Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1(Br)[C:6]2[CH:7]=[N:8][C:9]([Cl:11])=[CH:10][C:5]=2[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:3]1=[O:20].[NH4+].[Cl-]>C1COCC1.[Zn]>[Cl:11][C:9]1[N:8]=[CH:7][C:6]2[CH2:2][C:3](=[O:20])[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[C:5]=2[CH:10]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)C(Br)(Br)c2cnc(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)Cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
Crude 3,3-dibromo-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (˜5.4 mmol) was taken up in a mixture of THF (30 mL) and saturated aqueous NH4Cl (8 mL). Zinc powder (3.6 g, 0.055 mmol) was added, and a modest exotherm was maintained via ice bath. The reaction was stirred at r.t. for 1.5 h, and the reaction was then filtered through Celite, washing with EtOAc. The organic phase was washed with water, and the combined aqueous phase was extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (10-100% EtOAc in hexanes) to afford 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (1.04 g). LCMS-ESI+ (m/z): [M+H]+ calcd for C13H20ClN2O2Si: 299.10; found: 298.98.
Reaction SMILES: C(O)(C)C.C[O:6][C:7](=O)[CH2:8][CH2:9][SH:10].[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[CH2:12]([NH:20][C:7](=[O:6])[CH2:8][CH2:9][SH:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)CCS
Reactant: CCCCCCCCN
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCCCCCCNC(=O)CCS
Reaction time: 19.5 h

Procedure:
In a small multi-necked reaction vessel equipped with a magnetic stirrer and gas inlet was placed isopropanol (2 ml), methyl-3-mercaptopropionate (2.0 g, 16.64 mmol), and n-octylamine (2.19 g, 16.94 mmol). The reaction vessel was connected to a trap containing bleach to trap mercaptan vapors, and the reaction was stirred for 19.5 hours while the reaction temperature was held at 30°-35° C. Methylene dichloride was added and the crude product was transferred to a round bottom flask. Evaporation of the solvent under reduced pressure yielded crude N-(n-octyl)-3-mercaptopropionamide as an oily white solid in essentially quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]([CH2:49][NH2:50])[OH:48]>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:11]([NH:50][CH2:49][CH2:47][OH:48])=[O:13])=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: NCCO
Reactant: COC(=O)c1[nH]cc(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]cc(C(=O)NCCO)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
To a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-3-carboxylic acid (0.075 g, 0.368 mmol) in DMF (1 ml) was added DIPEA (0.097 ml, 0.553 mmol), HATU (0.168 g, 0.442 mmol) and ethanolamine (0.033 ml, 0.553 mmol) and the reaction stirred at RT for 3 h. Purification was accomplished by HPLC to afford methyl 3-chloro-4-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylate (0.06 g, 53% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.45 (br. s., 1H) 7.78 (t, 1H) 7.52 (d, 1H) 4.28 (br. s., 1H) 3.80 (s, 3H) 3.56-3.68 (m, 1H) 3.46 (t, 1H) 3.25 (q, 1H) 3.07-3.21 (m, 1H). MS: m/z 247.0 (M+1).
Reaction SMILES: [C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[H][H]>CO.[C].[Rh]>[CH2:6]1[CH2:5][CH2:4][C:3]([CH2:1][NH2:2])([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7]1
Reactant: N#CC1(CC(=O)O)CCCCC1
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1
Yield: 65.1 %

Procedure:
A solution of 3 g (1-cyanocyclohexyl)-acetic acid in 10.5 mL methanol is hydrogenated at 10 bar hydrogen pressure and 30° C. in the presence of rhodium-carbon (5%) over a period of five hours. The reaction mixture is filtered and the filtrate evaporated on a rotary evaporator at 30° C. The crystalline residue is stirred with isopropanol and the crystallizate is filtered off with suction and dried to constant weight in a vacuum drying cabinet at 30° C. 2.0 g of the title compound are obtained (65.2% of theory); m.p. 152° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7](C(OC(C)(C)C)=O)[CH:6]([C:19](=[O:31])[NH:20][C@H:21]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]1)[CH2:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH:6]([C:19]([NH:20][C@H:21]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]1)=[O:31])[CH2:5]2
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(O)cc2CC1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCCc2ccccc21)C1Cc2cc(O)ccc2CN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of tert-butyl 6-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (875 mg, 2.07 mmol) in CH2Cl2 (10.4 mL) was added TFA (2.4 mL, 31.1 mmol). The resulting solution was stirred at room temperature for 2 h and then quenched with sat. NaHCO3. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (340 mg, 51%) as pale yellow solid. MS (ESI+) m/z 323.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Br:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH2:18])=[N:13][NH:14]2)=[C:10]([F:19])[C:9]=1[F:20]>N1C=CC=CC=1>[Br:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH:18][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:13][NH:14]2)=[C:10]([F:19])[C:9]=1[F:20]
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2c(F)c(Br)c(F)c(F)c12
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2c(F)c(Br)c(F)c(F)c12
Temperature: 3 °C
Reaction time: 76 h

