Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>CO.ClCCl>[CH2:23]([NH:27][C:3](=[O:22])[C@H:4]([CH:19]([CH3:20])[CH3:21])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(C)C
Reactant: CC(C)CN
Solvent: ClCCl
Solvent: CO
Product: CC(C)CNC(=O)[C@@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(C)C

Procedure:
Following General Procedure H above and using N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-L-valine methyl ester (from Example 1 above) and isobutylamine (Aldrich), the title compound was prepared as a oil. The reaction was monitored by tlc (Rf=0.3 in 10% methanol/dichloromethane).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)[CH:9]=[C:10]([F:13])[CH2:11][OH:12])[CH2:7][CH2:6]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:12][CH2:11][C:10]([F:13])=[CH:9][CH:8]([CH:5]1[CH2:6][CH2:7]1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(C(C=C(F)CO)C2CC2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOc1ccc(C(C=C(F)COC(C)=O)C2CC2)cc1
Yield: 99 %

Procedure:
The method of Example 11 was repeated using acetyl chloride (1.2 ml), 4-cyclopropyl-4-(4-ethoxyphenyl)-2-fluorobut-2-enol (Example 7) (0.65 g), benzene (34 ml) and pyridine (0.24 ml) to yield the title compound (0.75 g, 99%).
Reaction SMILES: [NH2:1][C:2]([C:5]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2S(C)(=O)=O)=[O:12])[C:8]([OH:26])=[C:7]([OH:27])[N:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:35][CH2:36][S:37]([O:26][C:8]1[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:12])=[N:10][C:5]([C:2]([NH:1][S:37]([CH2:36][Cl:35])(=[O:39])=[O:38])([CH3:4])[CH3:3])=[N:6][C:7]=1[OH:27])(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(C)(N)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NS(=O)(=O)CCl)c1nc(O)c(OS(=O)(=O)CCl)c(C(=O)NCc2ccc(F)cc2)n1
Reaction time: 8 h

Procedure:
To a solution of 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide hydrochloride (prepared as described in WO2003035076 A1) in dichloromethane, triethylamine (4 eq.) was added and the mixture was cooled down with an ice/salt bath. A solution of chloromethanesulfonyl chloride in dichloromethane was added dropwise to the mixture. After 2 hours further triethylamine (1 eq.) and chloromethanesulfonyl chloride (1 eq.) were added at 0° C. and the reaction mixture was aged at room temperature overnight. To allow complete consumption of starting material, additional Et3N (0.5 eq.) and chloromethanesulfonyl chloride (0.5 eq.) were added at 0° C. After one hour, the mixture was poured in dichloromethane and washed with 1N HCl and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain title compound as yellow oil. 1H NMR (300 MHz, d6-DMSO) δ 13.32 (bs, 1H), 9.19 (t, J=6.0 Hz, 1H), 8.03 (s, 1H), 7.37 (dd, J=8.4 Hz, J=5.7 Hz, 2H), 7.15 (t, J=8.5 Hz, 2H), 5.59 (s, 2H), 4.86 (s, 2H), 4.45 (d, J=6.2 Hz, 2H), 1.64 (s, 6H); MS (ES) C17H19Cl2FN4O7S2 requires 545. Found: 546 (M+H+).
Reaction SMILES: C[O-].[Na+].[C:4]1([C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][O:21]S(C1C=CC(C)=CC=1)(=O)=O.[CH3:32]N(C)C=O>O>[CH3:32][O:13][C:12]([O:21][CH3:20])([C:10]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)C=O
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
6 parts of sodium methylate are added in portions in the course of 2 hours to a solution of 21 parts of benzil and 37 parts of p-toluenesulfonic acid methyl ester in 50 parts of dimethylformamide at room temperature, whilst stirring. The reaction mixture is then heated with 500 parts of water for 1 hour under reflux and subsequently cooled to room temperature, and the precipitate is filtered off and recrystallized from a mixture of isopropanol and water. 22 parts of benzil dimethylketal are obtained.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[C:6]1[C:15]([C:16]([C:18](=[CH:24]N(C)C)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])=[CH:14][C:13]2[C:8](=[C:9]([F:30])[C:10]([F:29])=[C:11]([F:28])[CH:12]=2)[N:7]=1>ClC(Cl)Cl.C(O)C.C1CCN2C(=NCCC2)CC1>[CH:1]1([N:4]2[C:6]3[N:7]=[C:8]4[C:9]([F:30])=[C:10]([F:29])[C:11]([F:28])=[CH:12][C:13]4=[CH:14][C:15]=3[C:16](=[O:17])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24]2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
4.12 g of cyclopropylamine are added in the course of 5 minutes to a solution of 7 g of ethyl 2-(2-chloro-6,7,8-trifluoroquinoline-3-carb onyl)-3-dimethylamino-acrylate in 100 cm3 of trichloromethane kept at a temperature close to 20° C. and the mixture is stirred for a further 4 hours at this temperature. The reaction mixture is concentrated under reduced pressure (20 kPa) at about 50° C. The oily residue obtained is taken up in 100 cm3 of ethanol and 3 g of DBU. The mixture is heated to 80° C. and kept at this temperature, with stirring, for 1 hour and a half. After cooling to about 20° C., the insoluble matter is drained and washed with twice 30 cm3 of ethanol and twice 30 cm3 of diisopropyl ether. 4.5 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthridine are obtained in the form of a colourless solid melting at 260° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:19][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH3:22])[C:14]([CH:16]2[CH2:17][CH2:18]2)=[O:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CN(C)C=CC(=O)c1cccc(NC(=O)C2CC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C=CC(=O)c1cccc(N(C)C(=O)C2CC2)c1
Reaction time: 1 h
Yield: 654.4 %

