Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[CH:6]1[C:22]2[CH2:21][C@H:20]3[N:23]([CH2:25][CH2:26][C@@:12]45[C@H:19]3[CH:18]=[CH:17][C@H:15]([OH:16])[C@@H:13]4[O:14][C:10]([C:11]=25)=[C:8]([OH:9])[CH:7]=1)[CH3:24].CCO>O>[CH3:24][N:23]1[C@@H:20]2[CH2:21][C:22]3=[CH:6][CH:7]=[C:8]([O:3][S:2]([OH:5])(=[O:1])=[O:4])[C:10]4[O:14][C@H:13]5[C:15]([CH2:17][CH2:18][C@@H:19]2[C@:12]5([C:11]=43)[CH2:26][CH2:25]1)=[O:16].[CH3:24][N:23]1[C@@H:20]2[CH2:21][C:22]3=[CH:6][CH:7]=[C:8]([OH:9])[C:10]4[O:14][C@H:13]5[C:15]([CH2:17][CH2:18][C@@H:19]2[C@:12]5([C:11]=43)[CH2:26][CH2:25]1)=[O:16]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Product: CN1CC[C@]23c4c5ccc(OS(=O)(=O)O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 10 °C

Procedure:
Additional trials were conducted in which the wt % of the catalyst was varied, the wt % of H2SO4 was varied, the presence of various co-catalysts were tested, and reaction times were varied. Table 1 lists the various reaction parameters. For each trial, a reaction flask was charged with morphine, EtOH, and water (the ratio of morphine to EtOH to water was 1 g:1.6-2 mL:0.8-1 mL). The reaction mixture was stirred and the flask was charge with catalyst (RuCl3.xH2O), acid (if applicable), and co-catalyst (if applicable). The reaction mixture was heated to reflux under nitrogen for the indicated period of time. The reaction was monitored by UHPLC. Upon completion of the reaction, the reaction flask was charged with anti-solvent, the pH of the mixture was adjusted, and the mixture was cooled to room temperature or 10° C. to precipitate the product. The mixture was filtered to give hydromorphone sulfate or hydromorphone base. The purity of the product was checked using orthogonal HPLC methods.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1.[Li+].[OH-]>C1COCC1.CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(CCc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CCc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2Br)cc1
Temperature: 45 °C

Procedure:
To a THF/MeOH/water solution (ca. 40 mL/40 mL/10 mL) of the intermediate from Step F (8.53 g, 17.84 mmol) was added LiOH (3.66 g, 89.2 mmol). The solution was stirred at 45° C. until no starting material remained by HPLC (ca. 2 hrs). The solution was concentrated to remove the majority of MeOH/THF and then partitioned between aqueous 1N HCl and ethyl acetate. The organic phase was washed with water (2×), brine and dried over Na2SO4. The solution was filtered and concentrated to give the title compound. The crude material was use in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH2:16]>>[NH2:16][C:15]1[CH:14]=[C:13]([O:12][CH3:11])[C:19]([O:20][CH3:21])=[CH:18][C:17]=1[C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])=[O:6]
Reactant: COc1ccc(N)cc1OC
Reactant: COc1ccccc1C=O
Product: COc1cc(N)c(C(=O)c2ccccc2OC)cc1OC

Procedure:
(2-amino-4,5-dimethoxyphenyl)-(2-methoxyphenyl)-methanone (Xaa) was prepared by reacting 2-methoxybenzaldehyde with 0.0196 moles of 3,4-dimethoxy aniline in a manner analogous to Example 1. MH+/Z=288.
Reaction SMILES: Br[C:2]1[C:3](=[O:48])[N:4]([CH3:47])[C:5](=[O:46])[C:6]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[NH:29][C:30]2[C:35]([C:36]=1[C:37]1[C:38](=[O:45])[N:39]([CH3:44])[C:40](=[O:43])[C:41]=1Br)=[CH:34][CH:33]=[CH:32][CH:31]=2.CN(C=O)C.[NH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CCN(CC)CC>[CH3:47][N:4]1[C:5](=[O:46])[C:6]2[C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[NH:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=4[C:36]=3[C:37]3[C:38](=[O:45])[N:39]([CH3:44])[C:40](=[O:43])[C:41]=3[N:57]3[CH2:58][CH2:59][N:54]([CH2:55][CH2:56]3)[C:2]=2[C:3]1=[O:48]
Reactant: CN1C(=O)C(Br)=C(c2c(CCCCCCCCCCCCc3[nH]c4ccccc4c3C3=C(Br)C(=O)N(C)C3=O)[nH]c3ccccc23)C1=O
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)C2=C(C1=O)N1CCN(CC1)C1=C(C(=O)N(C)C1=O)c1c([nH]c3ccccc13)CCCCCCCCCCCCc1[nH]c3ccccc3c12
Temperature: 80 °C
Reaction time: 48 h

