Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([N:6]([CH2:15][C@@H:16]2[O:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH2:33][CH2:32][N:31]([C:34]([C@@H:36]5[CH2:40][O:39]C(C)(C)[O:37]5)=[O:35])[CH2:30][CH:29]=4)=[C:24]([F:43])[CH:23]=3)[CH2:17]2)C(OCC(Cl)(Cl)Cl)=O)=[N:2]1.O>C(O)(=O)C.[Zn]>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:15][C@@H:16]2[O:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH2:33][CH2:32][N:31]([C:34](=[O:35])[C@@H:36]([OH:37])[CH2:40][OH:39])[CH2:30][CH:29]=4)=[C:24]([F:43])[CH:23]=3)[CH2:17]2)=[N:2]1
Reactant: CC1(C)OC[C@@H](C(=O)N2CC=C(c3ccc(N4C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c5ccon5)OC4=O)cc3F)CC2)O1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C([C@@H](O)CO)N1CC=C(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5(R)-[-N-isoxazol-3-yl-N-(2,2,2-trichloroethyloxycarbonyl)aminomethyl]-3-{3-fluoro-4-[N-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl]phenyl}oxazolidin-2-one (200 mg, 0.3 mM) in acetic acid (3 ml) was added zinc dust (195 mg, 3.0 mM). The mixture was stood in an ultrasonic bath for 10 min. then stirred vigorously for 24 hours under a nitrogen atmosphere at ambient temperature. Water (0.5 ml) was added and stirring was continued for a further 24 hours. The reaction mixture was filtered through celite and evaporated. The residue was dissolved in tetrahydrofuran (15 ml)/1.0 M aq. HCl (10 ml) and was stirred at ambient temperature for 3 days. It was evaporated to dryness and the residue was chromatographed by MPLC (8% MeOH/CH2Cl2, gradient to 25%). The title compound was obtained as a white powder on trituration with ether/ethanol (68 mg, 50%). NMR: δ2.42(s, 2H,partially obscured), 3.43(m, 2H), 3.57(m, 1H), 3.79(m, 3H), 4.16(m, 2H), 4.27(m, 1H), 4.38(m, 1H), 4.72(m, 1H), 4.91(m, 1H), 5.00(m, 1H), 6.00(m, 2H), 6.57(t, 1H), 7.30(d of d, 1H), 7.39(t, 1H), 7.50(d of d, 1H), 8.40(s, 1H); m/z ES+(M+H)=447.
Reaction SMILES: P.[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH3:3].C(O)C>O>[CH3:3][CH:2]([OH:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccccc1
Agent: P
Solvent: O
Solvent: CCO
Product: CC(O)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Into a 3 ounce glass pressure bottle are placed 180 milligrams of [Rh(norbornadiene) (iso-propylphenylmethylphosphine)2 ]BF4 ([α]D25 = +11.0° for the phosphine), 7.7 grams of acetophenone, 3 ml absolute ethanol, and 0.12 ml water. The bottle is flushed and filled with hydrogen as in Example 1 to 30 psig. The bottle is warmed to 60°C and the contents stirred for 5 hours. Distillation of the reaction mass affords pure α-methylbenzyl alcohol, [α]D25 = -1.78°, optical purity = 4.2%.
Reaction SMILES: Br[CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]2=[O:15])=[O:4].[CH3:35][NH:36][CH3:37].CO.[ClH:40].CCOCC>C(#N)C.C(Cl)Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH3:35][N:36]([CH3:37])[CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]2=[O:15])=[O:4].[ClH:40]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)C(C)Br)c3C2=O)ccc1OC
Reactant: CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)C(C)N(C)C)c3C2=O)ccc1OC
Reaction time: 48 h

