Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg+2].[Cl-].[Cl-].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1>C1COCC1>[CH:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc2ccccc12
Agent: [Cl-]
Agent: [Mg+2]
Agent: c1ccc2c(-c3cccc4ccccc34)cccc2c1
Solvent: C1CCOC1
Product: c1ccc2ccccc2c1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 7.2 %

Procedure:
Under vacuum (0.1 mbar), 3.70 g (150 mmol) of Mg powder was baked out (100-150° C.) and, after cooling, 0.66 g (2 mmol) of 9,10-diphenylanthracene (DA, Aldrich), 50 ml of THF and 2 to 3 drops of ethyl bromide was added. After stirring the mixture for 1 h, a deep-blue solution had formed (formation of the Mg-DA radical anion, see description). To this solution, 0.26 g (2 mmol) of anhydrous FeCl2, 20 ml of THF and 10.2 ml of an 0.49 M solution of MgCl2 in THF (5 mmol) was added, followed by stirring for another 30 min. Thereupon, 13.6 ml (100 mmol) of 1-chloronaphthalene was added dropwise within 30 min, the color of the solution turning from deep-blue to brown, and the solution warming up to 55° C. After 2 h of stirring, the yield of the Grignard compound of 1-chloronaphthalene was 63%, and after 5 h, it was 67% (as determined by acidimetric titration). The protolysis of a 10 ml sample of the solution (total volume 95 ml; cf. Example 1) yielded 0.92 g of naphthalene (corresponding to a yield of 1-C1OH7MgCl of 68%), binaphthyl and no other products (GC analysis).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[OH:12])[O:8][CH2:7][CH2:6][C:5]2=[O:14].N1C=CN=C1.[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>CN(C)C=O.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[O:12][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[O:8][CH2:7][CH2:6][C:5]2=[O:14]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc2c(c(C)c1O)OCCC2=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(c(C)c1O[Si](C(C)C)(C(C)C)C(C)C)OCCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6,8-dimethyl-7-hydroxychroman-4-one (the compound of Preparation 26, 0.50 g, 2.60 mmol), imidazole (0.35 g, 5.14 mmol), and triisopropylsilyl chloride (0.61 mL, 2.85 mmol) in dimethylformamide (10 mL) was stirred at ambient temperature overnight. The reaction was diluted with water and extracted with ether (2×). The combined organic phase was washed with 1N lithium chloride (2×) and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (1×4 inches packed in hexane) with elution proceeding as follows: 5% ethyl acetate/hexane (100 mL), nil; 5% ethyl acetate/hexane (100 mL) and 10% ethyl acetate/hexane (150 mL), 0.529 g (58%) of 6,8-dimethyl-7-triisopropylsilyloxychroman-4-one as a waxy lemon yellow solid which had: NMR δ 7.57 (s, 1 H), 4.52 (t, J=6.4 Hz, 2 H), 2.74 (t, J=6.4 Hz, 2 H), 2.21 (s, 3 H), 2.11 (s, 3 H), 1.40-1.26 (m, 3 H), 1.13 (d, J=7.2 Hz, 18 H); 13C NMR δ 191.60, 160.25, 159.93, 125.91, 122.55, 116.15, 115.29, 67.24, 37.52, 17.91, 17.69, 17.38, 14.24, 12.28, 9.97. A small silyl impurity was noted in the proton NMR at 1.06 ppm however, the material was found to be suitable for further transformations without additional purification.
Reaction SMILES: [CH2:1]=[O:2].[F:3][C:4]([F:11])(Br)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl-].[NH4+]>O1CCCC1.[Zn]>[F:3][C:4]([F:11])([CH2:1][OH:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CO

