Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH:2]=1.[CH3:15][O:16][C:17]1[N:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[CH3:15][O:16][C:17]1[N:22]=[C:21]([C:23]([NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:9]=2)=[O:24])[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc(Oc2cccnc2)c1
Reactant: COc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cccc(C(=O)Nc2cccc(Oc3cccnc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
Compound 5 (25 mg, 0.13 mmol, 1.0 eq), 6-methoxypicolinic acid (23 mg, 0.15 mmol, 1.1 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (56 mg, 0.15 mmol, 1.1 eq) and DIEA (25.7 μL, 0.148 mmol, 1.10 eq) were dissolved in CH2Cl2 (1.5 mL) and stirred at rt overnight. Water was added and the layers separated. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 39 mg (90%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.41 (d, J=2.5 Hz, 1H), 8.38 (dd, J=4.4, 1.5 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.70-7.69 (m, 2H), 7.65 (d, J=8.6 Hz, 1H), 7.48 (ddd, J=8.4, 2.7, 1.6 Hz, 1H), 7.45-7.39 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.84 (dd, J=8.1, 1.9 Hz, 1H), 4.04 (s, 3H); ES-MS [M+1]+: 322.2.
Reaction SMILES: C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]([O:26][C:27]([C@@H:29]1[CH2:37][C@H:36]2[C@H:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[NH:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ON1C2C=CC=CC=2N=N1.[C:48]([C@@H:53]([NH:57][C@H:58]([C:60](O)=[O:61])[CH3:59])[CH2:54][CH2:55][CH3:56])([O:50][CH2:51][CH3:52])=[O:49].C1(N=C=NC2CCCCC2)CCCCC1.C1(NC(=O)NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[CH3:56][CH2:55][CH2:54][C@H:53]([NH:57][C@H:58]([C:60]([N:30]1[C@@H:29]([C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:28])[CH2:37][C@H:36]2[C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35]2)=[O:61])[CH3:59])[C:48]([O:50][CH2:51][CH3:52])=[O:49]
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Temperature: 25 °C
Yield: 94 %

Procedure:
Triethyl amine (14 g, 0.1238 moles) was added to a suspension of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid-benzyl ester para toluene sulfonate (20 g, 0.0464 moles) in ethyl acetate (240 g), under stirring at 25° C. in one lot. Then 1-hydroxybenzotriazole (24 g, 0.1776 moles), N-[(S)-1-carbethoxybutyl]-(S)-alanine (30 g, 0.1382 moles) were added to the reaction mixture at 25° C., under stirring, followed by dicyclohexyl carbodiimide (28 g, 0.1357 moles) at ambient temperature. The reaction mixture was stirred, keeping the temperature in the range of 15-20° C. for 3 hrs, when the TLC and the HPLC indicated a completion of the reaction. The reaction mixture was then filtered to remove the precipitated dicyclohexyl urea. The filtrate was washed with water (100 ml, twice). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford a viscous oil, which was still contaminated with dicyclohexyl urea. The oil was redissolved in ethyl acetate (100 ml) and the solution was cooled to 2-5° C. under stirring for 1 hr. The precipitated dicyclohexyl urea was again filtered off and the filtrate was concentrated under reduced pressure to afford 20 g (94%) of perindopril benzyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl[CH:18]([OH:21])[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>[I-].[K+].O>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:20][CH2:19][CH2:18][OH:21])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CCC(O)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccccc1)c1ccc(OCCCO)cc1O
Temperature: 125 °C
Yield: 76.2 %