Procedure:
0.82 cm3 of butyryl chloride is added to 2.1 g of 6-bromo-4,5,7-trifluoro-1H-indazole-3-amine, prepared previously, in 20 cm3 of pyridine, after cooling to about 3° C., and the mixture is then left at room temperature for 76 hours. The reaction medium is concentrated under reduced pressure (2 kPa; 40° C.) and the residue is taken up in 100 cm3 of ethyl acetate, 100 cm3 of tetrahydrofuran and 40 cm3 of water. The organic phase is washed with 2×40 cm3 of distilled water and then with 40 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulphate, filtration and concentration under reduced pressure (2 kPa; 40° C.), the residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.); after drying (90 Pa; 40° C.), 0.53 g of N-(6-bromo-4,5,7-trifluoro-1H-indazol-3-yl)butanamide is obtained in the form of a pink solid melting at 255°-257° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[CH3:26][O:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17]
Reactant: COc1ccccc1C1CCC(CO)N1C(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CCC(c2ccccc2OC)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-hydroxymethyl-5-(2-methoxyphenyl)-N-(carbobenzyloxy)-tetrahydropyrrole (2.49 g, 7.30 mmol) in DMF (20 mL) at 0-40° C. was added methyl iodide (4.55 mL, 73 mmol) and NaH (60% oil dispersion, 1.75 g, 43.8 mmol) and the resulting suspension was stirred at room temperature for 1 hour. The reaction mixture was quenched with H2O at 0° C., ether was added, and the aqueous layer was extracted with ether (×4), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (5% EtOAc-95% hexanes) to provide the title compound as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ: 3.77 (3H, s, OMe), 3.38 (3H, s, OMe).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=[O:13])[C:9]([C:14]([OH:16])=O)=[CH:8]2.S(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=[O:13])[C:9]([C:14]([Cl:19])=[O:16])=[CH:8]2
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: O=S(Cl)Cl
Product: COc1cccc2cc(C(=O)Cl)c(=O)oc12

Procedure:
A mixture of 8-methoxycoumarin-3-carboxylic acid (0.66 g) and thionyl chloride (2.5 ml) was heated under reflux for one and half hours. Distilling off the excess thionyl chloride in vacuo gave 8-methoxycoumarin-3-carboxylic acid chloride. Reaction of this product with amoxycillin, 1.257 g, in the same manner as in example 16, yielded D(-)-α-(8-methoxycoumarin-3-carbonamido)-p-hydroxybenzylpenicillin (0.95 g), melting at 187°-9° C. (dec.).
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH3:17])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=[N:7][N:6]2[CH:21]=1.Br[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH3:17])[CH2:15][N:14]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=4)[CH2:13]3)=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=[N:7][N:6]2[CH:21]=1
Reactant: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#Cc1ccc(Br)nc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of 6-bromo-4-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (250 mg, 0.536 mmol), 6-bromonicotinonitrile (103 mg, 0.563 mmol) and potassium carbonate (222 mg, 1.609 mmol) in N,N-dimethylformamide (3 mL) was heated at 100° C. in a sealed tube for 90 min. The resulting mixture was cooled to room temperature, triturated with water and filtered. The filter cake was washed with water and dried under vacuum to give 6-bromo-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (0.228 g, 97% yield). 1H NMR (400 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.39-8.27 (m, 1H), 8.08 (s, 1H), 7.69-7.57 (m, 2H), 6.95-6.82 (m, 1H), 6.48 (d, J=9.0 Hz, 1H), 4.83 (br. s., 1H), 4.01-3.69 (m, 3H), 3.39 (t, J=9.6 Hz, 1H), 2.81 (br. s., 1H), 1.27 (d, J=6.8 Hz, 3H); MS (ES+) m/z: 440.2 (M+H); LC retention time: 3.885 min (analytical HPLC Method H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]2[Br:29])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2ccc(NC(=O)OC(C)(C)C)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc2ccc(NC(=O)OC(C)(C)C)c(Br)c2c1
Temperature: 40 °C
Yield: 99 %

