Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2I.[NH2:20][C:21]1[N:25]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:24]2[CH:32]=[CH:33][C:34]([CH2:36][OH:37])=[CH:35][C:23]=2[N:22]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCCC1>C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[NH:20][C:21]1[N:25]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:24]2[CH:32]=[CH:33][C:34]([CH2:36][OH:37])=[CH:35][C:23]=2[N:22]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)ccc21
Reactant: Nc1nc2cc(CO)ccc2n1C1CCCCC1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(Nc2nc3cc(CO)ccc3n2C2CCCCC2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.7 %

Procedure:
In a 20 mL microwave reaction tube was weighed 5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (653 mg, 0.00144 mol). To this was added (2-amino-1-cyclohexyl-1H-benzoimidazol-5-yl)methanol (322.1 mg, 0.001313 mol), trans-N1,N2-dimethylcyclohexane-1,2-diamine (121 mg, 0.000851 mol), copper(I) iodide (78 mg, 0.00041 mol) and potassium phosphate (554 mg, 0.00261 mol). The tube was purged with argon and tetrahydrofuran (14 mL, 0.17 mol) was then added. The reaction mixture was stirred for several minutes with argon sparging at room temp. The reaction mixture was then heated under microwave irradiation for 5 hours at 140° C. The reaction mixture was cooled and diluted with ethyl acetate and washed twice with aqueous sodium bicarbonate, once with dilute HCl and one final wash with dilute sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated. The residue (750 mg) was purified by flash chromatography using a 120 g silica gel cartridge and hexane and ethyl acetate eluent. The product was loaded onto the column with methylene chloride and the eluent was initially 10% ethyl acetate for 2 minutes then a gradient to 60% ethyl acetate over 20 mins. The product fractions were combined and concentrated to yield 334.6 mg of a pale greenish white solid.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:10])([CH3:9])[NH:7][C:6](=[O:11])[CH2:5][S:4]1)[OH:2].O1CCOCC1.[CH3:18][N:19]([S:23][C:24]([Cl:27])([Cl:26])[Cl:25])[C:20](F)=[O:21].C(N(CC)CC)C>O>[CH3:18][N:19]([S:23][C:24]([Cl:27])([Cl:26])[Cl:25])[C:20]([O:2][N:1]=[C:3]1[C:8]([CH3:9])([CH3:10])[NH:7][C:6](=[O:11])[CH2:5][S:4]1)=[O:21]
Reactant: CN(SC(Cl)(Cl)Cl)C(=O)F
Reactant: CC1(C)NC(=O)CSC1=NO
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(SC(Cl)(Cl)Cl)C(=O)ON=C1SCC(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A mixture of 3.5 g of 2-oximino-3,3-dimethyltetrahydro-1,4-thiazin-5-one, dioxane and N-methyl-N-(trichloromethylthio)carbamoyl fluoride (4.5 g) was charged to a stirred flask and 2.1 g of triethylamine was added dropwise at 30° C, over a 2-minute period. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then added to cold water and stirred for 10 minutes. The crystalline solid was filtered, washed thoroughly with water and dried overnight. After drying the crude product was recrystallized from isopropanol to yield 3 g of 2-[O-(N-methyl-N-trichloromethanesulfenylcarbamoyl)oximino]-3,3-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 189°-190° C. The nmr spectrum of this material was consistent with its proposed structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:26])(=[O:25])[N:22]([CH3:24])[CH3:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[CH3:36])[CH2:31][NH2:32]>>[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[CH3:36])[CH2:31][NH:32][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:25])(=[O:26])[N:22]([CH3:24])[CH3:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:3]
Reactant: Cc1ccc(CN)cc1C
Reactant: CCOC(=O)c1nc(-c2ccccc2S(=O)(=O)N(C)C)n(C)c(=O)c1O
Product: Cc1ccc(CNC(=O)c2nc(-c3ccccc3S(=O)(=O)N(C)C)n(C)c(=O)c2O)cc1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2 mmol) and 3,4-dimethylbenzylamine (0.14 mL, 1.0 mmol). The title product was obtained as white needles (0.0560 g, 60% yield). 1HNMR (500 MHz, CDCl3) δ: 12.19 (1H, s), 7.91 (1H, dd, J=7.48, 1.68 Hz), 7.71–7.65 (2H, m), 7.61 (1H, m), 7.36 (1H, dd, J=7.48, 1.68 Hz), 7.07 (1H, d, J=7.33 Hz) 7.00 (1H, s), 6.96 (1H, d, J=7.63 Hz), 4.57 (1H, dd, J=14.65, 7.02 Hz), 4.37 (1H, dd, J=14.65 Hz), 3.23 (3H, s), 2.63 (6H, s), 2.22 (6H, s). HRMS (ESI) calcd for C23H27SN4O5 (M+H): 471.1702; found 471.1708.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][C@@H:13]1[NH:18][CH2:17][C@@H:16]([CH2:19][N:20]([CH3:22])[CH3:21])[O:15][CH2:14]1.C(N(CC)CC)C.CN1CCCC1=O>C(Cl)Cl>[NH2:7][C:6]1[CH:8]=[C:2]([N:18]2[C@@H:13]([CH3:12])[CH2:14][O:15][C@H:16]([CH2:19][N:20]([CH3:21])[CH3:22])[CH2:17]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C[C@H]1CO[C@H](CN(C)C)CN1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CO[C@H](CN(C)C)CN1c1ccc([N+](=O)[O-])c(N)c1
Temperature: 140 °C