Procedure:
To a 250 mL 3-necked round-bottom flask equipped with a magnetic stirrer was charged 20 g (93.5 mmol) of 2,4-dihydroxybenzophenone, 8.8 g (93.5 mmol) of chloropropanol, 100 mg (0.6 mmol) of potassium iodide, 12.92 g (93.5 mmol) of potassium carbonate, and 100 mL of dimethyl sulfoxide. The flask was immersed in an oil bath and the mixture heated at a bath temperature of 125° C. for 14 hours. The mixture was poured into 1.4 L of water and extracted with four 500 mL portions of methylene chloride. The combined organic extracts were washed with five 1200 in L portions of water, followed by two 2 L portions of 0.025% aqueous NaOH, and another 1.2 L portion of water. The organic layer was dried (MgSO4), filtered through Celite, and concentrated, leaving 19.4 g of product as a yellow solid. 1H NMR (CDCl3): δ12.58 (s, 1H, ArOH); 7.60-7.35 (m, 6H, Ar—H); 6.45-6.30 (m, 2H, Ar—H); 4.10 (t, 2H, Ar—O—CH2—); 3.79 (t, 2H, H—O—CH2—); 1.99 (m, 2H, —CH2—CH2—CH2—).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[O:13][C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:15][C:16](=[O:17])[C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(COC)OC>[O:21]1[CH2:22][CH2:23][N:18]([C:14]2[O:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:64]5[CH2:69][CH2:68][O:67][CH2:66][CH2:65]5)=[CH:3][CH:4]=4)=[CH:9][S:10][C:11]=3[C:16](=[O:17])[CH:15]=2)[CH2:19][CH2:20]1
Reactant: O=c1cc(N2CCOCC2)oc2c(-c3ccc(Cl)cc3)csc12
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Product: O=c1cc(N2CCOCC2)oc2c(-c3ccc(N4CCOCC4)cc3)csc12
Temperature: 150 °C

Procedure:
A 2 mL conical microwave vial was charged with a magnetic stirring bar, 3-(4-chlorophenyl)-5-morpholino-7H-thieno[3,2-b]pyran-7-one (17) (80 mg, 230 μmol), sodium tert-butoxide (31 mg, 322 μmol), tris(dibenzylideneacetone)dipalladium(0) (3 mg, 3.5 μmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (8.8 mg, 21 μmol), dimethoxyethane (0.5 mL), and morpholine (24 μL, 276 μmol). The reaction mixture was sealed, and the reaction mixture was magnetically stirred and heated via microwave irradiation to 150° C. for 15 minutes to give 5-morpholino-3-(4-morpholinophenyl)-7H-thieno[3,2-b]pyran-7-one (72).
Reaction SMILES: C([C:7]1[O:8][C:9]2[CH:17]=[CH:16][C:15](OCC3C=CC=C(OCC4C=CC5C(=CC=CC=5)N=4)C=3)=[CH:14][C:10]=2[C:11](=[O:13])[CH:12]=1)(OCCC)=O.C(=O)(O)[O-].[Na+]>C(O)C.O>[O:13]=[C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH:7]=[CH:12]1
Reactant: CCCOC(=O)c1cc(=O)c2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1ccoc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.71g of 2-carbopropoxy-6-(3-(quinolin-2-yl-methoxy)benzyloxy)-4-oxo-4H-1-benzopyran and 0.45g of sodium bicarbonate in 20 ml of ethanol in 20 ml of water is refluxed for 1.5 hours, then stirred at room temperature overnight. The mixture was neutralized and the resulting solid is filtered off, washed with water and dried in vacuo to give 0.55g of 2-carboxy-6-(3-quinolin-2- ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran as a light yellow solid having an m.p. of 253°-54° C.
Reaction SMILES: [Cl:1][C:2]1[C:9](Cl)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][O:15][CH2:16][CH2:17][CH2:18][NH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([NH:6][CH3:7])=[CH:8][C:9]=1[NH:19][CH2:18][CH2:17][CH2:16][O:15][CH3:14]
Reactant: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: COCCCN
Product: CNc1cc(NCCCOC)c(Cl)cc1[N+](=O)[O-]

Procedure:
0.059 mole (13 g) of 4,5-dichloro-2-nitro-N-methylaniline prepared in the previous stage is heated for 4 hours in 40 ml of 3-methoxypropylamine on a steam bath. After dilution with iced water and acidifying with concentrated hydrochloric acid, the expected product is filtered off. Recrystallized from 96° ethanol, it melts at 99° C.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].N(OC(C)(C)C)=O.[Br:20][C:21]1[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:22]=1N>[Cu](F)F.N1C=CC=CC=1>[Br:20][C:21]1[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:22]=1[O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: Nc1ccc(Br)cc1Br
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CC(O)CC(C)(C)N1Oc1ccc(Br)cc1Br
Yield: 56.4 %

