Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:19]([C:21]1[CH:41]=[CH:40][C:24]2[N:25]([CH3:39])[C:26]([CH2:28][NH:29][C:30]3[CH:35]=[CH:34][C:33]([C:36](=[NH:38])[NH2:37])=[CH:32][CH:31]=3)=[N:27][C:23]=2[CH:22]=1)=[O:20].Cl[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:51].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][O:52][C:50](/[N:38]=[C:36](\[NH2:37])/[C:33]1[CH:32]=[CH:31][C:30]([NH:29][CH2:28][C:26]2[N:25]([CH3:39])[C:24]3[CH:40]=[CH:41][C:21]([C:19]([N:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=4)[CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:20])=[CH:22][C:23]=3[N:27]=2)=[CH:35][CH:34]=1)=[O:51]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1

Procedure:
55 g of 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide tosylate was dissolved in 437 ml of acetone and 273 ml of water. 16.4 g of hexyl chloroformate and 34 g of potassium carbonate was added to it at a temperature of about 15° C. After the end of the reaction, the precipitated product is filtered off and washed with acetone/water. Dissolved the obtained solid in 270 ml of acetone under heating and then filtered. The title product was crystallized by the addition of 220 ml of water. The isolated substance is dried under reduced pressure at 45° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=2)[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:18]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:29][CH:30]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: C#Cc1ccccc1CC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cc1
Temperature: 120 °C
Yield: 74 %

Procedure:
To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I39) (0.054 g, 0.788 mmol) and tert-butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I37) in dry DMF (4 mL) were added triethylamine (0.159 mL, 1.138 mmol), triphenylphosphine (0.011 g, 0.043 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.020 g, 0.028 mmol) and CuI (0.008 g, 0.04 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes. The reaction was concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I40) (0.122 g, 74% yield) as a yellow glassy solid; 1H NMR (400 MHz, d6-DMSO) δ 10.48 (s, 1H), 8.82 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.65-7.55 (m, 1H), 7.55-7.47 (m, 1H), 7.47-7.33 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 7.01 (s, 1H), 5.29-5.22 (m, 1H), 3.92 (d, J=13.1 Hz, 1H), 3.70 (s, 2H), 2.71 (t, J=13.3 Hz, 1H), 2.34-2.24 (m, 1H), 1.82-1.68 (m, 1H), 1.54 (d, J=11.3 Hz, 2H), 1.45-1.22 (m, 11H). LCMS Method C: rt 6.52 min; m/z 578.3 [M−H]−.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([CH3:19])[C:12](=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C1(C)C=CC=CC=1>[CH3:19][C:11]1[O:8][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:12]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: NC(=O)c1ccccc1
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C

Procedure:
A solution of benzamide (0.606 g, 5.00 mmoles) and methyl 4-bromo-3-oxopentanoate (1.05 g, 5.00 mmoles, example 31) are heated in toluene (6 ml) to 120° C. for 18 hours. The reaction is then purified by column chromatography (silica, 4:1 hex: EtOAc) to give the title compound as a clear oil. MS (APcI) 232 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:6]=[C:7](F)[CH:8]=[C:9]([Br:11])[CH:10]=1>CO.CN(C)C=O>[Br:4][C:5]1[CH:6]=[C:7]([O:2][CH3:1])[CH:8]=[C:9]([Br:11])[CH:10]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium methoxide (8.80 ml of a 4.5M solution in methanol, 41.0 mmol) was added dropwise to a stirred solution of 3,5-dibromofluorobenzene (5.00 g, 19.0 mmol) in N,N-dimethylformamide (95 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature, stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ether and the resulting solution was washed with water (3×300 ml) and brine (300 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (5.13 g) as a white solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[CH3:12]I>CS(C)=O>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH3:12]
Reactant: COC(=O)C(C)(C)CO
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCC(C)(C)C(=O)OC
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a solution of 3.52 g (63 mmol) of powdered potassium hydroxide in DMSO (150 mL) are added 2 mL (16 mmol) of hydroxypivalic acid methyl ester, followed by 3.9 mL (63 mmol) of methyl iodide. The reaction mixture is stirred for 0.5 h, then quenched with water (300 mL). The reaction mixture is extracted with DCM (3×300 mL). The combined organic extracts are washed with water (2×150 mL), brine (50 mL), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to yield 1.76 g of 3-methoxy-2,2-dimethyl-propionic acid methyl ester as a pale yellow oil, which is used in the next step without further purification. Yield: 77%; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.1 (6H, s), 3.2 (3H, s), 3.3 (2H, s), 3.6 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[S-:13][C:14]#[N:15].[Na+].BrBr.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:14]([NH2:15])[S:13][C:7]=2[CH:6]=1)=[O:12])[CH3:2]
Reactant: N#C[S-]
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2nc(N)sc2c1
Reaction time: 4 h
Yield: 67.2 %