Procedure:
A mixture of paraformaldehyde (4.5 g, 50 mmol), ethyl difluorobromoacetate (10.2 g, 50 mmol) and activated zinc dust (3.3 g, 40 mmol) in anhydrous tetrahydrofuran was heated under reflux for 0.5 h. Then the mixture was treated with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. After usual work-up the desired compound ethyl 2,2-difluoro-3-hydroxypropionate was obtained by flash chromatography on silica gel (ethyl acetate:hexane; 25:75) (4.1 g, 53%).
Reaction SMILES: [F:1][C:2]([F:21])([S:17]([O-:20])(=[O:19])=[O:18])[CH:3]([O:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([S+:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.[C:42](Cl)(=[O:46])[C:43]([CH3:45])=[CH2:44].C(N(CC)CC)C.Cl>ClCCl>[F:21][C:2]([F:1])([S:17]([O-:20])(=[O:18])=[O:19])[CH:3]([O:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([F:5])([F:7])[F:6].[C:42]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S+:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:46])[C:43]([CH3:45])=[CH2:44]
Reactant: C=C(C)C(=O)Cl
Reactant: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1

Procedure:
In 15 g of dichloromethane was dissolved 3 g of (4-hydroxyphenyl)diphenylsulfonium 1,1,3,3,3-pentafluoro-2-benzoyloxypropane-1-sulfonate (PAG29) prepared in Synthesis Example 45. Methacryloyl chloride, 1 g, was added to the solution, which was cooled in an ice bath, and 0.9 ml of triethylamine was added dropwise. 30 g of 3N dilute hydrochloric acid was added, after which the organic layer was separated, washed with 30 g of water three times, and concentrated. The concentrate was purified by silica gel column chromatography (elute: dichloromethane/methanol 20/1 in weight ratio), after which diethyl ether was added to the concentrate for crystallization. The crystals were filtered and dried, obtaining the target compound in an amount of 3.5 g.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:30]([NH2:32])[CH3:31]>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:32][CH2:30][CH3:31])=[O:4]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: CCN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 29.6 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 3.4 g (34 mmol) of acetylacetone, 1.9 g (31 mmol) of acetic acid, and 5.0 g of anhydrous sodium sulfate were added. The mixture was heated at 60° C. for 2 hours. Subsequently, sodium sulfate was filtrated off. To the filtrate, 20 g (310 mmol) of 70% ethylamine was added and the same procedure as in Example 1 was performed to obtain 1.6 g of theanine (yield: 29.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23]OS(C)(=O)=O)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[I-:29].[Na+]>CC(=O)CC>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][I:29])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCI)CC1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.50 g (1.11 mmol) of crude methanesulfonic acid 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl ester in 20 ml of 2-butanone was treated with 0.33 g (2.23 mmol) of sodium iodide and stirred at 95° C. for 30 min. The reaction was cooled, evaporated, suspended in 60 ml dichloromethane/Et2O (1:3), filtered and the organic solvent discarded. The residue was then washed again with dichloromethane to give after evaporation 0.27 g (51%) of the title compound as white solid. MS: 481.0 (MH+, 2Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([O:17]C)=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cc(-c2ccc(C)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2csc(/C=C/C(=O)O)c2)cc1
Reaction time: 144 h
Yield: 54.6 %

Procedure:
To a solution of methyl (E)-3-[4-(4-methylphenyl)-thiophen-2-yl)acrylate (2.40 g) in tetrahydrofuran (50 ml) was added 2N sodium hydroxide (6.0 ml) at room temperature, and the mixture was stirred for 6 days. Precipitated crystal was collected by filtration and washed with tetrahydrofuran. To the crystals was added 1N hydrochloric acid (20 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give (E)-3-[4-(4-methylphenyl)thiophen-2-yl]acrylic acid (1.24 g) as pale yellow crystals.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:20])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)([CH3:4])([CH3:3])[CH3:2].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N>CN(C)P(=O)(N(C)C)N(C)C>[C:21]([O:20][CH:7]([CH2:6][NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)NCC(O)COc1cccc2c1CC(=O)N2
Reactant: O=C(O)c1ccccc1
Agent: N
Agent: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)NCC(COc1cccc2c1CC(=O)N2)OC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
1 g of 4-(3-tert-butylamino-2-hydroxypropoxy)oxindole is dissolved in 20 cc of hexamethylphosphoric acid triamide and the solution is allowed to stand at room temperature for 16 hours together with 7.9 g of benzoic acid and 0.9 g of benzoic acid anhydride. The mixture is poured into ice water, is rendered alkaline with a 10% ammonia solution and is extracted with methylene chloride. The title compound is obtained as evaporation residue of the methylene chloride phase; the hydrogen oxalate of the title compound crystallizes from ethanol. M.P. 200°-203°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Br:19])[CH:18]=1)[O:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][C:27]=1[CH3:33])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:2]2[CH:3]=[C:4]([O:5][C:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH:16]=[C:17]([Br:19])[CH:18]=2)=[CH:28][C:27]=1[CH3:33])[CH3:21]
Reactant: FC(F)(F)c1cccnc1Oc1cc(Br)cc(Br)c1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3ncccc3C(F)(F)F)c2)cc1C

