Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:9])=[C:6]([OH:8])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:43]([O:47][C:48]([C@@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[CH2:55][CH2:56]O)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[C:43]([O:47][C:48]([C@@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[CH2:55][CH2:56][O:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[I:9])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: Oc1cc(Cl)ccc1I
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CCOc1cc(Cl)ccc1I
Reaction time: 0.33 h

Procedure:
5-Chloro-2-iodophenol (801 mg, 3.15 mmol) and PPh3 (1.15 g, 4.41 mmol) were dissolved in THF (25 mL). DIAD (0.91 mL, 4.62 mmol). was added dropwise and the solution was stirred for 20 min. A solution of 1-(2-hydroxy-ethyl)-pyrrolidine-2-(S)-carboxylic acid tert butyl ester (816 mg, 3.79 mmol) in THF (4 mL) was added via canulation. The mixture was stirred for 40 min at 0° C. then for 1.5 h at room temperature and finally for 3 h at 50° C. The mixture was diluted with heptanes (100 mL), washed with water (4×25 mL), dried over Na2SO4 and evaporated onto silica gel. After flash chromatography using silica gel, eluting with heptanes/EtOAc, 9:1, the title compound was obtained as a colorless oil (1.023 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12](O)=[O:13]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[CH2:12][OH:13]
Reactant: O=C(O)C1OCCc2c(Br)cccc21
Solvent: C1CCOC1
Product: OCC1OCCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylic acid (0.500 g, 1.94 mmol) in 1 mL of THF was added BH3. THF (3.88 mL, 3.88 mmol) drop wise at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with water and aqueous sodium hydroxide (1 N, 2 mL). The contents were stirred for 3 h, and then extracted with EtOAc. The organic layer was dried and concentrated to give (5-bromo-3,4-dihydro-1H-isochromen-1-yl)methanol 1H-NMR (400 MHz, CDCl3) δ 7.41 (t, J=2.4 Hz, 1H), 6.97˜7.04 (m, 2H), 4.75˜4.77 (m, 1H), 3.88˜3.92 (m, 1H), 3.73˜3.79 (m, 2H), 2.71-2.86 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(F)ccc1F
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)c(O)cc1F
Temperature: -13 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A solution of 2,5-difluorophenol (5 g, 38.4 mmol) in acetic acid (10 mL) was added slowly to a mixture of concentrated nitric acid (10 mL) and acetic acid (10 mL) cooled in an acetonitrile/dry ice bath in a manner that temperature did not exceed −18° C. After everything was added, solution was kept at −30° C. for 30 minutes, stirred at −13° C. for 30 minutes, and then at 0° C. for 1 hour. Solution was transferred into a separatory funnel, diluted with methylene chloride, and extracted three times with water. Organic phase was dried over magnesium sulfate, filtered, and concentrated. Residue was purified by column chromatography on SiO2 (hexane/acetyl acetate 1:1) to give 2,5-difluoro-4-nitro-phenol as a yellow solid (1.74 g, 26%). 1HNMR (MeOD, 400 MHz) δ 7.97-7.93 (m, 1H), 6.95-6.91 (m, 1H), 6.17 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]([NH:16]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.FC(F)(F)C(O)=O>CO>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH2:16])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2
Reactant: COC(=O)C(=Cc1cc(Cl)c2[nH]ncc2c1)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)Cc1cc(Cl)c2[nH]ncc2c1
Reaction time: 96 h

Procedure:
A solution of 2-benzyloxycarbonylamino-3-(7-chloro-1H-indazol-5-yl)-acrylic acid methyl ester (300 mg, 0.78 mmol) in methanol (10 mL) was treated with trifluoroacetic acid (0.2 mL), flushed with nitrogen, and treated with 10% palladium on charcoal (30 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen. After 4 days, all starting material had been consumed. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 78 mg (40%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][C:7](=O)[C:8]([F:11])([F:10])[F:9])[CH3:2].Cl.[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1.Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:19]2[C:18](=[CH:17][CH:16]=[C:15]([CH3:23])[CH:20]=2)[NH:21][C:7]=1[C:8]([F:11])([F:10])[F:9])[CH3:2]
Reactant: CCOC(=O)CCC(=O)C(F)(F)F
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1c(C(F)(F)F)[nH]c2ccc(C)cc12
Temperature: 0 °C
Yield: 59.4 %