Procedure:
A solution of ethyl-4-aminobenzoate (35 g, 212 mmol) in glacial acetic acid (300 mL) was added to a stirred solution of sodium thiocyanate (69 g, 848 mmol) in acetic acid (150 mL). The mixture was cooled in an ice-water bath and a solution of bromine (12 mL, 233 mmol) in acetic acid (60 mL) was added dropwise via an addition funnel. The reaction mixture was stirred at 0° C. to RT for 4 h and then poured into water (1.5 L). Saturated sodium carbonate solution was added to neutralize the solution. Precipitated solid was filtered, washed with water and EtOAc, and dried in vacuo to obtain the title compound of this step (31.65 g, 67.2% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12](O)=[O:13])=[CH:10][O:9][N:8]=1.FC1C=CC(C2C(C(O)=O)=CON=2)=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][OH:13])=[CH:10][O:9][N:8]=1
Reactant: O=C(O)c1conc1-c1ccccn1
Agent: O=C(O)c1conc1-c1ccc(F)cc1
Product: OCc1conc1-c1ccccn1
Yield: 76.1 %

Procedure:
As described for example 323e, 3-pyridin-2-yl-isoxazole-4-carboxylic acid (39.0 g, 200 mmol) was converted, instead of 3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid, to the title compound (26.8 g, 76%) which was obtained as a white solid. MS: m/e=177.2 [M]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[S:9]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
3,5-Dichlorobenzenesulphonyl chloride (5.0 g, 20.36 mmol) was added portionwise over 30 min to a solution of L-proline methyl ester hydrochloride (3.69 g, 22.4 mmol) and DIEA (7.8 ml, 44.8 mmol) in DCM (100 ml) at 0°. The reaction mixture was stirred overnight at room temperature then concentrated in vacuo. The residue was dissolved in EtOAc (100 ml) and washed with saturated aqueous NaHCO3 (100 ml), citric acid (10%, 100 ml) and saturated aqueous NaHCO3 (100 ml). The organic phase was dried (MgSO4) and concentrated in vacuo. Column chromatography (SiO2, EtOAc/hexane, 80:20) gave the title compound (3.77 g). δH (CDCl3) 7.8 (2H, d, J 2.0 Hz, ArH), 7.5 (1H, d, J 2.0 Hz, ArH), 4.4 (1H, m, CHα), 3.7 (3H, s, CO2Me), 3.4 (2H, m, CH2N), 2.0 (4H, m, NCH2CH2CH2); m/z (ES+, 70V), 338 (MH+).
Reaction SMILES: C(OC(Cl)=O)C.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.C(N(CC)CC)C.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CC(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:14])=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NCCN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.3 Ml. of chloroformic acid ethyl ester are added dropwise to a solution of 8.6 g. of p-chlorobenzoic acid and 7.6 ml. of triethylamine in 150 ml. of acetone, with stirring and cooling with ice-water. After one hour at 0° C., a solution of 6.5 g. of N-(2-aminoethyl)-morpholine in 50 ml. of acetone is added dropwise to the mixture and the mixture is then stirred overnight at room temperature. Thereafter it is concentrated, allowed to stand for 2 hours in the refrigerator and filtered. The filtrate is evaporated to dryness and the residue is taken up in 250 ml. of water and 250 ml. of methylene chloride. The phases are separated and the methylene chloride extract is dried over sodium sulfate and evaporated. The residue is recrystallized from isopropanol and 7.8 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].P(Br)(Br)[Br:12]>N1C=CC=CC=1>[Br-:12].[Br-:12].[CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9]
Reactant: BrP(Br)Br
Solvent: OCCOCCOCCO
Solvent: c1ccncc1
Product: [Br-]
Reaction time: 8 h