Procedure:
The procedure of Example 1 is repeated using 12.8 g (74 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 14.23 g (138 mmol) of tert-butyl nitrite, 0.73 g (0.74 mmol) of copper(II) fluoride, 200 mL of pyridine and 8.56 g (92 mmol) of 2,4-dibromoaniline at 65° C. The crude product obtained is purified by vacuum flash chromatography (5% ethyl acetate/heptane) to give 17 g of the title compound as a yellowish solid solid in 63.5% yield. The structure is confirmed by 1Hnmr analysis.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2>>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: COc1ccc(C=O)cc1C(C)C
Product: COc1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 5-fluoro-2-oxindole to give 0.25 g of 5-fluoro-3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.O.NN>>[CH3:26][C:23]1[C:22]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Agent: NN
Solvent: O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1Nc1ccccn1

Procedure:
Prepared according to the procedure described in Example 32, Step 1, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester. Additionally, hydrazine hydrate (10 eq.) was added to the reaction mixture.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.[CH3:20][N:21]1[C:26](=[O:27])[C:25]2[CH2:28][NH:29][CH2:30][CH2:31][C:24]=2[NH:23][C:22]1=[O:32]>CN(C)C=O>[CH3:20][N:21]1[C:26](=[O:27])[C:25]2[CH2:28][N:29]([CH2:11][CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH2:30][CH2:31][C:24]=2[NH:23][C:22]1=[O:32]
Reactant: ClCCOC1CCCCO1
Reactant: Cn1c(=O)[nH]c2c(c1=O)CNCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2c(c1=O)CN(CCOC1CCCCO1)CC2
Temperature: 70 °C
Yield: 26.9 %

Procedure:
40 g of ethyldiisopropylamine and 52.5 g of 2-(2-chloroethoxy)tetrahydropyran (96% pure according to GC) were added to 54.5 g of 3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione in 1.5 l of dimethylformamide, with stirring, and the mixture was heated for 30 h at 70° C. It was concentrated under vacuum, the residue was worked up by extraction with dichloromethane and water and the combined dichloromethane phases were dried and concentrated to give 25 g of 3-methyl-6-[2-(tetrahydropyran-2-yloxy) ethyl]-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione, which was purified by bulb-tube distillation at a bath temperature of 80° C. and 0.1 mbar and by column chromatography on aluminum oxide (activity grade III) and elution with dichloromethane/ethanol (volume ratio 95:5).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[O-]S([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])([CH3:30])[CH2:27][CH:28]=O>C(Cl)Cl>[C:2]([O:6][C:7](=[O:11])[C@@H:8](/[N:9]=[CH:28]/[CH2:27][C:26]([CH3:31])([CH3:30])[CH3:25])[CH3:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CC=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](/N=C/CC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A mixture of L-alanine tert-butyl ester hydrochloride (Bachem) (1.8 g, 10 mmol) and MgSO4 in CH2Cl2 (100 mL) was added triethylamine (1.5 g, 15 mmol). The mixture was stirred at room temperature for 1 h, and 3,3-dimethyl-butyraldehyde (1 g, 10 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered, and the filtrate was washed with water, brine, and concentrated. The residue was dried under reduced pressure to give (S)-2-[3,3-dimethyl-but-(E)-ylideneamino]-propionic acid tert-butyl ester as colorless oil (2.3 g, 100%) which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:12]=2[O:16][CH2:17][CH2:18][CH3:19])[N:7]1[C:26](=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl>[C:26]([N:7]1[C:8]2[C:13](=[C:12]([O:16][CH2:17][CH2:18][CH3:19])[C:11]([CH:20]3[CH2:25][CH2:24][N:23]([C:1](=[O:3])[CH3:2])[CH2:22][CH2:21]3)=[CH:10][CH:9]=2)[CH2:14][CH2:15][C@@H:6]1[CH3:5])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1c(C2CCN(C(C)=O)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Acetyl chloride (6 μL, 0.08 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (26.1 mg, 0.07 mmol) and triethylamine (0.03 mL, 0.21 mmol) in dichloromethane (1.0 mL), and the reaction stirred at room temperature overnight. The reaction solution was purified directly via column chromatography on silica gel (Biotage 10 g column, gradient elution with 10-20% methanol in ethyl acetate) to afford (S)-1-(4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-1-yl)ethan-1-one (19 mg, 71%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.05 (m, 6H), 1.17-1.29 (m, 1H), 1.38-1.47 (m, 1H), 1.54-1.59 (m, 1H), 1.65-1.81 (m, 5H), 2.01 (s, 6H), 2.16-2.35 (m, 2H), 2.48-2.59 (m, 1H), 2.71-2.78 (m, 1H), 3.01-3.03 (m, 2H), 3.55-3.76 (m, 2H), 3.90 (br d, J=14.66 Hz, 1H), 4.52 (br d, J=13.20 Hz, 1H), 7.04 (br s, 2H). MS (ESI, pos. ion) m/z 373 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F-:13].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([F:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a solution of 4-methoxy-benzenesulfonyl chloride (1.0 g, 4.8 mmol) in acetonitrile (20 mL) was added KF (563 mg, 9.7 mmol) and the resulting mixture was stirred for 16 h at room temperature. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (780 mg) as a colourless oil. 1H NMR (CDCl3): 7.97 (2H, d), 7.09 (2H, d), 3.94 (3H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:11][NH:12][CH3:13].CCOCC>O>[CH3:11][N:12]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[CH3:13]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CNC
Solvent: O
Solvent: CCOCC
Product: CN(C)Cc1cccc(C#N)c1
Yield: 62 %