Procedure:
A mixture of 5,5,5-trifluoro-4-oxo-pentanoic acid ethyl ester (6.00 g, 30.3 mmol) and p-tolylhydrazine hydrochloride (4.80 g, 30.3 mmol) in ethanol (25 mL) is cooled to 0° C. The solution is saturated with HCl gas and heated at reflux for 18 h under an argon atmosphere. After cooling to room temperature the reaction mixture is concentrated by rotary evaporation. The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc. The layers are separated and the aqueous phase is extracted with twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1) affords the title compound as orange crystals (5.14 g, 18.0 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=12.17 (bs, 1H), 7.63 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 4.06 (s, 2H), 2.57 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). MS (ES+): 286 (M(C14H14F3NO2)+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].[C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])[NH:30][NH2:31].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:31][NH:30][C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)O)nc2ccc(F)cn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)NNC(=O)OC(C)(C)C)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
2.2 250 mg (0.666 mmol) of 2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]pyridin-2-yl]benzoic acid, 88 mg (0.666 mmol) of tert-butyl carbazate, 153 mg (0.800 mmol) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (DAPECI) are dissolved in 1 ml of DMF and stirred at RT for 5 hours. The mixture is subsequently added to water, the precipitated solid is filtered off with suction and dried, giving 187 mg (57%) of tert-butyl N′-{2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]-pyridin-2-yl]benzoyl}hydrazinecarboxylate as solid; MS-FAB (M+H+)=490.8; Rf (HPLC, polar method): 1.47 min. This is employed in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[CH:22][C:21]3[CH:20]([N:24]([CH:26]4[CH2:28][CH2:27]4)[CH3:25])[CH2:19][CH2:18][C:17]([CH3:30])([CH3:29])[C:16]=3[CH:15]=2)=[CH:8][C:7]=1[F:31])C.CO.O.[OH-].[Li+]>O>[CH:26]1([N:24]([CH3:25])[CH:20]2[CH2:19][CH2:18][C:17]([CH3:30])([CH3:29])[C:16]3[CH:15]=[C:14]([C:13]#[C:12][C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[C:7]([F:31])[CH:8]=4)[CH:23]=[CH:22][C:21]2=3)[CH2:28][CH2:27]1
Reactant: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)c(F)c3)ccc21

Procedure:
Following general procedure J and using [4-(5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-2-fluoro-phenyl]-acetic acid ethyl ester (Compound 17, 0.025 g, 0.059 mmol), methanol (1 mL), tetrahydroftiran (1 mL), water (0.5 mL) and lithium hydroxide monohydrate (0.060 g, 1.43 mmol), the title compound was obtained as a white solid (0.023 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13].Cl.[CH3:17]O>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([O:14][CH3:17])=[O:13]
Reactant: CO
Reactant: Cc1ccccc1CC(=O)CCC(=O)O
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CCC(=O)Cc1ccccc1C

Procedure:
5-(2-Methylphenyl)-4-oxopentanoic acid (prepared as described above; 535 g.) was heated under reflux for 1 hour in methanol (5.5 liters) through which was passed gaseous hydrogen chloride. The flow of hydrogen chloride was then stopped and the solution was heated for a further 2 hours. The solution was then evaporated to give a dark coloured oil which was dissolved in diethyl ether (1500 ml.), washed with water and aqueous sodium bicarbonate solution, dried over sodium sulphate and distilled to give methyl 5-(2-methylphenyl)-4-oxopentanoate (248 g.), in the form of a clear yellow oil, b.p. 170°-200° C./0.7-1.0 mm.Hg.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])(=O)C.[CH3:12][NH:13][CH3:14]>>[OH:4][CH2:5][CH2:6][CH2:7][S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9]
Reactant: CNC
Reactant: CC(=O)OCCCS(=O)(=O)Cl
Product: CN(C)S(=O)(=O)CCCO

