Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=[O:24])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].C(C(CCCC)C([O-])=O)C.[Na+:45]>C(OCC)(=O)C>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([O-:25])=[O:24])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].[Na+:45]
Reactant: CCCc1c(OCc2ccc(S(=O)(=O)Nc3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCc1c(OCc2ccc(S(=O)(=O)Nc3cccc(C(=O)[O-])c3)cc2)ccc(C(C)=O)c1O
Reaction time: 12 h

Procedure:
Stir 3-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzenesulfonylamino]-benzoic acid (200 mg, 0.41 mmol) in ethyl acetate (10 mL) as a suspension. Add sodium 2-ethylhexanoate (92 mg, 0.90 mmol) in ethyl acetate (1 mL). After 12 hours at ambient temperature, concentrate the mixture under reduced pressure, sonicate the residue with ether (10 mL) and collect the title compound by filtration as a white solid (191 mg, 0.41 mmol): 1H NMR (DMSO-d6) δ 0.85 (t, 3H), 1.48 (m, 2H), 2.58 (m, 5H), 5.30 (s, 2H), 6.62 (d, 1H), 7.08 (m, 2H), 7.40 (m, 1H), 7.53 (m, 3H), 7.78 (m, 3H), 12.82 (s, 1H); MS (m/z): 482. (M−1).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([CH:2]=[C:3]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]2=3)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Product: FC(F)(F)c1ccc(C=C2c3ccccc3CCc3ccccc32)cc1

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and 4-(trifluoromethyl)phenyl boronic acid (0.33 g, 1.75 mmol using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product: MS (m/e): 350 (M+). HPLC (ISO80-10M)) t=17.32 min.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=1)[CH2:4][CH2:5][CH3:6].[CH2:39](Br)[CH:40]([CH3:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O.CCOC(C)=O.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:17]([N:19]([CH2:39][CH:40]([CH3:42])[CH3:41])[S:20]([CH3:23])(=[O:21])=[O:22])[CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(C)CBr
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NS(C)(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(N(CC(C)C)S(C)(=O)=O)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 117.7 %

Procedure:
To a solution of N-{5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}-methanesulfonamide dihydrochloride (0.1 mmol, 59 mg) in DMF (1.0 mL) was added isobutyl bromide (0.2 mmol, 22 μL), and potassium carbonate (0.4 mmol, 56 mg). And the mixture was stirred at 90° C. for 2 hours. It was then diluted with water/EtOAc. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, condensed, triturated with hexanes to provide the title compound (38 mg). LCMS: m/z 574 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.39 (1 H, d), 7.31 (1 H, s), 7.25 (1 H, d), 7.04 (1 H, s), 5.42 (1 H, bs), 4.46-4.53 (1 H, m), 3.42-3.48 (1 H, m), 2.98-3.30 (5 H, m), 2.95 (3 H, s), 2.90-2.94 (2 H, m), 2.69 (3 H, s), 2.09-2.30 (6 H, m), 1.82-1.88 (2H, m), 1.20-1.69 (11 H, m), 0.89-0.93 (6 H, m), 0.79 (3 H, t).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C@@H:5]([C:14]([OH:16])=O)[CH2:4][CH2:3]1.[NH2:17][CH:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:19]([OH:23])[C:20]([NH2:22])=[O:21].O[NH-].O=[N-].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[NH2:22][C:20](=[O:21])[C:19](=[O:23])[CH:18]([NH:17][C:14]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)=[O:16])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccncc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccncc1

Procedure:
Coupling of (R)-5-oxo-1-pyridin-4-ylmethyl-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide using Dess Martin reagent.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[N:5]=[CH:4][C:3]=1[C:20](OCC)=[O:21].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:20]([C:3]2[CH:4]=[N:5][C:6]3[C:7]([C:2]=2[OH:1])=[C:8]([C:16]([F:18])([F:19])[F:17])[CH:9]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:11]=3)=[O:21])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)cc(C(F)(F)F)c2c1O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(C(F)(F)F)cc(C(F)(F)F)c2c1O
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 0.35 g of ethyl 4-hydroxy-5,7-bis(trifluoromethyl)-3-quinolinecarboxylate (FR 2537140) and 3.0 mL of 4-chlorobenzylamine is stirred 1 h at 200° C. The mixture is cooled to 25° C. and it is diluted with 25 mL of hexanes. After stirring for an additional 1 h the solid precipitate is collected by filtration and washed with 10 mL of hexanes. It is dried in a stream of air and then it is suspended in 20 mL of glacial acetic acid. The mixture is heated until the solid is completely dissolved and the resulting solution is diluted with 200 mL of distilled water. The mixture is allowed to cool to 25° C. and the solid is collected by filtration. It is washed with a small volume of 10% aqueous acetic acid and then it is dried at torr and 45° C. for 18 h. The yield is 0.23 g.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[CH3:28])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:30]([Cu])#[N:31]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[CH3:28])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3c(C)cc(Cl)cc3C)cc2c1O
Reactant: N#C[Cu]
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cc(Cl)cc3C)cc2c1O