Procedure:
A mixture of carbamate 170 (420 mg, 1.47 mmol), NBS (292 mg, 1.62 mmol) and K2CO3 (244 mg, 1.77 mmol) in MeCN (10 mL) was heated at 40° C. under N2 for 30 min then concentrated under reduced pressure. EtOAc and water were added to the residue, and the EtOAc portion was washed with water, brine and dried to give tert-butyl 7-acetyl-1-bromo-2-naphthylcarbamate (171) (530 mg, 99%) as a colorless solid: mp (petroleum ether/EtOAc) 114-117° C.; 1H NMR (CDCl3) δ 8.70 (s, 1H), 8.50 (d, J=9.0 Hz, 1H), 7.97 (dd, J=3.5, 1.6 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.81 (d, J=9.6 Hz, 1H), 7.34 (br s, 1H), 2.76 (s, 3H), 1.58 (s, 9H); 13C NMR δ 197.9, 152.4, 136.0, 135.8, 133.0, 131.5, 128.7, 128.5, 128.0, 123.1, 122.0, 111.0, 81.6, 28.3, 26.7. Anal. (C17H18BrNO3) C, H, N.
Reaction SMILES: C(OC([NH:11][C:12]1([PH:20]([NH:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1([PH:20]([NH:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19]
Reactant: CCCC(=O)N[PH](=O)C1(NC(=O)OCc2ccccc2)CCCN(N)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCCC(=O)N[PH](=O)C1(N)CCCN(N)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Palladium black (30.0 mg) was added to a solution of (3S, P (SR))-3-benzyloxycarbonylamino-1-amino(n-butanoylamino)phosphinyl-2-piperidone (153.2 mg, 0.3865 mmol) in ethanol (10 mL), and the resulting mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Cl[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[CH:19][N:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: COc1cc(Cl)ncn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc(N2CCN(c3cnccc3C3CC3)C2=O)ncn1
Yield: 32.6 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 11 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 4-chloro-6-methoxypyrimidine (78 mg, 0.541 mmol), 2-dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphenyl (23 mg, 0.0492 mmol), Pd2(dba)3 (23 mg, 0.024 mmol), cesium carbonate (400 mg, 1.23 mmol) and toluene (10 mL) in seal tube at 115° C. for 14 hours. Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 50 mg of the product (34.6% yield).
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].Cl.[CH3:18][C:19]1[O:23][N:22]=[C:21]([C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[N:20]=1.C(OC(N[C@@H](CC(C)C)C(O)=O)=O)(C)(C)C>>[CH3:28][CH:27]([CH3:29])[CH2:26][C@H:24]([NH:25][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([S:5]([CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:6])=[O:7])[N:13]=1)=[O:16])[C:21]1[N:20]=[C:19]([CH3:18])[O:23][N:22]=1
Reactant: Cc1nc([C@@H](N)CC(C)C)no1
Reactant: CC(C)CS(=O)(=O)c1cccc(C(=O)O)n1
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: Cc1nc([C@H](CC(C)C)NC(=O)c2cccc(S(=O)(=O)CC(C)C)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(isobutylsulfonyl)picolinic acid (Example 330 b) and (S)-5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine hydrochloride (which was prepared from (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid (CAN 13139-15-6) in analogy to the procedures described in Example 38 a to e) as starting materials. MS (EI): m/e=395.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[F:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[N:8]([CH3:11])[C:7](=[O:12])[C:6]2([CH3:13])[CH3:14]
Reactant: CN1C(=O)C(C)(C)c2cc(F)c(N)cc21
Reactant: O=C(O)c1cccnc1
Product: CN1C(=O)C(C)(C)c2cc(F)c(NC(=O)c3cccnc3)cc21

Procedure:
Prepared in analogy to example 17 from 6-amino-5-fluoro-1,3,3-trimethylindolin-2-one (example 20 f) and nicotinic acid. The title compound was obtained as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([O:16]C)=[O:15])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[CH3:28])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([OH:16])=[O:15])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[CH3:28])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)O)n(C)c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 84.1 %

