Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:4][CH2:3]1.[CH3:33][Mg+].[Br-].[Cl-].[NH4+]>C1COCC1>[OH:1][C:2]1([CH3:33])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[N:10]=2)[N:5]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:4][CH2:3]1
Reactant: C[Mg+]
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3=O)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)C(C)(O)CCN3C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 8-oxo-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 2) (591 mg, 1.376 mmol) in THF (20 ml) at 0° C. was added 1M MeMgBr in THF (5.50 ml, 5.50 mmol). The mixture was left to stir at 0° C. for 30 mins under an atmosphere of nitrogen and then warmed to room temperature. After 1.5 hours, the reaction mixture was poured into a saturated ammonium chloride solution (30 ml). The product was extracted with ethyl acetate (2×30 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product as an oil. Purification of the oil by chromatography on silica eluting with EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@:32]1([CH3:39])[C:36](O)=[O:37])=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:36]([C@@:32]3([CH3:39])[CH2:33][CH2:34][CH2:35][N:31]3[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[O:37])=[C:16]2[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)O
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (22 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 68% acetonitrile/water to yield the N-Boc-protected product, (R)-tert-butyl 2-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2-methylpyrrolidine-1-carboxylate, as a beige solid (32 mg, 73% yield). The de-protection was carried out by adding 1 mL 4 N HCl solution in dioxane to the above protected product. After 1 hour at ambient temperature, the reaction mixture was concentrated, treated with ether (1 mL), and filtered, giving the final product as an off-white solid. MS (apci) m/z=427.2 (M+H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:19]N1C(=O)CCC1=O>CN(C=O)C>[Br:19][C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[C:13]([OH:18])[CH:14]=1
Reactant: Oc1ccccc1NC1CCC2(CC1)OCCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Oc1cc(Br)ccc1NC1CCC2(CC1)OCCO2
Yield: 32.9 %

Procedure:
A solution of intermediate D19 (1 g, 4.011 mmol) and N-bromosuccinimide (0.785 g, 4.412 mmol) in DMF (15 ml) was stirred at room temperature for 1 h. Subsequently, the reaction mixture was washed with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (Na2SO4), and the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc 8:2 as eluent): The desired fractions were collected and evaporated in vacuo to yield D22 (0.433 g, 32.89%) as a reddish solid.
Reaction SMILES: [C:1]([O:5][C:6]1[N:11]=[C:10]([CH:12]=[CH2:13])[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[O:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)C>[C:1]([O:5][C:6]1[N:11]=[C:10]([CH2:12][CH2:13][N:23]2[CH2:22][CH2:21][CH:20]([CH2:19][O:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[F:15])[CH2:25][CH2:24]2)[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1OCC1CCNCC1
Reactant: C=Cc1ccnc(OC(C)(C)C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)Oc1nccc(CCN2CCC(COc3ccccc3F)CC2)n1
Yield: 92.9 %

Procedure:
After dissolving 221 mg of 2-tert-butoxy-4-vinylpyrimidine and 200 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride in 5 ml of ethanol, 123 mg of anhydrous potassium carbonate was added and the mixture was heated to reflux for 50 minutes. Ethyl acetate was added to the reaction mixture, the insoluble portion was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (293 mg, 93% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH3:23])[CH2:14][C:13]2[C:15]([CH3:22])=[C:16](Br)[C:17]([CH3:20])=[C:18]([CH3:19])[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[CH2:1]([O:8][CH2:9][C:10]1([CH3:23])[CH2:14][C:13]2[C:15]([CH3:22])=[C:16]([N:35]3[CH2:34][CH2:33][N:32]([C:29]4[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=4)[CH2:37][CH2:36]3)[C:17]([CH3:20])=[C:18]([CH3:19])[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(COCc1ccccc1)O2
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(COCc3ccccc3)O4)CC2)cc1
Yield: 64.8 %

Procedure:
By using 2-[(benzyloxy)methyl]-5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (690 mg, 1.84 mmol) synthesized in Reference Example 159 and 1-(4-methoxyphenyl)piperazine (707 mg, 3.68 mmol), the reaction was carried out in the same manner as Example 1 to synthesize 580 mg of the title compound (yield 65%). An oily product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12](OC)=[O:13].[H-].C([Al+]CC(C)C)C(C)C.CO>C1COCC1.CCCCCC>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][OH:13]
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(Br)c(CO)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 37.6 %