Procedure:
The title compound was synthesized from 1-bromo-6-(4-chloro-2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and CuCN in analogy to example 3a; MS-(−)-ion: M−1=423.4.
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([OH:28])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([OH:26])([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)[C:15]([F:18])([F:17])[F:16]>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([OH:26])([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)[C:15]([F:17])([F:16])[F:18])[O:28][CH2:2][C:3]([NH2:5])=[O:4]
Reactant: NC(=O)CBr
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCC(N)=O)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 2-bromoacetamide and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=404.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:26].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>P([O-])([O-])([O-])=O.OO.S([O-])([O-])(=O)=O.[Fe+2]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[C:18]([OH:26])[CH:19]=2
Reactant: COc1cc(S(C)=O)ccc1-c1nc2ncccc2[nH]1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Fe+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=P([O-])([O-])[O-]
Product: COc1cc(S(C)=O)ccc1-c1nc2ncc(O)cc2[nH]1

Procedure:
7.2 gm of 2-(2-methoxy-4-methylsulfinyl-phenyl)-1H-imidazo[4,5-b]pyridine were dissolved in a mixture of a phosphate buffer of pH 7.2 and 120 ml of 3% hydrogen peroxide, and a solution of 9.3 gm of ethylenediamine tetraacetic acid, 4.4 gm of ascorbic acid, 3.8 gm of iron(II) sulfate in a phosphate buffer of pH 7.2 was added. After 30 minutes the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a polystyrene resin column (XAD-2 of Rohm & Haas) with water and methanol as eluants. After evaporation of the eluate the two compounds were separated by means of chromatography on silicagel [eluant: chloroform/methanol/ammonia water=85/15/2 (v/v)]. 2-(2-Methoxy-4-methylsulfinyl-phenyl)-6-hydroxy-1H-imidazo[4,5-b]pyridine was obtained as yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][N:22]([CH:25]=[O:26])[CH2:21][CH2:20]2)[C:8]1=[O:27].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:40][C:41]#[N:42]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:40][C:41]#[N:42])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][N:22]([CH:25]=[O:26])[CH2:21][CH2:20]2)[C:8]1=[O:27]
Reactant: N#CCBr
Reactant: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cc(OCC#N)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Yield: 60.5 %