Procedure:
To a suspension of 2-bromo-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}propanamide (500 mg, 0.9 mmol) in acetonitrile (5 mL) was added dimethylamine in methanol (1.5 mL, 2M, 3.0 mmol) at room temperature and the mixture was stirred for 2 days. The mixture was diluted with methylene chloride (50 mL) and sodium hydrogen carbonate (25 mL). The organic layer was separated, washed with brine (25 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. To a solution of the oil in ethyl acetate (20 mL) was added hydrogen chloride in ether (1.5 mL, 1N hydrogen chloride, 1.5 mmol). The resulting suspension was filtered and washed with ethyl acetate (10 mL) to give 2-(dimethylamino)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}propanamide, hydrogen chloride as a white solid (290 mg, 58% yield): mp, 138-140° C.; 1H NMR (DMSO-d6) δ 1.32 (t, J=6.9 Hz, 3H, CH3), 1.56 (brs, 3H, CH3), 2.83 (brs, 6H, CH3), 3.01 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.02 (q, J=6.9 Hz, 2H, CH2), 4.15 (dd, J=4.4, 14.2 Hz, 1H, CHH), 4.27 (s, 1H, CH), 4.34 (dd, J=10.6, 14.3 Hz, 1H, CHH), 5.78 (dd, J=4.3, 10.3 Hz, 1H, NCH), 6.91-6.99 (m, 2H, Ar), 7.72 (d, J=7.1 Hz, 1H<Ar), 7.87 (d, J=7.5 Hz, 1H, Ar), 8.14 (m, 1H, Ar), 10.4 (brs, 1H, HCl), 10.71 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.42, 14.67, 41.07, 41.47, 47.31, 52.98, 55.51, 52.74, 63.84, 111.75, 112.31, 119.70, 120.16, 128.92, 129.47, 131.80, 134.05, 135.87, 147.87, 148.91, 166.66, 166.86, 167.65, 168.53; Anal Calcd for C25H31N3O7S+1.1HCl+0.6H2O: C, 52.82; H, 5.90; N, 7.39, Cl, 6.86, H2O, 1.90. Found: C, 52.57; H, 5.77; N, 7.10; Cl, 6.90; H2O, 1.47.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9](=[O:14])[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([CH3:15])=[C:4]([CH3:16])[CH:3]=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[CH3:16][C:4]1[CH:3]=[CH:2][C:7]2[NH:8][C:9](=[O:14])[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]=1[CH3:15]
Reactant: Cc1cc(Br)c2c(c1C)S(=O)(=O)NC(=O)N2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc2c(c1C)S(=O)(=O)NC(=O)N2
Temperature: 25 °C

Procedure:
5-Bromo-7,8-dimethyl-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione (5.27 g, 17.3 mmol) was suspended in methanol (60 mL), and then ammonium formate (5.45 g, 86.5 mmol, 5 eq) was added and nitrogen substitution was performed. Next, 10% palladium-carbon powder (1.84 g, 1.73 mmol, 10 mol %) was added and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was cooled on ice and the precipitated crystals were filtered out and dried to obtain 7,8-dimethyl-2H, 4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[N:8][CH:9]=1.Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>CN(C=O)C>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([CH2:10][O:11][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: OCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCc2cncc(Br)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
To a suspension of NaH (1.12 g, 28.0 mmol) in DMF (75 mL) was added a solution of (5-bromopyridin-3-yl)methanol (4.21 g, 22.4 mmol) in DMF (8 mL) at 0° C. The mixture was allowed to stir at 0° C. for 15 min and then 1-(chloromethyl)-4-methoxybenzene (5.41 g, 34.6 mmol) was added followed by tetra-N-butylammonium iodide (0.91 g, 2.4 mmol). The reaction mixture was allowed to vigorously stir and warm to rt overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous solution was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-bromo-5-{[(4-methoxybenzyl)oxy]methyl}pyridine (4.40 g, 64%) as a yellow oil. LCMS: (FA) ES+ 308.1.
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1.C(Cl)Cl.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(N(CC)CC)C>[CH3:30][S:31]([O:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OS(C)(=O)=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2.48 g. of ethyl 15-hydroxy-9-oxo-prostanoate (Example 50) in 18 ml. of methylene chloride containing 1.4 ml. of triethylamine, cooled in an ice-salt bath is added dropwise 0.58 ml. of methanesulfonyl chloride. The resulting mixture is stirred for 15 minutes and is then washed successively with ice cold water, 10% hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 2.7 g. (90%) of oil; λmax. 5.78 (carbonyl groups), 7.45 and 8.55 μ (sulfonate).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)([O-:3])=[O:2].ON1C2C=CC=CC=2N=N1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][C:34]=1[C:42]([F:45])([F:44])[F:43].C(N(CC)CC)C>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:37](=[O:38])[C:36]2[CH:40]=[CH:41][C:33]([Cl:32])=[C:34]([C:42]([F:45])([F:43])[F:44])[CH:35]=2)=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(Oc2ccnc3c([N+](=O)[O-])cccc23)cc1
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Oc2ccnc3c([N+](=O)[O-])cccc23)cc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Yield: 55.7 %