Procedure:
To a −78° C. solution of dimethyl 4-bromoisophthalate (21.0 g, 77 mmol)(commercially available from Maybridge) in THF (100 mL) was slowly added diisobutylaluminum hydride (269 mL, 269 mol, 1.0 M solution in hexane, commercially available from Sigma-Aldrich, St. Louis, Mo., USA) over 20 minutes. After stirring at −78° C. for 3 hours, the resulting mixture was treated with MeOH. Organic solvents were removed under reduced pressure and the residue was redissolved in EtOAc and washed with 1.0 N HCl. After removal of organic solvents under reduced pressure, purification of the residue through silica gel chromatography with 0-35% EtOAc in hexanes as eluents afforded 132.1 (7.1 g, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-:17])=[O:16])[C:9]2=[O:18])=[CH:5][CH:4]=1.[CH2:21]=[O:22].C[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:21][OH:22])=[C:10]([N+:15]([O-:17])=[O:16])[C:9]2=[O:18])=[CH:5][CH:4]=1
Reactant: C=O
Reactant: COc1ccc(Cn2ccc(C)c([N+](=O)[O-])c2=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ccc(CCO)c([N+](=O)[O-])c2=O)cc1
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 1-(4-methoxybenzyl)-4-methyl-3-nitro-2-pyridone (1.38 g, 5.0 mmol) and paraformaldehyde (0.152 g) in dimethylsulfoxide (8 mL) was added sodium methoxide (0.018 g). After 2 hours, the mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was dried, filtered and evaporated. The residual solid was triturated with chloroform/ethyl acetate (10 mL, 1/1) and 1-(4-methoxybenzyl)-4-hydroxyethyl-3′-nitro-2-pyridone was collected by filtration (0.496 g). Fractionation of the supernatant over silica gel (chloroform/ethyl acetate to ethyl acetate/methanol 99/1) gave additional product (0.404 g) (total yield, 2.96 mmol, 59%).
Reaction SMILES: O.C([O-])([O-])=O.[K+].[K+].[CH2:8]([C@@:15]12[CH2:28][CH2:27][C:26]([O:29]CC)=[CH:25][C:24]1=[CH:23][CH2:22][C:21]1[CH:20]=[C:19]([C:32]#[N:33])[CH:18]=[CH:17][C:16]2=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H][H]>C1COCC1.CCOC(C)=O>[CH2:8]([C@@:15]12[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][C@H:24]1[CH2:23][CH2:22][C:21]1[CH:20]=[C:19]([C:32]#[N:33])[CH:18]=[CH:17][C:16]2=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCOC1=CC2=CCc3cc(C#N)ccc3[C@]2(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2c(c1)CC[C@@H]1CC(=O)CC[C@@]21Cc1ccccc1
Reaction time: 5 h
Yield: 56 %

Procedure:
To a solution of water wet 5% palladium on carbon (7.0 grams) and K2CO3 (7.0 g) in THF (100 mL) was added 4b(S)-Benzyl-7-ethoxy-4b,5,6,10-tetrahydro-phenanthrene-2-carbonitrile (35.0 g, 103 mmol) in tetrahydrofuran (600 mL). The resulting slurry was transferred to a 1 L hydrogenator with overhead stirring under 50 psi of hydrogen. After 5 hours no starting material could be detected by HPLC and the reaction mixture was filtered through a pad of Celite. The filtrate was diluted with 1N hydrochloric acid (70 mL) and after standing for 1 hour no vinyl ether could be detected by HPLC. The solution was diluted with EtOAc (700 mL), water (700 mL) and brine (100 mL) and phases were separated. The organic was washed with water (700 mL) and brine (700 mL). The organic was concentrated under reduced pressure to approximately 500 mL and EtOAc (500 mL) was added and the solution concentrated again to approximately 300 mL. To the vigorously stirring solution were added hexanes (1 L) in one portion. The resulting solids were allowed to granulate for 1 hour and then filtered. HPLC showed some impurities so the solids were allowed to granulate in hexanes (75 mL) and EtOAc (25 mL) for 24 hours. The solids were filtered and allowed to air dry. The mother liquor was concentrated to give orange solids, which were granulated in EtOAc (15 mL) and hexanes (85 mL) for 24 hours. The solids were filtered and combined with the first crop. After air drying overnight a white solid was collected: 18 grams (57.1 mmol), 56% yield; mp 128-129° C.; IR (film) ν 2226, 1713 cm−1; [α]25D−252.50; 1H NMR (CDCl3) δ 7.43 (s, 1H), 7.21-7.08 (m, 4H), 6.58 (d, 2H, J=7.1 Hz), 6.40 (d, 1H, J=7.9 Hz), 3.21 (d, 1H, J=13.3 Hz), 3.13-2.97 (m, 2H), 2.85 (ddd, 1H, J=14.9, 14.9, 6.2 Hz), 2.80 (d, 1H, J=14.1 Hz), 2.66-2.51 (m,2H), 2.60 (d, 1H, J=14.1 Hz), 2.45-2.40 (m, 1H), 2.24-2.16 (m, 1H), 2.09-1.98 (m, 1H), 1.83-1.76 (m, 1H), 1.61 (dd, 1H, J=14.1, 14.1, 5.4 Hz); 13C NMR (CDCl3) δ 210.1, 147.6, 137.3, 136.5, 133.1, 130.9, 128.4, 128.1, 128.0, 127.0, 119.3, 110.4, 44.5, 42.7, 40.7, 38.2, 36.2, 33.0, 28.0, 24.7. Anal. Calcd for C22H2, NO: C, 83.77; H, 6.71; N, 4.44. Found: C, 83.76; H, 6.90; N, 4.40. The structure and absolute configuration were confirmed by single crystal X-ray analysis.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:30].[OH-].[Na+].Cl>C(O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]([CH3:30])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)COc1ccc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)ccc1OCC(=O)O
Temperature: 5 °C
Reaction time: 18 h