Procedure:
2-(3,5-Dibromo-phenoxy)-3-trifluoromethyl-pyridine (2.05 g; 5.17 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.9 g; 4.0 mmol) was condensed to give the title product applying the procedure described for {4-[3-Bromo-5-cyclopentylmethoxyphenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by flash chromatography (heptane→ethyl acetate:heptane 2:9). Yield 1.26 g (58%). HPLC-MS: m/z: 544.3 (M+2); Rt: 2.77 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[H-].[Na+].Cl[C:9]1[N:14]2[CH:15]=[C:16]([CH3:18])[N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1>C(O)C>[NH2:2][CH2:3][CH2:4][S:5][C:9]1[N:14]2[CH:15]=[C:16]([CH3:18])[N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: NCCS
Reactant: Cc1cn2c(Cl)cccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cn2c(SCCN)cccc2n1
Yield: 53.1 %

Procedure:
To a suspension of cysteamine hydrochloride (2.95 g, 26 mmoles) in ethanol (100 ml) was added 60% sodium hydride (oily; 2.08 g, 26 mmoles) with stirring under ice-cooling and the mixture was stirred for 5 minutes. 5-chloro-2-methylimidazo[1,2-a]pyridine (3.33 g, 20 mmoles) was added to the mixture, followed by heating at reflux for 3 hours. After the solvent was distilled off, chloroform was added to the residue which was washed with 1N-NaOH and dried over anhydrous potassium carbonate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate/ethanol/triethylamine=6:2:1) to obtain 2.2 g of the desired product (53.6%, brown oily product).
Reaction SMILES: Cl.O[CH:3]([CH2:17][OH:18])[CH2:4][O:5][C:6]1[N:7]=[N:8][C:9]([NH:12][N:13]=[C:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=1.Br>C(O)(=O)C.C(OC(C)C)(C)C>[O:18]1[CH2:17][CH:3]1[CH2:4][O:5][C:6]1[N:7]=[N:8][C:9]([NH:12][N:13]=[C:14]([CH3:15])[CH3:16])=[CH:10][CH:11]=1
Reactant: CC(C)=NNc1ccc(OCC(O)CO)nn1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: CC(C)=NNc1ccc(OCC2CO2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
A mixture of 3-(2,3-dihydroxypropoxy)-6-isopropylidenehydrazinopyridazine hydrochloride (34.7 g), acetic acid (50 ml) and 33% hydrogen bromide in acetic acid (143 ml) was stirred at room temperature for 2 hours, and diluted with diisopropyl ether (1.5 liter). After 30 minutes the precipitate was collected, protecting it from moisture with dry nitrogen, and dried under vacuum at room temperature. The solid was dissolved with methanol (600 ml) and heated at reflux for 2 hours. After stirring at room temperature for 15 hours, the solvent was removed under vacuum and the residue was diluted with acetone and evaporated again to dryness. To the residue were added dichloromethane (400 ml), cetyltrimethylammonium bromide (3.4 g) and, with vigorous stirring and keeping the internal temperature under 10° C., 2N sodium hydroxide (100 ml). Stirring was continued at room temperature for 90 minutes, then the phases were separated and the organic layer was washed with water (2×200 ml), then with a saturated solution of ammonium sulfate (135 ml). The organic solution was dried over MgSO4, evaporated under vacuum and the residue was triturated with diisopropyl ether (200 ml) to yield 20 g of the title compound as a pale yellow solid, m.p. 106°-109° C. (with decomposition).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>C(#N)C>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1
Reactant: N#Cc1ncc(Br)c2ccccc12
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC#N
Product: COc1ccc(CNc2cnc(C#N)c3ccccc23)c(OC)c1
Yield: 30.3 %