Procedure:
Methyl 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylate (compound 49γ, 1.6 g, 3.82 mmol) was suspended in ethanol (100 ml) and treated with solution of NaOH (0.76 g 19.13 mmol) in water (20 ml) at 0° C. The reaction mixture was then heated at 80° C. under stirring for 15 h. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The reaction mixture was then treated with dilute HCl to bring pH of the mixture to between 6 and 7. The obtained mixture was then extracted with ethyl acetate (2×100 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (1.3 g, 84.4%).
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.[CH3:12][C:13]1(C)[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=2)[NH+:14]1[O-]>ClC(Cl)C>[Cl:10][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=2)[N:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2c(c1)C=CC(C)(C)[NH+]2[O-]
Solvent: CC(Cl)Cl
Product: Cc1ccc2nc(CCl)ccc2c1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
To a stirring solution of p-toluenesulfonyl chloride (6.19 g, 0.0325 mol) in dichloroethane (75 mL) was added 2,6 dimethylquinaldine N-oxide (2) (5 g, 0.0289 mol) under N2. The reaction mixture was then heated to 100° C. for 24 hours, cooled, concentrated and extracted with 10% K2CO3 and ethyl acetate. The organic layer was dried with MgSO4, concentrated and purified on a small silica flash column (2:1 dichloromethane:hexanes). The resulting yellow solid was then recrystallized in hexanes to afford 3.31 g (60%) of a white solid. H1 NMR (CDCl3): δ 2.50 (s, 3H) 4.80 (s, 2H), 7.40-7.50 (m, 2H), 7.58-7.61 (d, 1H), 8.02-8.99 (m, 1H), 8.11-8.14 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[C:13]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:14]=2[S:15](=[O:25])[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[C:13]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:14]=3[S:15](=[O:25])[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(Oc3ccc(Br)cc3)c3ccc(OC)cc3S2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a solution of 4-bromophenol (469 mg, 2.71 mmol) in DMF (3 mL) was added sodium hydride (60% suspension in oil, 108 mg, 2.71 mmol), the resulting mixture was allowed to stir for 10 min at room temperature. To the solution was added 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (900 mg, 2.46 mmol) as a solid. The reaction was heated to 80° C. for 18 h. Upon completing the reaction was cooled to room temperature, quenched with water and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to afford the crude product. The crude material was purified by column chromatography (SiO2, 0-60% EtOAc/Heptane) to afford 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (980 mg, 2.14 mmol, 87% yield) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[N:25][CH:26]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[N:25][CH:26]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCOCC2)nc1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCOCC3)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.30 g, 1.21 mmol), 4-(5-(tributylstannyl)-pyridin-2-yl)morpholine (0.66 g, 1.45 mmol), palladium tetrakistriphenylphosphine (0.140 g, 0.12 mmol) in toluene (2 mL) to give 4-(5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)morpholine as a white solid. Mass Spectrum (ESI) m/e=376.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[N:20]#[C:21]Br>O1CCOCC1.O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]2[O:8][C:21]([NH2:20])=[N:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: N#CBr
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
To a solution of 4-(trifluoromethyl)benzohydrazide (0.5 g, 2.449 mmol) in dioxane (10 mL) and water (2 mL) was added sodium bicarbonate (0.617 g, 7.35 mmol) and cyanic bromide (0.519 g, 4.90 mmol). The reaction was stirred at room temperature for 15 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc, dried over sodium sulfate, and evaporated to yield 5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-amine (0.28, 50%). 1H NMR: 400 MHz, DMSO-d6: δ 7.43 (s, 2H), 7.91 (d, J=8.40 Hz, 2H), 8.00 (d, J=8.40 Hz, 2H). LCMS: RT 1.55 min. LCMS (ES-API), m/z 230.0 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].Br.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of cis chrysanthemic acid (10 g) in toluene (53 ml) was added a solution of 25% hydrogen bromide-acetic acid (1.3 g) at room temperature under a nitrogen atmosphere. Irradiation with a high pressure mercury lamp (110 W) was made for 30 minutes under stirring. After the irradiation was over, similar after-treatment as in Example 1 was applied to obtain chrysanthemic acid (9.6 g). Gas chromatography assay of the product gave the isomer ratio: cis, 8.6%; and trans, 91.4%.