Procedure:
66 g. of triethylene glycol and 13.3 g. of anhydrous pyridine are slowly added to 100 g. of phosphorous tribromide while agitating and cooling the mixture. After standing overnight at room temperature, the mixture is poured on to ice and the organic phase is decanted, washed with water and dilute hydrochloric acid and dried over sodium sulphate. After distillation under vacuum (95°C and 0.5 mm. Hg) the title compound is obtained.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:8]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1CCCCC1
Reaction time: 2 h
Yield: 63.6 %

Procedure:
Ethyl bromoacetate (8.5 g, 50.9 mmol) was added dropwise to a stirred solution of piperidine (4.3 g, 50.5 mmol) and triethylamine (5.5 g, 54.4 mmol) in chloroform (20 ml) at such a rate as to maintain a gentle reflux. After the addition was complete stirring was continued for 2 hours and the reaction mixture washed with water (20 ml×3). The chloroform layer was dried (MgSO4) filtered and the solvent evaporated to leave a yellow oil. This oil was passed through a short column of silica eluting with a CH2Cl2/Pet Ether 40:60 mixture (1:1). Removal of the solvent from the resulting solution gave the required product as a pale yellow oil (Yield 5.5 g, 64%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[CH3:19])[NH2:15].Cl.O>C(OCCO)C>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1ccc(N)cc1F
Agent: Cl
Solvent: CCOCCO
Solvent: O
Product: Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 82342.5 %

Procedure:
45 g (0.28 mmol) of 2-chloro-3-nitropyridine was dissolved in 2-ethoxyethanol (300 ml), and 36 g (0.28 mmol) of 3-fluoro-4-methylaniline, 12N-hydrochloric acid and water (300 ml) were added thereto. Mixed solution was heated to reflux for 24 hours while stirring. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The solution was extracted with ethyl acetate, and washed with saturated brine, and then the obtained organic layer was dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue thus obtained was washed with diisopropyl ether to obtain 57 g (yield: 82%) of N-(3-fluoro-4-methylphenyl)-3-nitro-2-pyridylamine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].[Al+3].[Cl-].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: Brc1ccc2ccccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 14.7 (70.9 mmol) of 2-bromonaphthalene and 6.40 g (81.5 mmol) of acetyl chloride in 55 mL of nitrobenzene was added dropwise to a vigorously stirred solution of 10.4 g (78 mmol) of anhydrous AlCl3 in 25 mL of nitrobenzene at 25°-30° C. over a period of 1.3 h. After being stirred for 1 h more at 25° C., the reaction mixture was poured onto 200 g of ice and 30 mL of concentrated HCl. The product was extracted with Et2O (300, 200, and 100 mL). The extracts were washed with brine and saturated NaHCO3, dried (MgSO4), and concentrated at reduced pressure to afford a brownish oil. Short-path distillation (45°-55° C./25 mm) was used to remove nitrobenzene. The crystalline residue was dissolved in hot hexane (300 ml), filtered, and concentrated at reduced pressure to give 16.3 g (92% yield) of crude 2-acetyl-6-bromonaphthalene. Two crystallizations from hexane afforded 5.3 g (21% yield) of pure product, which had only one spot by TLC (10% EtOAc/hexane) Rf 0.22, mp 99°-101.5° C.; IR (mull) 1670, 1623, 1365, 1355, 1265, 1225, 1175, 880, 820, 800 cm-1 ; 1H NMR (CDCl3) δ 2.71 (s, 3, CH3CO), 7.5-8.2 (m, 4, 3,4,7,8-ArH), 8.03 (s, 1, 5-ArH), 8.44 (s, 1, 1-ArH).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[S:16][S:15][C:14](=[S:17])[CH:13]=1>>[C:4]1([CH:3]=[CH:2][CH:1]=[CH:11][C:12]2[S:16][S:15][C:14](=[S:17])[CH:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: Cc1cc(=S)ss1
Product: S=c1cc(C=CC=Cc2ccccc2)ss1

Procedure:
In the same manner as in Example 1, a corresponding cinnamaldehyde derivative (i.e., 4-chloro-cinnamaldehyde, 4-methoxy-cinnamaldehyde, 4-dimethylamino-cinnamaldehyde, p-methyl-cinnamaldehyde, o-chloro-cinnamaldehyde or m-methyl-cinnamaldehyde) was reacted with 5-methyl-1,2-dithiol-3-thione to prepare the following compounds.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[OH:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1COc2cccc(O)c2N1
Reaction time: 16 h
Yield: 64.3 %