Procedure:
A mixture of 5-fluoro-2-nitroaniline (1.1 equivalents), [((2S,5S)-5-methylmorpholin-2-yl)methyl]dimethylamine (1 equivalent), triethylamine (3 equivalents), and N-methylpyrrolidinone was heated at 140° C. for 48 hours in a sealed high pressure vessel. The reaction mixture was then cooled to 25° C. and dissolved in CH2Cl2. The solution was washed with water (×2) and dried over Na2SO4. Purification via chromatography on silica gel (10% MeOH in dichloromethane) afforded the desired product as a dark yellow foam. LC/MS (m/z) 295.2 (MH+) Rt 1.55 minutes.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@H:9]([OH:25])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C>CC(O)=O.O.[Pd]>[NH2:22][C@@:10]1([C:12]([OH:14])=[O:13])[C@@H:9]([OH:25])[CH2:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1O)[C@@H]2C(=O)O
Temperature: 23 °C
Yield: 82.3 %

Procedure:
A solution of (1S,2R,3S,5R,6S)-2-azido-3-hydroxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (X-1) (50 mg, 0.145 mmol) in HOAc (4 mL) and H2O (1 mL) was hydrogenated in the presence of Pd/C (11 mg, 10% Pd/C) at 23° C. for 23 h. The catalyst was removed by filtration, the filter cake washed with 50% aqueous acetic acid. After removal of the solvent in vacuum, the beige residue was refluxed in 10% HCl (6.75 mL) for 4 h. The solution was cooled to 23° C., filtered, washed with water and evaporated to dryness. The remaining pale yellow solid was dissolved in EtOH (5 mL) and propylene oxide (2 mL) and refluxed for 15 min, whereupon the amino acid precipiated. After cooling to 23° C., the product was filtered off, washed with ether and dried to give (1S,2R,3S,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-2) (24 mg, 86%) as a white solid. 1H-NMR (250 MHz, D2O) □2.05 (1H, d,J=15 Hz), 2.10-2.20 (2H, m), 2.12 (1H, m), 2.61 (1H, m), 4.20 (1H, d, J=7.2 Hz); MS[ISP] 202 (M+H+); mp 208° C. (dec.); □D20 +27.52° (c=1.03, H2O).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)(=[O:3])C.Cl[O-].[Na+].S([O-])(O)=[O:20].[Na+].Cl>O>[C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)([OH:3])=[O:20]
Reactant: O=S([O-])O
Reactant: CC(=O)c1ccc2c(c1)C(=O)C1(CC1)O2
Agent: *CCO*
Agent: CCCCCCCCOc1ccccc1
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)C1(CC1)O2
Temperature: 60 °C
Reaction time: 3 h