Procedure:
0.17 g of 4-[3-(3,4-dimethoxybenzyl)-6-hydroxy-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde obtained in stage 1.8 and 0.25 g of Cs2CO3 in 3 ml of DMF are stirred for 15 min at AT. 0.056 g of bromoacetonitrile is added and the reaction mixture is subsequently irradiated under a microwave field at 100° C. for 15 min. It is filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an MeOH/DCM mixture, (1/99, v/v) as far as (4/96, v/v), to give 0.112 g of the expected product.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH2:33][CH3:34])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([CH2:33][CH3:34])[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCNC1CCCC1C(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCCC1N(CC)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1665 g, 0.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-Ethylamino-cyclopentanecarboxylic acid ethyl ester (0.0926 g, 0.5 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1003 g, 0.525 mmol). Then N-methylmorpholine (115 μL, 1.05 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{ethyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester, as a yellow oil. LC-MS (ESI) calcd for C20H28N4O7S2 500.14, found 501.2 [M+H+].
Reaction SMILES: [BH4-].[Na+].[Br-].[C:4]([O:8][C:9]([N:11]1[C:19]2[CH:18]=[CH:17][N+:16]([CH:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:15][C:14]=2[CH:13]=[CH:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CCO>[C:4]([O:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([C:9]([O:8][CH2:4][CH3:5])=[O:10])([CH3:28])[CH3:27])[CH2:15][C:14]=2[CH:13]=[CH:12]1)=[O:10])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)CCCCCC(c1ccccc1Cl)[n+]1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2c(ccn2C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
Portions of sodium borohydride (0.16 g, 4.28 mmol) were added to a solution of 1-tert-butoxycarbonyl-5-[1-(2-chlorophenyl)-7-methyloctyl]-1H-pyrrolo[3,2-c]pyridin-5-ium bromide (1.3 g, 2.14 mmol) in 70% EtOH (30 mL) at room temperature over 30 minutes. Once the addition was complete, the mixture was stirred for 0.5 hours. The solvent was evaporated under reduced pressure and water (60 mL) was added. The product was extracted with dichloromethane (3×80 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The resultant tertiary amine was purified by column chromatography (silica gel, ethyl acetate/heptane=1/10 to 1/3) to yield 5-[1-(2-chlorophenyl)-7-ethoxycarbonyl-7-methyloctyl]-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.53 g, 46.9%) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.52 (d, 1H, J=7.8 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.27 (t, 1H, J=6.6 Hz), 7.19 (t, 1H, J=7.5 Hz), 7.12 (d, 1H, J=3.3 Hz), 5.95 (d, 1H, J=3.3 Hz), 4.16-4.13 (m, 1H), 4.09 (q, 2H, J=7.2 Hz), 3.31 (d, 1H, J=13.8 Hz), 2.85-2.59 (m, 4H), 1.95-1.76 (m, 2H), 1.55 (s, 9H), 1.45-1.40 (m, 2H), 1.28-1.14 (m, 6H), 1.21 (t, 3H, J=7.2 Hz), 1.11 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 178.00, 149.47, 139.70, 134.90, 129.45, 129.15, 127.89, 127.60, 126.80, 120.94, 119.76, 109.18, 83.24, 63.80, 60.30, 48.78, 42.32, 40.88, 33.20, 30.56, 28.31, 26.45, 25.44, 25.38, 25.03, 14.52. HRMS (HR): Calculated for C30H43ClN2O2 (M+H)+: 531.2990. found 531.2933.
Reaction SMILES: Cl[Si:2]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[O:3][Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6].[CH2:18]([O:25][C@H:26]1[C:30](=[CH2:31])[C@H:29]([CH2:32][OH:33])[C@H:28]([OH:34])[C@@H:27]1[OH:35])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:18]([O:25][C@@H:26]1[C@@H:27]([OH:35])[C@@H:28]2[O:34][Si:2]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[O:3][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[O:33][CH2:32][C@H:29]2[C:30]1=[CH2:31])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C=C1[C@H](CO)[C@H](O)[C@H](O)[C@H]1OCc1ccccc1
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Solvent: c1ccncc1
Product: C=C1[C@@H]2CO[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)O[C@H]2[C@H](O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane (5.5 mL, 16.8 mmol) was added dropwise to a solution of triol 5 (4.0 g, 16.0 mmol) in anhydrous pyridine at −30° C. The reaction mixture was allowed to warm up to room temperature gradually and kept at the same temperature for 2 h. After removing the pyridine in vacuo, the residue was dissolved in EtOAc and washed with H2O and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on a silica gel (EtOAc:Hexanes=1:30 to 1:5) to yield the alcohol 6 (6.5 g, 82%) as a syrup. [α]24D −105.94° (c 0.58, CHCl3); 1H NMR (500 MHz, CDCl3) δ7.41-7.26 (m, 5H), 5.36 (t, J=2.5 Hz, 1H), 5.11 (t, J=2.5 Hz, 1H), 4.77 (d, J=12.0 Hz, 1H), 4.62 (d, J=12.5 Hz, 1H), 4.18-4.14 (m, 2H), 4.05 (dd, J=4.5 and 12.0 Hz, 1H), 3.78 (dd, J=8.0 and 12.0 Hz, 1H), 2.90-2.88 (m, 1H), 1.08-0.97 (m, 27H); 13C NMR (125 MHz, CDCl3) δ 147.3, 138.1, 128.4, 127.6, 127.5, 111.1, 80.2, 74.2, 71.2, 71.1, 64.9, 50.1, 17.6, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0. Anal. Calcd. for C26H44O5Si2: C, 63.37; H, 9.00. Found: C, 63.64; H, 9.05.
Reaction SMILES: [C:1]([CH:3]1[CH:8]2[CH:4]1[CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7]2)#[N:2].[CH:16]1([CH2:19]Br)[CH2:18][CH2:17]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[C:1]([C:3]1([CH2:19][CH:16]2[CH2:18][CH2:17]2)[CH:4]2[CH:8]1[CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]2)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC2C(C#N)C2C1
Reactant: BrCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2(C#N)CC1CC1
Reaction time: 18 h