Procedure:
{4-[3,3-Bis-(4-chloro-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (100 mg, 0.218 mmol) was dissolved in ethanol (10 ml). 1N NaOH (3 ml, 3 mmol) was added at room temperature and the reaction mixture was stirred for 18 h at 5° C. after which it was treated with 1N HCl (3 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases were dried and evapotated to give the title compound in 50 mg (10%) yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8](=[O:27])[NH:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH2:28](O)[CH3:29].CN1CCCN(C)C1=O.ICC>C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([O:27][CH2:28][CH3:29])=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=c1[nH]c(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Reactant: CCO
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCI
Solvent: CN1CCCN(C)C1=O
Product: CCOc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Temperature: 40 °C

Procedure:
A 80 mL sealed tube is charged with 8-chloro-1-(2-phenyl-quinolin-7-yl)-2H-imidazo[1,5-a]pyrazin-3-one (50.00 mg, 0.1341 mmol), silver carbonate (74 mg, 0.27 mmol), anhydrous ethanol (2.00 mL, 0.034 mol), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.002 mL, 0.01 mmol), and iodoethane (0.012 mL, 0.15 mmol). The reaction was sealed under an atmosphere of nitrogen and heated at 40° C. for 24 hours. The reaction was cooled and filtered. Water and EtOAc were added and the organic layer was isolated, dried over sodium sulfate, filtered and concentrated in vacuo to yield a yellow gum. The crude product was purified via silica gel column chromatography, (Jones, 5 gram column eluting with 50% EtOAc: Hex) to yield the title compound as a yellow gum; MS (ES+): m/z 401.03 (100) [MH+], 402.98 (30) [MH+++]; HPLC: tR=4.13 min (OpenLynx, polar—5 min); 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.41-1.72 (m, 3H), 4.55-4.86 (m, 2H), 7.18 (d, J=4.80 Hz, 1H), 7.38-7.65 (m, 4H), 7.75-8.00 (m, 3H), 8.09-8.33 (m, 3H), 8.52 (br. s., 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:16]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:8][C:6]1[CH:7]=[CH:2][C:3]2[C:9]3[C:10]([CH:16]([CH3:17])[N:18]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)(=[O:20])=[O:21])[C:4]=2[CH:5]=1)=[CH:11][CH:12]=[C:13]([F:15])[CH:14]=3
Reactant: COc1ccc(S(=O)(=O)NC(C)c2ccc(F)cc2-c2ccc(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2c3cc(F)ccc3-c3cc(F)ccc3C2C)cc1

Procedure:
The title compound was prepared from N-[1-(2′,4′,5-trifluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzenesulfonamide (161 mg, 0.38 mmol), anhydrous N,N-dimethylformamide (1 mL), and potassium carbonate (106 mg, 0.76 mmol) according to the procedure and in the same manner as described in Example 105, step d resulting in the isolation of 143 mg (93%) of a white solid. This material was used without further purification in Example 114, step e;
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([S:9][CH2:10][CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:5][C:4]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22].[OH:25]O>>[ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([S:9]([CH2:10][CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])=[O:25])[CH:6]=[CH:5][C:4]=1[NH:20][S:21]([CH3:24])(=[O:22])=[O:23]
Reactant: Cc1cc(SCCCN(C(C)C)C(C)C)ccc1NS(C)(=O)=O
Reactant: OO
Agent: Cl
Product: Cc1cc(S(=O)CCCN(C(C)C)C(C)C)ccc1NS(C)(=O)=O

Procedure:
React N-[2-methyl-4-[[3-[bis(1-methylethyl)amino]propyl]thio]phenyl]methanesulfonamide hydrochloride with 30% aqueous hydrogen peroxide in a manner similar to Example 8 to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2O.[F:20][C:21]1[CH:22]=[C:23]([C:27]([C:29]2[CH:30]=[N:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[O:28])[CH:24]=[CH:25][CH:26]=1.[Cl:36]C1C=C(C(C2C=NC=CC=2)=O)C=CC=1>>[Cl:36][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:27]([C:29]3[CH:30]=[N:31][C:32]([Cl:35])=[CH:33][CH:34]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=3)[OH:28])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1cccnc1)c1cccc(Cl)c1
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1
Reactant: O=C(c1ccc(Cl)nc1)c1cccc(F)c1
Product: OC(c1ccc(Cl)nc1)(c1cccc(F)c1)c1ccc2ncc(-c3ccccc3)c(Cl)c2c1