Procedure:
A mixture of 10.33 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]cyclopropanecarboxamide and 1.92 g of 60% sodium hydride in oil in 50 ml of dimethylformamide was stirred for one hour under argon, then cooled in an ice bath. A solution of 0.81 g of methyl iodide in 10 ml of dimethylformamide was added dropwise. The mixture was then stirred at room temperature for 0.5 hour and extracted three times with hexane. The mixture was diluted with water and this mixture extracted with dichloromethane. This extract was evaporated and the residue crystallized from hexane, giving 10.17 g of the desired compound, mp 120°-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:42]1([NH2:51])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43]1>CC(N(C)C)=O>[CH:42]1([NH:51][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:11][C:3]=2[O:2][CH3:1])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43]1
Reactant: NC1CCc2ccccc21
Reactant: COc1cc(-c2ccncc2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2ccncc2)ccc1C(=O)NC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methoxy-4-(pyridin-4-yl)benzoic acid (34 mg, 0.15 mmol), dissolved in DMA (0.5 ml) was added a solution of HATU (68 mg, 0.18 mmol) dissolved in DMA (0.5 ml). Then a solution of TEA (55 mg, 0.5 mmol), dissolved in DMA (0.4 ml) was added, followed by a solution of 2,3-dihydro-1H-inden-1-amine (27 mg, 0.2 mmol) dissolved in DMA (0.7 ml). The resulting mixture was shaken for 4 hours at room temperature. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/methanol and purified by reverse phase HPLC (TFA method) to afford the title compound.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([CH:7]1[CH2:10][N:9]([C:11](=[O:26])[C@H:12]([CH2:24][OH:25])[NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8]1)=[O:6].Cl.C(OCC)(=O)C>O.CO>[C:14]([NH:13][C@H:12]([C:11]([N:9]1[CH2:10][CH:7]([C:5]([OH:6])=[O:4])[CH2:8]1)=[O:26])[CH2:24][OH:25])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: COC(=O)C1CN(C(=O)[C@H](CO)NC(=O)OCc2ccccc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(N[C@@H](CO)C(=O)N1CC(C(=O)O)C1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
20 ml of a ca. 1M solution of lithium hydroxide in water was added to a stirred solution of 3.36 g of 1C in 100 ml of methanol at 0° C., and the mixture was stirred for 1.5 hours at 0° C. The mixture was neutralized (to pH 6-7) with 6N hydrochloric acid, the filtrate was stripped of solvent under reduced pressure and a temperature up to 55° C., and the residue was subjected to very low pressure (<1 Torr.). The residue was dissolved in 75 ml of methanol, 100 ml of ethyl acetate was added, the mixture was filtered, and the solvents were evaporated under reduced pressure. The residue was purified by flash chromatography, using a 2:1 v:v mixture of ethyl acetate and methanol as eluent. The solvents were evaporated and the residue was recrystallized from ethanol/ether, to give N-(N-carbobenzyloxy-L-seryl)-3-azetidinecarboxylic acid (1D) as a colorless hygroscopic solid, m.p.: 138°-143° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6]Br.[NH2:8][C@@H:9]([CH3:12])[CH2:10][OH:11]>ClCCl>[O:4]1[CH2:5][CH2:6][N:8]([C@@H:9]([CH3:12])[CH2:10][OH:11])[CH2:2][CH2:3]1
Reactant: C[C@H](N)CO
Reactant: BrCCOCCBr
Solvent: ClCCl
Product: C[C@@H](CO)N1CCOCC1
Reaction time: 0.32 h
Yield: 87.5 %