Procedure:
Using 3-acetoxy-1-propanesulfonylchloride and dimethylamine, substantially the same reaction was conducted as in reference example 47 and 48 to produce the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:24])[CH2:21][C:22]#[CH:23].Br[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>C(N(CC)CC)C.CCOCC.[Pd](Cl)Cl>[OH:24][CH2:20][CH2:21][C:22]#[C:23][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]
Reactant: O=Cc1ccccc1Br
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=Cc1ccccc1C#CCCO
Temperature: 25 °C

Procedure:
To a suspension of palladium chloride (11.0 mg, 0.618 mmol) and cuprous iodide (Aldrich gold label, 43.5 mg, 0.229 mmol) in triethylamine (distilled from calcium hydride, 53 mL) was added, sequentially, triphenylphosphine (439 mg, 1.67 mmol), 3-butyn-1-ol (8.0 mL, 106 mmol), and 2-bromobenzaldehyde (10.6 mL, 88.3 mmol). The mixture was refluxed for 7 hours. The mixture was cooled to room temperature, diluted with ether (300 mL) and filtered. The pad was washed with ether (3×50 mL) and the combined filtrates were concentrated in vacuo to an oil: 16.1 g; 1H NMR (270 MHz, deuteriochloroform) δ 10.4 (1H, s), 7.85 (d, J=7 Hz), 7.35-7.50 (m, 3H), 3.0-4.0 (br s, 1H), 3.85 (t, J=6 Hz, 2H), 2.74 (t, J=6 Hz, 2H);
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].Cl>C(Cl)(Cl)Cl>[Cl:20][CH2:21][CH2:22][CH2:23][S:24]([NH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)(=[O:26])=[O:25]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (4.08 g) obtained in Reference Example 2(1) is suspended in chloroform (50 ml), and thereto is added triethylamine (8.8 ml) under ice-cooling. Subsequently, a solution of 3-chloropropanesulfonyl chloride (3.35 ml) in chloroform (20 ml) is added dropwise over 20 minutes under the same temperature. After stirring for 2 hours at room temperature, 5% hydrochloric acid is added to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in diisopropylamine, and filtered to collect precipitates to give methyl trans-4-{[(3-chloropropyl)sulfonyl]amino}cyclohexanecarboxylate (6.14 g).
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[OH-].[Na+]>CCCCCC.C(OCC)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]([NH2:6])=[NH:17])=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1ccc(F)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Product: N=C(N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
380 mL 1N LiHMDS-solution in n-hexane was added to 20 g 4-fluoro-benzonitrile in 1 L diethylether. The reaction was stirred for 2 h at RT and decomposed with 1 L 4 NHCL-solution at 0° C. 4 N sodium hydroxide was added until pH 12 was reached and the water layer was extracted with chloroform. The organic layer was dried and evaporated to give 6.6 g of the desired product. Rt: 0.30 min (method B), (M+H)+: 139
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Br)[CH3:11].[H-].[Li+].O>CS(C)=O>[CH2:10]([O:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:11]
Reactant: Cc1cccc(O)c1C
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1cccc(C)c1C
Temperature: 0 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
To a solution of 2,3-dimethylphenol (25 g, 204 mmol) in DMSO (205 Ml) was added 4-bromo-butyric acid ethyl ester (40.96 g, 210 mmol) and lithium hydride (2.0 g, 250 mmol) at room temperature. The resulting light brown solution was stirred for 2 days. Then, the reaction mixture was cooled to 0° C. and water (200 Ml) was added slowly. The organic compound was extracted into hexanes (2×200 Ml). The combined organic extracts were washed with brine solution (150 Ml) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave light brown oil. The crude mixture was purified by using a Biotage (40L) column chromatography eluting with 5% ethyl acetate in hexanes to isolate 4-(2,3-dimethyl-phenoxy)-butyric acid ethyl ester (45.32 g, 94%) as a colorless oil: ES(+)-HRMS m/e calculated for C14H20O3 (M+)+ 236.1412, found 236.1419.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[NH:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][OH:20])[CH2:14]1.C(N(CC)CC)C>C(#N)C>[N:4]1([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][C@H:15]([CH2:19][OH:20])[CH2:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: OCC1CNCCO1
Reactant: ClCCN1CCc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1