Procedure:
To a solution of 3 (1.68 g, 8.08 mmol) and cyclopropylmethyl bromide (1.31 g, 9.70 mmol) in toluene (25 mL) at 0° C. was added a solution of KHMDS (0.5 M in toluene, 17.8 mL, 8.89 mmol) and stirred for 18 h. The reaction was partially concentrated under vacuum and purified by column chromatography (silica gel) using 0 to 65% EtOAc in hexanes to 4a (minor diastereomer, 290 mg, 14%) and 4b (major diastereomer, 685 mg, 32%) as clear oils; 1H-nmr (400 MHz, CDCl3) δ (minor diastereomer) 3.60 (td, J=12.0, 4.0 Hz, 1H), 3.49 (d, J=12.0 Hz, 1H), 3.41 (d, J=12.0 Hz, 1H), 2.28-2.24 (m, 1H), 1.43 (s, 9H), 1.43-1.28 (m, 2H), 0.94-0.86 (m, 1H), 0.66-0.59 (m, 1H), 0.21 (q, J=6.0 Hz, 1H); LC-MS (214 nM) 3.18 min (>98%), m/z 207.1 [M-tBu]. 1H-nmr (400 MHz, CDCl3) δ (major diastereomer) 3.81 (d, J=12.0 Hz, 1H), 3.75 (d, J=12.0 Hz, 1H), 3.57 (td, J=12.0, 4.0 Hz, 1H), 1.83-1.78 (m, 2H), 1.43 (s, 9H), 1.46-1.40 (m, 2H), 0.92-0.84 (m, 1H), 0.61-0.52 (m, 2H), 0.22-0.16 (m, 2H); LC-MS (214 nM) 3.11 min (>98%), m/z 162.9 [M-Boc], 285.2 [M+Na].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:12][C:13]2[CH:14]=[C:15]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])[CH:16]=[CH:17][CH:18]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: Nc1cccc(N2CCCC2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1CCCN1c1cccc(Nc2ncc(Br)cc2[N+](=O)[O-])c1
Yield: 65.4 %

Procedure:
A suspension of 5-bromo-2-chloro-3-nitropyridine (3.79 g, 16 mmol), 1-(3-aminophenyl)pyrrolidin-2-one (2.56 g, 15 mmol) and potassium carbonate (2.0 g, 15 mmol) in 1,2-dichloroethane (25 ml) was heated at reflux for 60 hours. The reaction was cooled, diluted with dichloromethane (200 ml) and extracted with water. The organic phase was then dried over anhydrous sodium sulphate, filtered and pre-adsorbed on to silica (25 g). Purification by column chromatography eluting with isohexane on a gradient of ethyl acetate (10%-40%) gave 1-[3-(5-bromo-3-nitropyridin-2-ylamino)phenyl]pyrrolidin-2-one as a red solid (3.7 g, 68%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[CH:22]=[N:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#Cc1ccc(N)cn1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: c1ccncc1
Product: N#Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 5-aminopicolinonitrile (24 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 307.3, found 308.3 (M+1)+. Retention time 2.87 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16]>O1CCCC1.O>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:22])([O-:17])=[O:16]
Reactant: Nc1cccnc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)c1cccc([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 99.1 %

Procedure:
A solution of 3-aminopyridine (2 g, 20 mmol) in tetrahydrofuran (100 ml) was treated at 0° C. with triethylamine (3 ml, 2.2 g, 22 mmol) and then a solution of 3-nitrobenzoyl chloride (3.7 g, 20 mmol) in tetahydrofuran (50 ml). After 0.5 h the reaction mixture was diluted with water (400 ml) and set aside in the fridge for 3 days. Filtration and drying afforded the title compound as a purple crystalline solid (4.82 g, 99%).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:22][CH:23]=[O:24])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:22][CH:23]=[O:24])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: O=CNc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CO
Product: O=CNc1ccc2c(c1)[nH]c1cc(O)ccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To N-(7-(benzyloxy)-9H-carbazol-2-yl)formamide (250 mg, 0.79 mmol) in 50 mL MeOH was added Palladium on activated carbon (60 mg). The mixture was stirred at rt under H2 atmosphere for 15 h. The mixture was concentrated under reduced pressure and dried under high vacuum to afford N-(7-hydroxy-9H-carbazol-2-yl)formamide mixed with the catalyst as a black solid (240 mg). This material was used directly for the next reaction without purification. MS (ESI) m/z 227 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2.S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:14][C:13]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([OH:12])=[CH:8][CH:9]=2)[CH:4]=1)=[O:15]
Reactant: CO
Reactant: O=C(O)c1cc2cc(O)ccc2cc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2cc(O)ccc2cc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3,7-dihydroxynaphthalene-2-carboxylic acid (4.0 g, 19.6 mmol) in MeOH (80 mL) is added thionyl chloride (10 mL, 136 mmol) and it is stirred at RT for 48 h. The solvent is removed and purified to give the title compound.