Procedure:
The title compound was prepared using 6-bromo-4-chloro-3-phenylquinoline (Intermediate 3, step c) and (3-fluorophenyl)(6-chloropyridin-3-yl)methanone in place of 6-bromo-2,4-dichloro-3-phenylquinoline and (3-chlorophenyl)(pyridin-3-yl)methanone, respectively, according to the procedure described in Example 25. 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.40 (d, J=2.69 Hz, 1H), 8.30 (d, J=2.20 Hz, 1H), 8.10 (d, J=8.80 Hz, 1H), 7.68 (ddd, J=2.20, 8.62, 17.55 Hz, 2H), 7.46-7.54 (m, 5H), 7.33 (d, J=8.56 Hz, 2H), 7.05-7.11 (m, 3H); MS m/e 474.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:15]=O.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:21][C:22]3=[CH:26][CH:25]=[N:24][N:23]23)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: CC1(C)CCC2=C(C1=O)C(c1ccc(Cl)c(Cl)c1)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 3,4-dichlorobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [OH2:1].COC1C(N2C[C@@H]3[C@@H](CCCN3)C2)=C(F)C=C2[C:20]([C:22]([C:28]([OH:30])=O)=CN(C3CC3)C=12)=[O:21].[OH:31][CH2:32][CH:33]([CH2:35][OH:36])[OH:34]>>[CH2:32]([OH:31])[C@H:33]([C@H:35]([C@@H:28]([C@@H:22]([CH2:20][OH:21])[OH:1])[OH:30])[OH:36])[OH:34]
Reactant: O
Reactant: OCC(O)CO
Reactant: COc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
For preparation, water for injection is initially charged in a 201 glass bottle, and moxifloxacin and glycerol are dissolved therein with stirring at RT. The solution has a pH of about 4.4. The solution is then filtered through a filter having a pore size of 0.22 μm into an enamel-coated intermediate container, and in each case 100 ml are filled into infusion bottles. The filled bottles are sterilized in an autoclave at 121° C. for 20 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[C:21]1(B(O)O)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:29]3[C:30]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:26]=[CH:27][CH:28]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cccc2ccccc12
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc4ccccc34)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 1-naphtaleneboronic acid (56 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl.[NH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[NH2:14]>C(O)(=O)C>[N:18]1[CH:19]=[CH:20][C:15]([NH:13][N:14]2[CH2:4][C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:1]2)=[CH:16][CH:17]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NNc1ccncc1
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc2c(c1)CN(Nc1ccncc1)C2
Yield: 110.3 %

Procedure:
Phthalic anhydride (5.1 g) and 4-hydrazinopyridine hydrochloride (5.0 g) were suspended in glacial acetic acid (300 ml), and the mixture was heated under reflux for 8 hrs. The reaction mixture was evaporated, and the residue was triturated with 2-propanol. The solid was collected and dried to give 8.0 g of N-(4-pyridinylamino)-1H-isoindole. 1M lithium aluminum hydride in tetrahydrofuran (72.5 ml) was added dropwise to a portion (4.0 g) of the above solid suspended in tetrahydrofuran (200 ml) at 0° C., under nitrogen. The reaction mixture was warmed to ambient temperature, stirred overnight, under nitrogen, and was added to ice water, with stirring. The mixture was extracted with 2-propanol/chloroform (1/4). The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with 5% methanol/chloroform. The appropriate fractions were collected and evaporated to yield 1.3 g (36%) of product free base. The free base was dissolved in methanol, and methanolic hydrogen chloride was added. The precipitate was collected to give 0.25 g (5.8%) of product, mp 253-255° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[H-].[Na+].F[C:12]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:13]=1[C:14]#[N:15]>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:12]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: CN1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1ccc(C(F)(F)F)cc1C#N
Temperature: 22 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (5.2 g, 45.1 mmol) in 25 mL of THF was added sodium hydride (1.970 g, 49.3 mmol). The reaction was stirred at 22° C. for 20 min. and 2-fluoro-5-(trifluoromethyl)benzonitrile (Aldrich) (8.54 g, 45.1 mmol) was added in 5 mL of THF. The reaction was stirred at 22° C. for 3 h. The solvent was evaporated under reduced pressure. The residue was dissolved in ether, washed with brine, water, dried with magnesium sulfate and concentrated to afford the title compound. MS (ESI) m/z 285 (M+H)+.