Procedure:
4-(8-Nitroquinolin-4-yloxy)phenylamine (103 mL, 0.46 mmol), N-hydroxybenzotriazole (HOBt) (62 mg, 0.46 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarboimide (EDCl) (102 mg, 0.53 mmol) and 4-chloro-3-trifluoromethylbenzoic acid (103 mg, 0.46 mmol) were dissolved in dimethylformamide (3.6 mL), and to which triethylamine was added dropwise at room temperature, which was then heated and stirred at 80° C. When the reaction was completed, the resultant was extracted with ethyl acetate and saturated sodium bicarbonate, combined organic layers were dried with anhydrous sodium sulfate, and then filtered. The solvent was removed by vacuum distillation, and the residue was purified by a column chromatography (ethyl acetate/n-hexane=½) to obtain 125 mg of the desired compound as a brown solid (yield 71.2%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[NH:16][N:17]=[CH:18][CH:19]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:19]=[CH:18][N:17]([CH2:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[N:16]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccc(F)cc1
Reactant: BrCCC1CC1
Product: Cc1nc(-c2ccn(CCC3CC3)n2)sc1C(=O)NCc1ccc(F)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)thiazole-5-carboxylic acid 4-fluoro-benzylamide and (2-bromo-ethyl)cyclopropane as describe in Example 83 and isolated as a white solid (0.045 g, 38% yield). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J=2 Hz, 1H), 7.29-7.35 (m, 2H), 7.05 (t, J=8 Hz, 2H), 6.80 (d, J=2 Hz, 1H), 5.96-6.01 (bm, 1H), 4.57 (d, J=4 Hz, 2H), 4.23 (t, J=7 Hz, 2H), 2.75 (s, 3H), 1.78 (q, J=7 Hz, 2H), 0.58-0.68 (m, 1H), 0.40-0.48 (m, 2H), 0.0-0.04 (m, 2H); MS (M+H)+=385.2; Rt=1.48 min; HRMS (M+H)+=385.15.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C>C1COCC1>[F:21][C:22]1[CH:27]=[C:26]([B:29]([OH:34])[OH:30])[C:25]([F:28])=[CH:24][N:23]=1
Reactant: Fc1ccc(F)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1cc(F)ncc1F
Temperature: -20 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
Diisopropylamine (1.74 ml, 1.24 g, 12.20 mmol) was dissolved in anhydrous THF (22 ml) and placed under argon. The solution was cooled to −20° C. and then treated with n-butyllithium (7.66 ml, 12.25 mmol, 1.6 M in hexanes) by slow addition over 10 min. The newly formed LDA (LDA=lithium diisopropylamide, this acronyl should be listed in the general session) was then cooled to −78° C. and treated with a solution of 2,5-difluoropyridine (1.05 ml, 1.33 g, 11.56 mmol) dissolved in anhydrous THF (3 ml) by slow addition over 30 min. Once the addition was complete the reaction mixture was allowed to stir at −78° C. for 4 hr. At this time the reaction mixture was treated with a solution of triisopropyl borate (5.90 ml, 4.78 g, 25.4 mmol) dissolved in anhydrous THF (8.6 ml) by dropwise addition. Once the addition was complete the reaction mixture was allowed to warm to ambient temperature then stirred at ambient temperature for an additional hour. The reaction mixture was then quenched by adding 4% aq NaOH (34 ml). The layers were separated and the aqueous layer was cooled in an ice bath. It was then acidified to pH=4 with 6N HCl (˜10 ml) not letting the temperature go above 10° C. This was then extracted with EtOAc (3×50 ml). The extracts were then washed with brine (1×50 ml), dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was triturated with Et2O to give 0.8084 g (44%) of 2,5-difluoropyridin-4-ylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18](=O)[CH3:19]>CC(C)=O.ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:9][CH:17]=[C:18]([CH3:19])[C:7]=2[CH:8]=1
Reactant: CC(=O)CCl
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: CC(C)=O
Product: COc1ccc2scc(C)c2c1
Yield: 26.9 %

Procedure:
A mixture of 4-methoxythiophenol (2.8 g, 20 mmol), K2CO3 (5.5 g, 40 mmol) and chloroacetone (6.6 mL, 82 mmol) in acetone (50 mL) was heated at reflux over night. The reaction mixture was filtered and the solvent was evaporated giving 5.0 g crude product. The intermediate thioether was dissolved in chlorobenzene (50 mL) and polyphosphoric acid (PPA, 0.5 g) was added (Plé et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). The reaction mixture was refluxed over night. The solvent was decanted and the PPA residue was treated with CH2Cl2. The combined organic extracts were washed with water and dried before the solvents were evaporated. The crude product was purified on silica using heptane as eluent to give the title compound (0.96 g, 27% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 2.44 (d, J=1.20 Hz, 3 H) 3.93 (s, 3 H) 7.03 (ddd, J=8.78, 2.51, 0.50 Hz, 1 H) 7.11 (dq, J=1.20, 0.50 Hz, 1 H) 7.17 (d, J=2.51 Hz, 1 H) 7.73 (dd, J=8.78, 0.50 Hz, 1 H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[N:26](S(C3C=CC(C)=CC=3)(=O)=O)[CH:27]=[C:28]([C:29]([F:32])([F:31])[F:30])[C:21]=12.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[C:28]([C:29]([F:30])([F:31])[F:32])[C:21]=12
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(F)(F)F)c3c(Cl)ccnc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: FC(F)(F)c1c[nH]c2nccc(Cl)c12
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
52.3 g (200 mmol) of tetra-n-butylammonium fluoride are added to a solution of 30 g (80.0 mmol) of 4-chloro-1-(toluene-4-sulphonyl)-3-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine in 250 ml of absolute THF and the mixture is stirred at 20° C. for 20 minutes. On completion of conversion (TLC monitoring), the mixture is admixed with 300 ml of saturated NaHCO3 solution and subsequently extracted three times with 500 ml each time of ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried over MgSO4 and freed of volatile constituents in a water-jet vacuum. Purification of the crystalline crude product by chromatography through silica gel (CH2Cl2: MeOH=30:1) results in 13.1 g (59.5 mmol; 74%) of 4-chloro-3-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc2[nH]c(C)cc12
Solvent: O
Product: COc1cccc2c1cc(C)n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
4-Methoxy 2-methyl-1H-indole (1 g, 6.2 mmol) was added to 248 mg (6.2 mmol)) of 60% sodium hydride/mineral oil (washed with hexane before adding DMF) in 15 mL of DMF and after stirring for 0.5 hour, 0.74 mL (6.2 mmol) of benzyl bromide was added. The mixture was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4) and after concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.3 g (84% yield) of 4-methoxy-2-methyl-1-(phenylmethyl)-1H-indole, melting at 96-116° C.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:27]3[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NS(=O)(=O)c1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)s1