Procedure:
A mixture of 3-(bromomethyl)-benzonitrile (3 g, 15.3 mmol) and a solution of 40% dimethylamine in water was heated in a sealed teflon vessel under microwave irradiation (7 min, 600 watts, 150° C., 11 bar). After cooling the resulting mixture was partioned between water and ether, the aqueous phase was extracted three times with ether, washed with satd. NaCl then dried with Na2SO4 and the solvent evaporated. The resulting yellow oil was distilled in a Kugelrohr apparatus at 60-80° C. and 0.002 mbar affording the title compound (1.53 g, 9.55 mmol, 62% yield) as a pale yellow oil. MS: m/e=160 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[N+:12]([O-])[CH:13]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:15][Cl:18])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2ccc(F)cc2)c[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(-c2ccc(CCl)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-fluorophenyl)-2-methylpyridine-N-oxide (2.9 g, 14.5 mmol) in CH2Cl2 (15 mL) is added a 1.5 mL portion of a CH2Cl2 (15 mL) solution of POCl3 (1.72 g, 1.7 mmol). Subsequently, the remainder of this POCl3 solution and a solution of triethylamine (1.76 g, 17.4 mmol) in CH2Cl2 (15 mL) are added simultaneously, so as to maintain reflux. After addition is complete the resulting solution is stirred at ambient temperature for 2 hours. The reaction mixture is then neutralized by addition of saturated NaHCO3 (50 mL). The organic phase is separated, dried over MgSO4 and concentrated in vacuo. Chromatography (silica gel, 1:1 EtOAc/hexanes) affords 5-(4-fluorophenyl)-2-(chloromethyl)pyridine as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2].[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[OH:40].C([O-])([O-])=O.[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:40][C:34]2[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=2[Cl:32])=[CH:7][C:6]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2]
Reactant: Oc1ccc(F)cc1Cl
Reactant: CCOC(=O)CN(Cc1cc(OC)ccc1OC)Cc1cc(Br)ccc1C(=O)OCC
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CN(Cc1cc(OC)ccc1OC)Cc1cc(Oc2ccc(F)cc2Cl)ccc1C(=O)OCC
Temperature: 130 °C
Yield: 53.2 %

