3:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)=[C:32]([CH3:37])[O:31][N:30]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1noc(C)c1B(O)O
Product: Cc1noc(C)c1-c1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 3,5-dimethyl-4-isoxazolylboronic acid were the coupling partners.
Reaction SMILES: [Li]CCCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].O1CCCC1.ClCCCCC#C.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>CCCCCC>[CH2:33]([Sn:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[C:6]#[C:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCCCCC
Agent: C#CCCCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CC1CCC1)(CCCC)CCCC
Reaction time: 6 h

Procedure:
To a solution of n-BuLi/hexane (7.28 mL, 18.2 mmol, 2.5 M) at −5° C. was added tetrahydrofuran dropwise, maintaining the temperature below +9° C. 6-Chloro-1-hexyne (1.00 mL, 8.92 mmol) was added at +5° C., and the solution was stirred for six hours. The reaction was quenched by the addition of tri-n-butyltin chloride (2.66 mL, 9.81 mmol), and was allowed to stir for an additional 10 minutes. The solution was poured into hexane, washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a colorless liquid which was used without further purification.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19]>C(Cl)Cl>[C:5]([O:4][C:3]([NH:2][O:1][C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19])=[O:9])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)NO
Reactant: COCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)ONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl N-hydroxycarbamate (1.5 g, 11.3 mmol) in DCM (50 ml) is added triethylamine (1.6 ml, 11.3 mmol) at 0° C. Chloro(2-methoxyethoxy)methanone (1.56 g, 11.3 mmol) is added dropwise. Reaction is stirred for 18 hours at room temperature before being washed with water (2×10 ml), NaHCO3 (2×10 ml), dried (MgSO4) and concentrated in vacuo to give the title product as an oil. (0.67 g, 25%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.74-8.46 (1H, m), 4.23-4.73 (2H, m), 3.45-3.84 (2H, m), 3.34 (3H, s), 1.41 (9H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].I[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]>[I:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:4]([C:1](=[O:3])[CH3:2])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: CC(=O)Nc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)N(c1ccccc1)c1ccc(-c2ccc(I)cc2)cc1
Yield: 64.9 %

Procedure:
20.3 g (0.15 mol) of acetanilide, 73.1 g (0.18 mol) of 4,4'-diiodobiphenyl, 22.1 g (0.16 mol) of anhydrous potassium carbonate, 2.16 g (0.034 mol) of copper powder, and 35 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 190° C. to 205° C. for 10 hours. The reaction product was then extracted with 200 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 6/1 mixture of toluene and ethyl acetate) to obtain 40.2 g (yield: 64.8%) of N-(4'-iodo-4-biphenylyl)acetanilide. The melting point of the product was from 135.0° C. to 136.0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](C(OC(C)(C)C)=O)[CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:20][C:21]([O:24][C:25]([N:27]1[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CO.O1CCOCC1>[NH:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([C:35]2[CH:36]=[CH:37][C:31]3[O:30][CH2:29][CH2:28][N:27]([C:25]([O:24][C:21]([CH3:22])([CH3:20])[CH3:23])=[O:26])[CH2:33][C:32]=3[CH:34]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Reactant: CC(C)(C)OC(=O)n1ccnc1-c1ccc(Br)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)cc3)cc2C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
1,1-Dimethylethyl 2-(4-bromophenyl)-1H-imidazole-1-carboxylate (457 mg, 1.41 mmol) and (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (456 mg, 1.55 mmol) were taken into dioxane (5 mL) and water (1 mL) followed by addition of DIPEA (1.1 mL, 6.2 mmol) and dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (58 mg) then the mixture was heated at 80° C. over 12 h. The mixture was cooled then partitioned with ethyl acetate and 10% aqueous citric acid. The organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. The residue thus obtained was taken into methanol (10 mL) followed by addition of sodium hydroxide (180 mg, 4.5 mmol) in water (1 mL). The mixture was stirred at room temperature for 30 minutes then neutralized by addition of 10% aqueous citric acid then concentrated. The aqueous residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated to give 1,1-dimethylethyl 7-[4-(1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (490 mg, 89% yield). MS (EI) for C23H25N3O3: 392 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cc(O)cc(OCc2ccccc2)c1
Yield: 29.4 %

Procedure:
To a mixture of 3,5-dihydroxybenzonitrile (1.08 g, 8 mmol) and K2CO3 (1.104 g, 8 mmol) in CH3CN (50 mL), benzyl bromide (1.438 g, 8 mmol) was added. The mixture was heated to reflux for 2 hours. Solvent was evaporated under vacuum. The residue was treated with EtOAc (200 mL) and 1M HCl (200 mL). The organic layer was washed, dried, and evaporated in vacuo. The residue was chromatographed (gradient, Hexanes-CH2Cl2-MeOH) to give 3-benzyloxy-5-hydroxybenzonitrile (529 mg, 29%), 3,5-dibenzyloxybenzonitryl (784 mg, 31%) and 256 mg (23.7 mg, 24%) of the starting material. The product 3-benzyloxy-5-hydroxybenzonitrile had: MP 144-145° C.; 1H NMR δ 9.15 (s, 1H, OH), 7.47 (d, 2H, J=7.0 Hz, 2′ and 6′), 7.40 (ddd, 2H, J=7.0, 7.0, 2.0 Hz, 3′ and 5′), 7.34 (dd, 1H, J=7.7 and 2.1 Hz, 4′), 6.89 (dd, 1H, J=1.5 Hz, 4), 6.78 (d, 2H, J=1.8 Hz), 5.16 (s, 2H). 3,5-dibenzyloxybenzonitryl