Procedure:
A microwave vial was charged with 1-(chloroethyl)-indoline (compound 50; 724 mg, 4.00 mmol), hydroxymethylmorpholine (compound 54; 562 mg, 4.80 mmol), triethylamine (2.2 ml, 16.00 mmol) and acetonitrile (4 ml). The vial was irradiated with microwaves for 2 hrs at 100° C., 40 min at 120° C. and 1 hr at 110° C. The residue was purified by flash column chromatography (silica, DCM/MeOH 1:0 to 8:2); and the product was isolated as an off-white solid (347 mg; 33%).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[F:5][C:6]([F:12])([F:11])[C:7](OC)=[O:8]>>[CH2:1]([NH:4][C:7](=[O:8])[C:6]([F:12])([F:11])[F:5])[C:2]#[CH:3]
Reactant: COC(=O)C(F)(F)F
Reactant: C#CCN
Product: C#CCNC(=O)C(F)(F)F
Yield: 91.4 %

Procedure:
Propargylamine (24.79 g, 0.450 mole; Aldrich, 99%) was added dropwise over 1 hour to methyl trifluoroacetate (69.19 g, 0.540 mole, 1.2 eq, Aldrich) at 0°. After stirring an additional hour at 0°, distillation through a 15 cm Vigreaux column afforded 62.12 g (91%) of trifluoroacetamide 18 as a colorless liquid (bp 68.5°-69.5° at 11 torr). This material was homogeneous by NMR and GC and was used interchangeably with spectroscopically-identical material prepared by acylating propargylamine with trifluoroacetic acid anhydride.
Reaction SMILES: [C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([SH:18])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OC)(O[CH3:23])(=O)=O>[OH-].[Na+].O>[C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([S:18][CH3:23])[N:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1nc(S)ccc1[N+](=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc([N+](=O)[O-])c(C(=O)c2ccccc2)n1

Procedure:
150 grams of 2-benzoyl-3-nitro-6-mercaptopyridine were dissolved in a solution of 45 grams of sodium hydroxide in 2.5 liters of water and hereto there was added dropwise at 35° C. with stirring 90 ml. of dimethyl sulfate. Then the composition was stirred for one hour at 40° C. After cooling the precipitated crystals were filtered off with suction and recrystallized from 1.8 liters of methanol.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])[N:6]([CH3:19])[C:5]=1[CH2:20][C:21]([OH:23])=[O:22])([OH:3])=[O:2].Cl.[CH2:25](O)[CH3:26]>>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])[N:6]([CH3:19])[C:5]=1[CH2:20][C:21]([O:23][CH2:25][CH3:26])=[O:22])([OH:3])=[O:2]
Reactant: Cc1ccc(C(=O)c2c(C)c(C(=O)O)c(CC(=O)O)n2C)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1c(C(=O)O)c(C)c(C(=O)c2ccc(C)cc2)n1C