Procedure:
A stirred solution of 2-aminobenzene-1,3-diol (2.0 g, 16.0 mmol) and TEA (1.94 g, 19.2 mmol) in anhydrous DMF (30 mL) was treated with 2-chloroacetyl chloride (1.81 g, 16.0 mmol) and stirring continued for 16 h at room temperature, then K2CO3 (2.65 g, 19.2 mmol) was added and the mixture further stirred for 16 h at the same temperature. The reaction mixture was diluted with DCM (100 mL), washed twice with water and then with brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by chromatographic column of silicagel to give desired product (1.7 g, 64% yield) LCMS (m/z): 166.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH:17]=[O:18])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.CI.[CH3:21]N(C=O)C.[H-].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=3)[N:8]2[CH3:21])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c(-c2cncc(C=O)c2)cc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
A flask is charged with 5-(6-chloro-1H-indol-2-yl)-pyridine-3-carbaldehyde (Example 104, 7.8 g, 28.9 mmol), MeI (5.33 g, 37.5 mmol) and DMF (300 mL), and 60% NaH in mineral oil (1.386 g, 34.6 mmol) is added at 0° C. The mixture is stirred for 2 h. Water (100 mL) is added. The mixture is extracted with EtOAc twice and the combined organic phase is washed with water (2×200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography with a 0 to 2% methanol-DCM gradient to give 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole. MS (ESI) m/z 271.0, 272.9 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C@@H:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7].C(#N)C>O>[C:18]([O:17][C:15]([N:9]1[CH2:10][C:11]([F:13])([F:14])[CH2:12][C@H:8]1[C:6]([OH:7])=[O:5])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide monohydrate (469 mg, 11.2 mmol) is added to a solution of (S)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.48 g, 5.59 mmol) in 3:1 acetonitrile in water (20 mL). The reaction is stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure and diluted with water and extracted with ether. The aqueous layer is acidified to PH˜1 and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound. ESI m/z 152 [M+H+−100].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 4-bromo-2-methyl-benzoic acid 10.0 g, 46.5 mmol) in methanol (100 mL) at room temperature was added sulfuric acid (conc. 1 mL) dropwise. The solution was heated at reflux for 16 h. The solution was removed from heat and sulfuric acid (conc. 0.5 mL) was added. The solution was heated at reflux 2 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, then with saturated sodium chloride. The solution was dried (MgSO4), filtered, and concentrated in vacuo to a crude colorless oil. Flash chromatography (SiO2, 5% ethyl acetate/hexane) gave the title compound as a colorless oil (9.2 g, 87%). 1H NMR (400 MHz, CDCl3): δ ppm 2.58 (s, 3H) 3.88 (s, 3H) 7.38 (dd, J=8.46, 1.89 Hz, 1H) 7.42 (d, J=1.52 Hz, 1H) 7.78 (d, J=8.34 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reaction time: 0.5 h
Yield: 35 %

Procedure:
2-bromopyridine (14.9 g, 93.1 mmol) in anhydrous THF (700 mL) was cooled to −78° C. under a stream of nitrogen gas, n-BuLi in hexane (54 mL) were added thereto and the mixture was stirred for 30 min. Tributyltin chloride (29 mL, 108 mmol) was added and the mixture was stirred, at −78° C. for 2 hours and afterwards at −20° C. for 3 hours. It was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and the solvent was evaporated. The residue was purified by chromatography (petroleum ether/ethyl acetate=9/1) to give 2-(tributylstannyl)pyridine (12 g, yield 34%) as a yellow liquid, LC-MS (ESI) m/z: 370 (M+1)+.
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(N=NC(C#N)(C)C)(C#N)C>O1CCOCC1>[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C=Cc1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(O)cc1

Procedure:
300 g of p-t-butoxystyrene, 30 g of styrene, and 1.6 g of azobis-iso-butylonitrile were dissolved in 330 g of dioxane, and reacted for 12 hours under a nitrogen atmosphere at 70° C. After the reaction, unreacted monomers were removed to obtain a copolymer of p-hydroxystyrene and styrene. This resin was hydrolyzed with an acid to produce 180 g of a copolymer of p-hydroxystyrene and styrene with Mw of 18,000. NMR measurement confirmed that the molar ratio of p-hydroxystyrene and styrene was 85:15.