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (360 mg, 1 mmol) and commercially available 5-bromothiophene-2-sulfonamide (221 mg, 1 mmol) according to general procedure II. Obtained as an off-white solid (300 mg, 57%). MS (ISP) 516.2 [(M+H)+]; mp 248-250° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:19]([CH:16]([CH2:17][CH3:18])[CH2:15][N:11]1[C:12]2[C:7](=[C:6]([OH:28])[C:5]([C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]1=[O:21])[CH3:20]
Reactant: NCCC(=O)O
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)ncc21
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 19.9 %

Procedure:
A mixture of 1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.092 mmol), β-alanine (492 mg, 5.5 mmol) and NaOMe solution (8.3 mL, 4.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 8 mg of the title compound as a yellow solid. MS: (+) m/z 438.33 (M+1).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[CH3:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:29](=[O:30])[CH2:28][CH:25]3[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: CC1CCC(CC(=O)O)CC1
Reactant: COc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Product: COc1ccc(-c2nn(NC(=O)CC3CCC(C)CC3)c(=O)c3ccccc23)cc1

Procedure:
The product from Example 151A and 2-(4-methylcyclohexyl)acetic acid were treated using a method similar to that described in Example 5 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 8.37-8.44 (m, 1H), 7.86-8.04 (m, 2H), 7.74-7.80 (m, 1H), 7.51-7.55 (m, 2H), 7.10-7.14 (m, 2H), 3.85 (s, 3H), 2.23-2.34 (m, 2H), 1.95-2.09 (m, 1H), 1.77-1.88 (m, 1H), 1.42-1.72 (m, 5H), 1.20-1.35 (m, 2H), 0.88-1.06 (m, 1H), 0.92 (d, J=6.7 Hz, 3H); MS (ESI+) M/Z 406 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([I:16])[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC.O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([I:16])[C:14]=1[O:15][CH3:17])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(I)c(O)c(C(C)(C)C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(I)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
Methyl 3-t-butyl-4-hydroxy-5-iodobenzoate (2.77 g) was dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (12.0 g) and dimethylsulfuric acid (4.1 mL) were added to the solution, and then the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.77 g) as a brown crystal.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][CH:13]([F:16])[CH2:14][OH:15]>N1C=CC=CC=1>[F:12][CH:13]([F:16])[CH2:14][O:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCC(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(F)F)cc1
Reaction time: 72 h

Procedure:
Combine p-toluenesulfonyl chloride (12.9 g, 67.4 mmol) in pyridine (15 mL) at room temperature and treat dropwise with 2,2-difluoroethanol (5.0 g, 60.9 mmol) via syringe. Stir the reaction mixture under nitrogen for 72 hours, partition between water (20 mL) and dichloromethane (20 mL). Separate the aqueous phase and extract with additional dichloromethane (2×40 mL). Combine the organic extracts and wash sequentially with 1N hydrochloric acid (2×50 mL), sodium bicarbonate (2×50 mL), and brine (2×50 mL). Dry the organic layer over sodium sulfate and concentrate in vacuo to give the title compound as a yellowish oil: 1H NMR (300 MHz, CDCl3): 7.82 (d, 2H, J=9.0 Hz), 7.40 (d, 2H, J=9.0 Hz), 5.92 (tt, 1H, J=55.0, 0.4 Hz), 4.19 (td, 2H, J=12.6, 4.0 Hz), 2.48 (s, 3H).