Procedure:
A mixture of compound 470B (699 mg, 3.00 mmol) and 2,4-dimethoxybenzylamine (4.8 mL, 30 mmol) in 15 mL of acetonitrile was refluxed for 16 h. After concentration in vacuo, the residue was purified on a 5×15 cm silica gel column, eluting with 3:2 hexane:ethyl acetate to afford 290 mg (30%) of 470C as a light yellow solid. HPLC: 1.76 min (retention time) (Phenomenex C-18, 5 micron column, 4.6×30 mm, eluting with 10–90% aqueous methanol over 2 min containing 0.1% TFA, 4 ml/min, monitoring at 254 nm).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([N:15]([CH2:28][CH2:29][OH:30])[CH2:16][CH:17]([OH:27])[C:18]2[N:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[S:21][CH:22]=2)[CH3:14])=[CH:8][CH:7]=1)(O)=[O:2].B#B.C(OCC)(=O)C.CO>O1CCCC1>[OH:2][CH2:1][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([N:15]([CH2:28][CH2:29][OH:30])[CH2:16][CH:17]([OH:27])[C:18]2[N:19]=[C:20]([C:23]([F:25])([F:24])[F:26])[S:21][CH:22]=2)[CH3:14])=[CH:10][CH:11]=1
Reactant: CC(Cc1ccc(OCC(=O)O)cc1)N(CCO)CC(O)c1csc(C(F)(F)F)n1
Agent: B#B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(Cc1ccc(OCCO)cc1)N(CCO)CC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared by analogy to Example 71 by reaction of N-[2-(4-carboxymethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine in tetrahydrofuran with diborane in tetrahydrofuran and purification of the base on a silica gel column using an ethyl acetate/methanol=20:1 as eluant.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]3=[C:10](O)[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=[C:12]2[CH:14]=[CH:15][S:16][C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccc(F)cc2)nc2ccsc12
Product: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Yield: 88 %

Procedure:
A solution of 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (1.6 g) in phosphorus oxychloride (50 mL) is refluxed for 3 hours. After the excess amount of phosphorus oxychloride is removed under vacuum, the residue is treated with ethyl acetate (20 mL), and NaOH (2N, 20 mL). The mixture is extracted with ethyl acetate (3×20 mL). The combinded organic layers are washed with brine and dried over MgSO4. Evaporation of the solvent affords 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (1.5 g, 88% yield) as a white solid, m.p. 119-121°C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2].[CH3:22][CH2:23][O:24][C:25](OCC)(OCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:11]=2)[C:6](=[C:25]([O:24][CH2:23][CH3:22])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2cc(C(=O)c3ccccc3)ccc21
Reactant: CCOC(OCC)(OCC)c1ccccc1
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccc(C(=O)c3ccccc3)cc21)c1ccccc1

Procedure:
Prepared from 1-acetyl-5-benzoyl-2-indolinone and triethyl orthobenzoate
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[C:19]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])[CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cccnc1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: OBO
Product: O=Cc1cccnc1-c1cccc(C(F)(F)F)c1

Procedure:
2-(3-(trifluoromethyl)phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (3-(trifluoromethyl)phenyl)boronic acid (100 mg, 135.1 mg theoretical, 74%). LC-MS m/z 252.2 (M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23](C(Cl)=O)=[CH:22][CH:21]=1.[CH2:35]([N:37]1[C:49]2[CH:48]=[CH:47][C:46]([NH2:50])=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:36]>>[C:29]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:30]=[CH:31][C:32]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]2[C:17]([NH:50][C:46]2[CH:47]=[CH:48][C:49]3[N:37]([CH2:35][CH3:36])[C:38]4[C:43]([C:44]=3[CH:45]=2)=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:19])=[O:7])=[CH:33][CH:34]=1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 70% purity by LC/MS. MS(ESI+): m/z=545.4.
Reaction SMILES: [N+:1](CCC)([O-:3])=[O:2].[CH2:7]1[CH2:17][CH2:16]N2[C:10](=NCCC2)[CH2:9][CH2:8]1.C(=[O:21])CC>C(OCC)(=O)C>[OH:21][CH:7]([CH2:17][CH3:16])[CH:8]([N+:1]([O-:3])=[O:2])[CH2:9][CH3:10]
Reactant: CCC[N+](=O)[O-]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCC=O
Solvent: CCOC(C)=O
Product: CCC(O)C(CC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h
Yield: 837.8 %