Procedure:
5-Acetylspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (13.5 g.) was added to 300 ml. of aqueous solution of sodium hypochlorite. To the mixture was further added a small amount of surface active agent (polyoxyethylene octyl phenyl ether), and the mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was diluted with water, and to the mixture was added 40% aqueous solution of sodium hydrogen sulfite. The reaction mixture was made acidic with hydrochloric acid, and resulting crystals were collected by filtration. After washing with water and drying, the crystals were recrystallized from ethanol to give colorless needles of 5-carboxyspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (12.68 g.). m.p. 215°-228° C.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[C:7]([O:12][CH2:13][CH2:14][OH:15])(=[O:11])[C:8]([CH3:10])=[CH2:9].C(N(CC)CC)C.COC1C=CC(O)=CC=1>C(OCC)(=O)C>[C:7]([O:12][CH2:13][CH2:14][O:15][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)OCCO
Reactant: CC(Br)C(=O)Br
Agent: COc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)OCCOC(=O)C(C)Br
Reaction time: 8 h
Yield: 63.9 %

Procedure:
2-Bromopropionyl bromide (18 g, 0.083 mol, 1 m.e) in ethyl acetate (30 mL) was added dropwise to a mixture of 2-hydroxyethyl methacrylate (HEMA) (16.26 g, 0.125 mol, 1.5 m.e) and triethylamine (9.26 g, 0.091 mol, 1.1 m.e) in ethyl acetate (80 mL) at 0° C. under a N2 environment. Hydroquinone monomethyl ether (MEHQ) was added as an inhibitor at this stage (−15 mg, 1.2×10−4 mol). The reaction mixture was stirred overnight, then filtered, further treated with more MEHQ (˜15 mg) and then evaporated to dryness to give a clear colourless oil (14 g, 0.053 mol, 63% yield). 1H NMR (200 MHz, CDCl3) δ 1.82 (d, J=8 Hz, 3H, CH3CH—), 1.95 (s, 3H, (CH3CCO—), 4.36-4.46 (m, 5H, 2× —CH2O— and —CHBr), 5.60 (br. s, 1H, vinyl), 6.13 (s, 1H, vinyl) ppm.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:12])=O>>[CH:1]1([CH2:6][C:7]([Cl:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1CCCC1
Product: O=C(Cl)CC1CCCC1
Yield: 81 %

Procedure:
Cyclopentane acetic acid (17 g, 0.132mole) was stirred into 50 mls of thionyl chloride and refluxed for two hours. The mixture was cooled and the excess solvent was removed via distillation at atmospheric pressure. The residue was distilled (b.p.=38°-39° C. at 0.1 mm Hg) to give 15 g of the title compound (81% distilled yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([PH:8](=[O:12])OCC)[O:5][CH2:6][CH3:7])[CH3:2].[CH:13]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[CH:13]1([PH:8](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCOC(OCC)[PH](=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(OCC)[PH](=O)C1CCCCC1

Procedure:
Following a procedure analogous to that of Example 1, but using 9.81 g of ethyl diethoxymethylphosphinate and 50 ml of a 2 molar solution of cyclohexylmagnesium chloride in diethyl ether and adding 20.7 g of potassium carbonate in 25 ml of water to precipitate inorganic salts, cyclohexyl(diethoxymethyl)phosphine oxide is obtained as colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:65]=[CH:64][C:53]2[NH:54][C:55]([C@@H:57]([NH2:63])[CH2:58][O:59][CH2:60][C:61]#[CH:62])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:63][C@H:57]([C:55]1[NH:54][C:53]2[CH:64]=[CH:65][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][O:59][CH2:60][C:61]#[CH:62])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Br)c1
Reactant: C#CCOC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 92 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-prop-2-ynyloxyethylamine in tetrahydrofuran. Yield: 92%; Rf value: 0.54 (silica gel: dichloromethane/ethanol=9:1); C24H20BrClN4O3 (527.804); mass spectrum: (M+H)+=527/529/531 (chlorine isotope).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C@@:17]3([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]3)[C:16]3[C:11](=[N:12][CH:13]=[C:14]([Br:24])[CH:15]=3)[O:10][C:7]2=[CH:8][CH:9]=1)=[N+]=[N-].[B-].[Na+].[BH4-].[Na+].O>CO.CCOC(C)=O>[Br:24][C:14]1[CH:15]=[C:16]2[C@:17]3([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]3)[C:6]3[C:7](=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=3)[O:10][C:11]2=[N:12][CH:13]=1
Reactant: [N-]=[N+]=Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(Br)cnc1O2
Agent: [B-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1ncc(Br)cc12
Reaction time: 1 h