Procedure:
A solution of 37 g. (0.118 mole) of 3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid in 370 ml. of ethanol containing 1.8 g. of dry hydrogen chloride is heated under reflux for 45 min. The solution is cooled and the solid which precipitated, ethyl 3-carboxy-1,4-dimethyl-5-(o-toluoyl)-pyrrole-2-acetate, is collected, m.p. 200°-202°C.
Reaction SMILES: [O:1]=[C:2]([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])[OH:3].C([O-])([O-])=O.[Na+].[Na+].[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].Cl>O>[C:21]([NH:5][C@H:4]([C:2]([OH:3])=[O:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:12]([OH:13])[CH:14]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
1.15 g (5.69 mmol) of Na2B4O7 was dissolved in 30 ml of water. The solution was degassed with Ar for 30 minutes, after which 0.592 g (3.0 mmol) of L-DOPA was added and stirred for 15 minutes. 0.317 g (3.0 mmol) of Na2CO3 was then added, the solution was cooled to 0° C., and 0.3 ml (3.0 mmol) of methacryloyl chloride was slowly added with stirring. The pH of the solution was maintained above 9 with Na2CO3 during the reaction. After stirring for 1 hour at room temperature, the solution was acidified to pH of 2 with concentrated HCl. The mixture was extracted with ethyl acetate three times. After washing with 0.1 N HCl and drying over anhydrous MgSO4, the solvent was removed in vacuo to yield crude light brown solid. The product was further purified by elution from a silica gel column with dichloromethane (DCM) and methanol (95:5). After evaporating the solvent, a white, sticky solid was obtained with a product yield of 35%. 1HNMR (500 MHz, acetone-d6): ÿ 7.1 d (1H, —NH—); 6.6-6.8 (3H, C6H3(OH)2—); 5.68 s (1H, CHH═); 5.632 s (unknown peak); 5.33 s (1 H, CHH═); 4.67 m (1H, —CH—); 2.93-3.1 m (2H, CH2—); 1.877 s (3 H, —CH3).
Reaction SMILES: [Si]([O:8][C:9]([C:11]1[C:12]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:13][CH:14]=[CH:15][CH:16]=1)=[CH2:10])(C(C)(C)C)(C)C>C(COC)OC.C(Cl)Cl.[Ag+].FC(F)(F)S([O-])(=O)=O>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[CH:10]=[C:9]([OH:8])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[CH:17]=1
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cccnc1C#Cc1ccccn1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: COCCOC
Product: Oc1cc(-c2ccccn2)cc2ncccc12
Temperature: 70 °C
Reaction time: 7 h
Yield: 24.4 %

Procedure:
Step 3 (=Reaction 5): 1.025 g 3-(1-(tert-butyldimethylsilyloxy)vinyl)-2-(pyridin-2-ylethynyl)pyridine was dissolved in 100 mL dimethoxyethane and 126 mg of trifluormethanesulfonic acid silver salt added and stirred 7 h at 70° C. The mixture is diluted with DCM and extracted with saturated NaHCO3 solution (3×). The organic phase was dried (MgSO4) and concentrated in vaccuo. The residual mixture was dissolved in 10 mL THF, 1.2 mL of tertbutylammoniumfluoride in THF (1N) was added and the mixture stirred for 2 h at 25° C. The mixture was diluted with DCM and extracted with water (1×) and the organic phase concentrated in vacuo and purified via FCC (100 g SiO2, DCM→DCM 93:7) to yield 165 mg of 7-(pyridin-2-yl)quinolin-5-ol 6.3 as solid. HPLC-MS: Rt=0.78 min (method E), M+H=223.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.O>C1(C)C=CC=CC=1>[C:1](=[N:14][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Nc1cccc(O)c1
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1cccc(N=C(c2ccccc2)c2ccccc2)c1

Procedure:
3-(Benzhydrylidene-amino)-phenol was prepared as follows: A stirred solution of benzophenone imine (15.0 g, 82.8 mmol) and 3-aminophenol (9.03 g, 82.8 mmol) in 25 mL toluene was heated at reflux with removal of H2O with a Dean-Stark trap for 3.5 h. The crystals that formed from the cooled reaction mixture were collected by vacuum filtration, washed with hexanes and air dried. In this manner, 3-(benzhydrylidene-amino)-phenol was obtained as a light yellow solid (17.3 g, 76%): 1H NMR (CDCl3) δ 7.64 (d, 2H, J=7.1 Hz), 7.38 (d, 1H, J=7.1 Hz), 7.34–7.15 (m, 7H), 7.04 (d, 2H, J=7.2 Hz), 6.88 (t, 1H, J=8.1 Hz), 6.82 (d, 1H, J=8.2 Hz), 6.23 (s, 1H), 6.21 (d, 1H, J=7.8 Hz). Anal. Calc. for C19H15NO: C, 83.49; H, 5.53; N, 5.12. Found: C, 83.51; H, 5.65; N, 5.03.