Procedure:
Bis(2-bromoethyl)ether (2.3 g, 10 mmol) was added to (5)-2-aminopropan-1-ol (3.8 g, 50 mmol) at room temperature with vigorous stirring. The reaction slowly exothermed and the internal temperature peaked at 42° C. after 19 min. After 24 h, the reaction was diluted with dichloromethane (10 mL) and quenched with saturated aqueous potassium carbonate solution (10 mL). Water (˜2.5 mL) was added to the heterogeneous mixture until the solids dissolved. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude material was purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give 1.27 g of (S)-2-morpholinopropan-1-ol. 1H NMR (DMSO-d6): δ 4.29 (dd, 1H), 3.54 (t, 4H), 3.45 (ddd, 1H), 3.25 (ddd, 1H), 2.54-2.40 (m, 5H), 0.92 (d, 3H); LCMS: 146.1 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]CCC.[OH2:13].CN1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]>[Co]>[C:16]([OH:20])(=[O:13])[CH2:17][CH2:18][CH2:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C=CCCCCCCCCCC
Reactant: CN1CCCC1=O
Reactant: O
Agent: [Co]
Product: CCCCCCCCCCCCC(=O)O
Yield: 83 %

Procedure:
Using the method described in Example 1, a solution of 165 g (=0.98 mole) of dodec-1-ene and 1.65 g (=0.28 mole equivalent) of cobalt in the form of dicobalt-octacarbonyl, and a mixture of 157 g of N-methylpyrrolidone and 23 g (=1.28 mole) of water, were hydrocarboxylated under a CO pressure of 300 bars at 190° C. Conventional working up gave a yield of 83% of tridecanoic acid, of which 60% consisted of the particularly valuable n-isomer. 13% of the olefin had not reacted and the remainder consisted of by-products, including 2% of dodecane.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>CC(O)C.C(OCC)(=O)C>[C:1]1([C@H:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](Nc1ncnc2sc3c(c12)CCN(C(=O)OC(C)(C)C)C3)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@@H](Nc1ncnc2sc3c(c12)CCNC3)c1ccccc1
Temperature: 80 °C
Yield: 78.6 %

Procedure:
tert-Butyl 4-{[(1R)-1-phenylethyl]amino}-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 17A (413 mg, 1.00 mmol) was dissolved in 2-propanol (4 mL), and 4 M gaseous hydrogen chloride in dioxane (0.5 mL, 2 mmol) was added. The mixture was heated to 80° C. for 3 h. Further hydrogen chloride solution (0.5 mL) was added, and the mixture was heated to 80° C. for further 30 min. Subsequently, the solution was diluted with ethyl acetate, washed with satd. aqueous sodium carbonate solution, dried over sodium sulfate, and the solvent was removed in vacuo. The product was purified by column chromatography on silica gel (eluent: DCM/MeOH 10:1) to yield 244 mg (78%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[I:13]Cl.O>C(O)(=O)C.II>[I:13][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: ClI
Reactant: COc1cccc(CC(=O)O)c1
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(I)c(CC(=O)O)c1
Yield: 64.7 %