Procedure:
To a mixture of 4-bromo-2-{[(2,5-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-benzoic acid ethyl ester (3.44 g, 6.96 mmol) and 2-chloro-4-fluorophenol (2.04 g, 13.9 mmol) in NMP (6.8 mL) was added Cs2CO3 (4.53 g, 13.9 mmol). The resultant mixture was degassed and re-filled with N2 gas prior to the addition of 2,2,6,6-tetramethyl-heptane-3,5-dione (128 mg, 0.70 mmol) and Cu(I)Cl (344 mg, 3.48 mmol). It was de-gassed and filled with N2 gas again. The resultant mixture was heated in a 130° C. oil bath for 24 h. Reaction mixture was filteredthrough a pad of celite and washed with EtOAc until no UV active spot was detected from the filtrate. Filtrate was washed with 1 N HCl (100 mL and 50 mL), water and brine. It was dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with CH2Cl2, to provide the title compound 2.07 g (3.70 mmol) in 44% yield. 1H NMR (200 MHz) in CDCl3, δ ppm: 7.80 (d, J=8.4 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.20 (m, 1H), 7.03 (m, 3H), 6.73 (dd, J=8.4, 2.6 Hz, 1H), 6.38 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 4.18 (s, 2H), 4.11 (q, J=7.0 Hz, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.70 (s, 2H), 3.28 (s, 2H), 1.4-1.2 (m, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH:14](Cl)(Cl)Cl.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:14][O:2][C:1](=[O:3])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:12])(=[O:11])[NH2:13])=[CH:6][CH:5]=1
Reactant: ClC(Cl)Cl
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 0.08 h
Yield: 98 %

Procedure:
4-Carboxyphenylsulfonamide (2.00 g, 9.9 mmol) is suspended in 3:1 chloroform:methanol (200 mL). (Trimethylsilyl)-diazomethane is added as a 2.0 M solution in Hexanes (7.4 mL, 14.8 mmol) at ambient temperature and stirred for 5 min. The solution is concentrated in vacuo, and the crude is chromatographed on silica gel, 0.5% MeOH/0.1% AcOH in CH2Cl2. The product is a white solid, 2.11 g, 98% yield.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[N:13][S:14][C:10]=2[C:9]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:7])(C)(C)C.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:9]1[C:10]2[S:14][N:13]=[CH:12][C:11]=2[CH:15]=[CH:16][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-6-carboxylic acid tert-butyl ester (710 mg, 1.51 mmol) in DCM (5 mL) were added water (0.15 mL) and TFA (5 mL). The reaction mixture was stirred at room temperature for 1 hour before being concentrated in vacuo. The resultant residue was azeotroped with toluene to give the title compound as a yellow solid (571 mg, 91%). LCMS (method B): RT=3.95 min, [M+H]+=415.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:11](O)[CH2:12][OH:13].O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:11][CH2:12][O:13][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2OCCO2)cc1
Yield: 51.1 %

Procedure:
To a solution of 4-cyanobenzaldehyde (25 g, 0.190 mol) in dry toluene (300 mL) was added ethyleneglycol (15 g, 0.228 mol) and PTSA (0.5 g) and allowed to reflux at 130° C. with azeotropic removal of water for 12 h. The reaction mixture was cooled, washed with 10% aqueous NaHCO3 (100 mL), dried and concentrated under vacuum. The crude solid was recrystallised from PetEther/EtOAc to give the 4-(1,3-dioxolan-2-yl)benzonitrile (17 g, 51%) as white solid. TLC (PetEther/EtOAc 4/1), Rf=0.6
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)[CH:2]=[CH2:3].[CH3:25][C:26]1([CH3:33])[O:30][C@@H](CO)C[O:27]1>>[CH3:25][C:26]1([CH3:33])[O:30][C@@H:2]([CH2:1][O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:23]#[N:24])[N:6]=2)[CH2:3][O:27]1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: C=CCOc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Product: COc1ccc2c(OC[C@H]3COC(C)(C)O3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allyloxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (S)-(+)-2,2,-dimethyl-1,3-dioxolane-4-methanol in place of allyl alcohol, the title compound was synthesized.