Procedure:
(S)-7-azido-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (200 mg, 0.517 mmol) was dissolved in MeOH (2 mL) and sodium borohydrate (195 mg, 5.17 mmol) was added at rt. After 1 h, additional MeOH (2 mL) and 10 equiv of NaBH4 were added at rt. The reaction mixture was allowed to stir overnight. Additional MeOH (2 mL) and 10 equiv of NaBH4 were added and the reaction was allowed to stir for 1 h. Water was added, followed by EtOAc. The organic phase was separated, dried over MgSO4. The solvent was removed under reduced pressure to give (S)-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine as a light-yellow solid. The compound was used in the next step without further purification. MS m/z=362.8 [M+H]+. Calculated for C15H13BrN4O2: 361.19.
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]([C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[C:18]([NH2:20])=[NH:19].[OH-].[Na+]>CO.O>[N:25]1[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][C:21]=1[N:17]=[C:18]1[NH:20][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:20][C:18](=[N:17][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[NH:19][C:8]2([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:19]1
Reactant: O=C(C(=O)c1ccncc1)c1ccccc1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccncc2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1

Procedure:
Following the procedure of Example 1, 1 -phenyl-2-(4-pyridinyl)ethanedione (500 mg, 2.42 mmol) and 2-guanidinobenzimidazole (1.0 g, 6.0 mmol) in methanol (10 mL) was treated with a solution of sodium hydroxide (40 mg, 1.0 mmol) in 1 mL of water. The title compound was isolated as pale yellow crystals (45 mg, 3% yield). 1H NMR (300 MHz, d6 -DMSO) δ 11.5 (br s, NH, 1 H), 1 1.0 (br.s, NH, 1H), 10.0 (br s, NH, 1 H), 8.6 (br s, NH, 1 H), 8.4 (m, 2 H), 7.4-6.8 (m, 15H); MS (ESI) m/z 526 [M+H]+.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=1)[CH2:8][CH2:9][CH3:10].S(Cl)(Cl)=O.[CH3:24][C:25]1[C:34]([CH3:35])=[C:33]2[C:28]([CH2:29][CH2:30][C:31]([CH2:37][CH2:38][CH2:39][CH:40]([CH2:42][CH2:43][CH2:44][CH:45]([CH2:47][CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[CH3:46])[CH3:41])([CH3:36])[O:32]2)=[C:27]([CH3:53])[C:26]=1O>N1C=CC=CC=1>[CH3:10][CH2:9][CH2:8][CH2:7][C:11]1[CH:12]=[CH:13][C:14]([C:17]([O:19][C:26]2[C:27]([CH3:53])=[C:28]3[CH2:29][CH2:30][C:31]([CH2:37][CH2:38][CH2:39][CH:40]([CH2:42][CH2:43][CH2:44][CH:45]([CH2:47][CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[CH3:46])[CH3:41])([CH3:36])[O:32][C:33]3=[C:34]([CH3:35])[C:25]=2[CH3:24])=[O:18])=[N:15][CH:16]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reactant: CCCCc1ccc(C(=O)O)nc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)Oc2c(C)c(C)c3c(c2C)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O3)nc1
Temperature: 0 °C
Yield: 46.6 %