Procedure:
A solution of 45 g (0.27 mole) of 3-methoxybenzeneacetic acid, 52.6 g (0.32 mole) of iodine monochloride and 1 g of iodine was allowed to stand in 500 ml of glacial acetic acid for six days at room temperature. The reaction was poured into water and the solid collected. It was recrystallized from toluene to give 51 g of crystalline 2-iodo-5-methoxybenzeneacetic acid, mp 133.5°-134.5° C. (65% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[C:16]([O-:19])([O-])=O.[K+].[K+].[C:22]1([CH:29]=[CH:28][C:26]([OH:27])=[CH:25][CH:24]=1)[OH:23]>CN(C=O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]([CH2:13][CH2:14][O:11][C:8]2[CH:9]=[CH:10][C:16]([OH:19])=[CH:6][CH:7]=2)[CH2:3][CH2:2][O:23][C:22]2[CH:29]=[CH:28][C:26]([OH:27])=[CH:25][CH:24]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(O)cc1
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(CCOc2ccc(O)cc2)CCOc2ccc(O)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 16.7 %

Procedure:
A mixture of compound 26a (100 mg, 0.6 mmol), K2CO3 (110 mg, 0.8 mmol), and KI (15 mg, 0.02 mmol) in DMF (50 mL) was bubbled with argon for 10 min. Hydroquinone (220 mg, 2 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc (3:1) to provide the compound 26 (20 mg, 0.05 mmol, 13% yield). 1H NMR (CDCl3, 400 MHz) δ 6.82-6.87 (m, 2H), 6.72-6.78 (m, 10H), 4.90 (bs, 2H), 4.07 (t, J=6.0 Hz, 4H), 3.76 (t, J=8.0 Hz, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Li]CCCC.[I:24]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])=[C:4]([I:24])[C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1I
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A THF (20 mL) solution of known N-[4-chloro-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (1.49 g, 5.34 mmol) at ca. −5° C. was treated with n-BuLi (2.5 M, 5.33 mL). After 30 min, the reaction was treated with I2 (2.03 g, 8.01 mmol) dissolved in THF (3 mL). The resulting mixture was then quenched with sat. aqueous NH4Cl after 10 min. Excess I2 was removed with 10% aqueous sodium metabisulfite. The mixture was diluted with EtOAc (20 mL) and H2O (20 mL) and partitioned. The aqueous portion was extracted with EtOAc (20 mL). The combined organic portions were washed with H2O followed by brine. Drying (Na2SO4) was followed by filtration and concentration. 1H NMR of the crude mixture showed a 3.7:1 ratio of the desired (2-iodo) to the undesired regioisomer. Column chromatography (SiO2; hexanes/EtOAc) provided the title compound as a white solid (1.34 g, 62%): 1H NMR (CDCl3) δ 8.33 (d, J=6.0 Hz, 1H), 8.16 (bs, 1H), 7.49 (d, J=6.0 Hz, 1H), 1.38 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Br-].[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][Zn+]>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[CH:12]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: Fc1cccc(C[Zn+])c1
Agent: [Br-]
Product: Fc1cccc(Cc2cccc(Br)n2)c1