Procedure:
A reaction vessel was replaced with nitrogen, and 1-nitropropane (8.93 ml, 100 mmol) and dry-THF (50 ml) were added. After DBU (1,8-diazabicyclo[5.4.0]-7-undecene) (1.5 ml, 10 mmol) had been added, propionaldehyde (4.68 ml, 100 mmol) was added while the vessel was cooled in an ice bath. After the mixture had been stirred at room temperature for 10 hours, ethyl acetate (100 ml) was added, and the whole was washed with dilute hydrochloric acid, water, and a saturated salt solution. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to yield 4-hydroxy-3-nitrohexane (12.33 g, 84% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11]Br)[C:4]=1[C:5]#[N:6].CC1C=CC=C(C)C=1N.[C-]#N.[CH3:24][O-:25].[Na+].CN(C)[CH:29]=[O:30]>O>[CH3:24][O:25][CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:30][CH3:29])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(CBr)cccc1CBr
Reactant: CN(C)C=O
Reactant: C[O-]
Agent: Cc1cccc(C)c1N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COCc1cccc(COC)c1C#N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2.0 g of 2,6-bis(bromomethyl)benzonitrile (F. Voegtle, P. Neumann, M. Zuber, Chem. Ber., 105, 2955 (1972)), prepared starting from 2,6-dimethylaniline by the Sandmayer reaction with cupreous cyanide and next by the bromination with N-bromosuccinimide,are dissolved in 2 ml of anhydrous N,N-dimethylformamide and added to the suspension of 1.24 g of sodium methylate in 10 ml of N,N-dimethylformamide at 0° C. After stirring the mixture for three hours at 0° C., the same is added with 20 ml of water and extracted with 120 ml of ethyl ether divided into three portions. The extracts, after drying with anhydrous sodium sulfate and evaporation to dryness, give a solid residue which, after sublimation at 100° C./0.04 Torr, gives 2,6-bis(methoxymethyl)benzonitrile with melting point 80°-81° C.; the yield obtained is 40%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C=CC=1F)N.C(O)(=O)C=C.C(OC)(=O)C=C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:12](=[O:14])[CH2:11][CH2:10][NH:9]2)=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CCNc1ccc(F)c(Cl)c1
Agent: C=CC(=O)O
Agent: Nc1ccc(F)c(Cl)c1
Solvent: O
Solvent: C=CC(=O)OC
Solvent: ClCCl
Product: O=C1CCNc2cc(Cl)c(F)cc21
Temperature: 110 °C
Reaction time: 1.17 h
Yield: 57.4 %

Procedure:
A mixture of polyphosphoric acid (600 g) and 3-(3-chloro-4-fluorophenylamino)propionic acid (38 g), which was synthesized from 3-chloro-4-fluoroaniline and acrylic acid or methyl acrylate by the method of W. S. Johnson et al. (The Journal of American Chemical Society, volume 71, page 1901, (1949)), was stirred at 110° C. for 70 minutes. The reaction mixture was poured into 1500 ml of water, then shaken with dichloromethane (1500 ml). The organic layer was washed twice with saturated aqueous NaCl solution (200 ml each) and dried over anhydrous sodium sulfate. Dichloromethane was removed in vacuo and the residue was subjected to silica gel column chromatography using a mixed solvent (n-hexane : ether=4:1) to obtain 7-chloro-6-fluoro-2,3-dihydro-4(1H)-quinolinone (yield 20 g) as pale yellow crystal.