Procedure:
Ten milliliters of benzene was added to 4.51 g of 5-butylpicolinic acid, and 9 g of thionyl chloride was further added. The mixture was heated under reflux for 22 minutes. The excess of thionyl chloride and benzene were disiled off under reduced pressure, and 10 ml of benzene was added to the residue. The mixture was cooled to 0° C. and stirred. To the solution was added dropwise a solution of 5 g of dl-α-tocopherol in 4.25 ml of pyridine to perform the reaction for 1 hour and 40 minutes. The insoluble matter was removed by filtration from the reaction mixture, and the residue was washed with water, 1 N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order. Benzene was distilled off, and the residue was chromatographed on a silica gel column using benzene/ethyl acetate (4:1) as an eluent to give 3.2 g of dl-α-tocopheryl 5-butylpicolinate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1.[OH:16][CH2:17][C@@H:18]([N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])[CH2:19][CH:20]([CH3:22])[CH3:21].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:14]1[CH:13]=[N:12][CH:11]=[C:10]2[CH2:9][O:8][C:6]3[CH:7]=[C:2]([O:16][CH2:17][C@@H:18]([N:23]4[C:24](=[O:33])[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:31]4=[O:32])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH:3]=[CH:4][C:5]=3[C:15]=12
Reactant: Clc1ccc2c(c1)OCc1cnccc1-2
Reactant: CC(C)C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1ccc2c(c1)OCc1cnccc1-2)N1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 101.7 %

Procedure:
To a stirred suspension of 8-chloro-5H-chromeno[3,4-c]pyridine (1 g, 4.59 mmol), (S)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (3.43 g, 13.88 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (1.17 g, 2.76 mmol) and cesium carbonate (2.245 g, 6.89 mmol) in toluene (4 mL) was added palladium (II) acetate (0.309 g, 1.38 mmol). Nitrogen gas was bubbled through the mixture for 5 min, and then the mixture was heated at 80° C. for 14 h. The reaction was diluted with ethyl acetate (25 mL) and filtered through celite. The filtrate was washed with water (1×20 mL) and brine (1×20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (60% ethyl acetate in hexanes) to afford (S)-2-(1-((5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (2 g, 4.67 mmol, quantitative yield) as a semi solid. LCMS (ESI) m/e 429 [(M+H)+, calcd for C26H25N2O4 429.2].
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17](=[O:21])[NH:18]2)=[C:13]([C:22](=[O:25])[CH2:23]Cl)[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[Cl-].[Na+]>C1COCC1.C(O)(=O)C>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17](=[O:21])[NH:18]2)=[C:13]([CH:22]2[CH2:23][O:25]2)[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(CCl)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1ccc2c(C3CO3)cc(OCc3ccccc3)cc2[nH]1
Reaction time: 0.5 h

Procedure:
Lithium borohydride (434 mg, 19.93 mmol) is added to a suspension of 7-benzyloxy-5-(2-chloroacetyl)-1H-quinolin-2-one (6 g, 18.31 mmol) in THF (150 mL) at 0–5 ° C. and the mixture is stirred for 30 minutes. 2.5 N sodium hydroxide solution (43 mL, 107.50 mmol) is added and the mixture is stirred for 2 hours at 5–10 ° C. and for 2.5 hours at ambient temperature. Then the reaction mixture is slowly combined with glacial acetic acid (6.5 mL) followed by semi-saturated sodium chloride solution (100 mL) and stirred for a further 5 minutes. The precipitate formed is filtered off and the aqueous phase is extracted with ethyl acetate/THF (1/1.5×100 mL). The solid filtered off and the organic phases are combined, dried with sodium sulphate and evaporated down. The crude product is stirred with methanol (30 mL) and the precipitate is filtered off and dried at ambient temperature. Yield: 4.8 g (89%); mass spectroscopy: [M+H]+=294.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1B(O)O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:33]4[S:32][CH:36]=[CH:35][CH:34]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, part B), 2-thiophenyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.