Procedure:
Prepared according to the procedure described in Example 53, Step 2, using 2,6-dibromo-pyridine and 3-fluoro-benzylzinc bromide.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Si:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([CH:32]=O)[CH:28]=[CH:27]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CCO>[Si:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([CH:32]=[N:2][NH:1][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][N:4]=1)[CH:28]=[CH:27]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: COCCOc1ccnc(NN)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Solvent: CCO
Product: COCCOc1ccnc(NN=Cc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
2-Hydrazinyl-4-(2-methoxyethoxy)pyridine (0.076 g, 0.415 mmol) and 8-(tert-butyldimethylsilyloxy) quinoline-2-carbaldehyde (0.119 g, 0.415 mmol) were heated to reflux in EtOH (2 mL) for 16 hours. After cooling to ambient temperature the reaction mixture was filtered and washed with EtOH to provide 105 mg (56%) of desired product as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1.N1C=CC=CC=1.[Br:14][CH2:15][C:16](Br)=[O:17].O>C1(C)C=CC=CC=1>[Br:14][CH2:15][C:16]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1)=[O:17]
Reactant: Cc1cc(N)on1
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(NC(=O)CBr)on1
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
To a solution of 5-amino-3-methylisoxazole (0.165 g, 1.67 mmol) in anhydrous toluene (6.5 ml) and anhydrous pyridine (0.18 ml, 2.0 mmol) cooled in an ice/water bath (T=˜10° C.) was slowly added bromoacetyl bromide (0.402 g, 2.0 mmol). The reaction mixture was stirred for 1.5 h under argon, then poured into water (20 ml), and extracted with ethyl acetate (2×40 ml). The combined organics were washed with water (30 ml), brine (30 ml), dried (Na2SO4), and concentrated in vacuo. The residue was triturated with diethyl ether, the precipitate was removed by filtration, and the filtrate was concentrated in vacuo to afford the title compound as a white solid (0.200 g, 55%); 1H-NMR (500 MHz, DMSO-d6) 2.18 (s, 3H, CH3), 4.08 (s, 2H, CH2Br), 6.15 (s, 1H, isoxazole C—H), 11.94 (s, 1H, CONH);
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].C(Cl)Cl.[C:8]([Si:12](Cl)([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:9]>C(OC(=O)C)C>[Br:1][CH2:2][CH2:3][O:4][Si:12]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 1.8 %

Procedure:
To a solution of 2-bromoethanol (3.4 mL, 48.34 mmol) in dry DCM (25 mL) imidazole (9.86 g, 143 mmol) and tert-butylchlorodimethylsilane (10.9 gm, 72.52 mmol) were added at 0° C. The reaction mixture was stirred at r.t. for 24 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with ethylacetate (350 mL) and washed with water (4×20 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 0.2:9.8 Ethyl acetate:Pet. Ether) to afford title compound (204 mg, 77.5%) as liquid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[NH:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[Br:17]Br>C(Cl)(Cl)Cl.O>[Br:17][C:11]1[C:12](=[O:14])[NH:13][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:9][CH:10]=1
Reactant: BrBr
Reactant: O=c1ccnc(Nc2ccccc2)[nH]1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]c(Nc2ccccc2)ncc1Br
Reaction time: 0.67 h

Procedure:
To a suspension of 2-(phenylamino)pyrimidin-4(3H)-one (0.200 g, 1.07 mmol) in CHCl3 (5 mL) and a small amount of MeOH at 0° C. was added bromine (0.0547 ml, 1.07 mmol). The reaction was stirred for 40 minutes, diluted with H2O, and then quenched with 10% sodium bisulfite solution. The reaction mixture was diluted with EtOAc, the layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The product was obtained (0.284 g; 100%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.32 (br s, 1H), 8.89 (br s, 1H), 8.04 (s, 1H), 7.55 (d, 2H), 7.33 (m, 2H), 7.06 (t, 1H). LRMS (ESI pos) m/e 266, 268 (M+, Br pattern).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:32]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33]1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[C:26]([CH3:27])([CH3:28])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:38][S:35]([CH:32]5[CH2:34][CH2:33]5)(=[O:37])=[O:36])=[O:30])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2cccc(C3Nc4ccc(C(=O)NS(=O)(=O)C5CC5)cc4CC3(C)C)c2)cc1
Yield: 21.9 %

Procedure:
A mixture of 2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (90 mg, 0.22 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (63 mg, 0.33 mmol), 4-dimethylaminopyridine (40 mg, 0.33 mmol), cyclopropane sulfonamide (80 mg, 0.66 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (25 mg, 22%) as a light yellow solid: LC/MS m/e calcd for C30H34N2O4S (M+H)+: 519.68, observed: 519.4.