Procedure:
0.75 mmol of 3-bromo-4-(2-(12-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)dodecyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione is dissolved in 200 ml of absol. DMF, treated with 0.5 ml of abs. NEt3 and heated to 80° C. The solution of 0.75 mmol of piperazine in 100 ml of absol. DMF and 0.5 ml of NEt3 is then slowly added dropwise to the warm solution and the mixture is then stirred at 80° C. for 48 h. The solvent is then removed in vacuo to the greatest possible extent and the residue is treated with 100 ml of 1N HCl. This solution is then extracted with ethyl acetate (in total about 600 ml), the combined extracts are dried over Na2SO4 and the solvent is stripped off in vacuo. Purification is carried out by column chromatography (SiO2, CH2Cl2/EA9.5:0.5) orange crystals, yield: 0.267 g (52%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:6][C@H:5]([O:7][C:8]2[C:9]3[C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:13]=2)[CH2:4]1.O.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C(OCC)(=O)C>[CH3:1][N:2]([C@H:3]1[CH2:6][C@H:5]([O:7][C:8]2[C:9]3[C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:13]=2)[CH2:4]1)[C:31](=[O:34])[CH:32]=[CH2:33]
Reactant: CN[C@H]1C[C@H](Oc2nc(Nc3cnn(C)c3)nc3[nH]cc(-c4cccnc4)c23)C1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(=O)N(C)[C@H]1C[C@H](Oc2nc(Nc3cnn(C)c3)nc3[nH]cc(-c4cccnc4)c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Crude 4-{[trans-3-(methylamino)cyclobutyl]oxy}-N-(1-methyl-1H-pyrazol-4-yl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (0.4 mmol) was partitioned between water (8 mL) and ethyl acetate (15 mL). Acryloyl chloride (36 μL, 0.44 mmol) was added and the mixture stirred at ambient temperature for 1 hr. The organic layer was separated, dried over Na2SO4 and evaporated to give a residue, which was purified by SFC (Zymor Spher Diol Monol, 150×21.2 mm, 5 μm column at 35° C. eluting with a 20%-50% EtOH gradient at 5%/min in CO2 at 140 bar with a flow rate of 60 mL/min) to give the title compound (7.4 mg, 4% yield). 1H NMR (700 MHz, DMSO-17 mm) δ ppm 11.64 (br. s., 1H) 8.87-9.00 (m, 2H) 8.43 (d, J=3.96 Hz, 1H) 8.12 (d, J=7.26 Hz, 1H) 7.87 (br. s., 1H) 7.52 (s, 1H) 7.42 (br. s., 1H) 7.33 (s, 1H) 6.59-6.80 (m, 1H) 5.95-6.15 (m, 1H) 5.65 (br. s., 2H) 5.47 (br. s., 1H) 3.74-3.88 (m, 3H) 3.07 (br. s., 1H) 2.91-3.00 (m, 1H) 2.72 (br. s., 2H) 2.29-2.46 (m, 2H). m/z (APCI+) for C23H24N8O2 445.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9](=[O:26])(=[O:25])[CH2:10][C:11]3[C:15]([C:16]([O-])=[O:17])=[N:14][N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N([OH:54])N=NC=2C=1>C(Cl)Cl>[N:27]1([C:16]([C:15]2[C:11]3[CH2:10][S:9](=[O:26])(=[O:25])[C:8]4[C:7](=[CH:6][CH:5]=[CH:4][C:3]=4[C:1]([NH2:2])=[O:54])[C:12]=3[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)=[O:17])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: N#Cc1cccc2c1S(=O)(=O)Cc1c(C(=O)[O-])nn(-c3ccccc3)c1-2
Reactant: C1COCCN1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: NC(=O)c1cccc2c1S(=O)(=O)Cc1c(C(=O)N3CCOCC3)nn(-c3ccccc3)c1-2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 6-cyano-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (50 mg, 0.135 mmol) in dry DCM (10 mL) are added morpholine (0.02 mL, 0.156 mmol) and TEA (0.03 mL, 0.196 mmol) after which reaction mixture is cooled to 0° C. EDC.HCl (38 mg, 0.196 mmol) and HOBt (2 mg, 0.013 mmol) are then added to the reaction mixture which is stirred at RT for 12 h under nitrogen. After this time, DCM is added and organic phase is washed with Na2CO3 sat, dried over Na2SO4 concentrated under reduced pressure and purified by silica gel column chromatography (3% MeOH in DCM) to afford the title compound as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.89 (s, 1H), 7.63-7.60 (m, 3H), 7.55-7.44 (m, 4H), 6.84-6.82 (d, J=7.8 Hz, 1H), 5.74 (s, 2H), 4.78 (s, 2H), 3.97 (m, 2H), 3.66-3.61 (m, 6H). MS (ESI+): 453.0. HPLC (max plot) 96.54%; Rt 3.98 min.
Reaction SMILES: S1C=CC=C1S([NH2:9])(=O)=O.[C:10]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[C:10]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]([S:16]([NH2:9])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NS(=O)(=O)c1cccs1
Product: NS(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
5.2.3 4-biphenylsulfonamide was prepared according to the procedure for thiophene-2-sulfonamide YG1-030 except using 4-biphenylsulfonyl chloride, which afforded the title compound 642.2 mg (90.6%) as a white solid, m.p.: 223-225° C.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2]([O:4]CC)=O.[O-:11][CH2:12]C.[Na+].CO[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>C(O)C>[CH3:12][O:11][C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:18](=[O:19])[CH2:17][C:2](=[O:4])[C:1]([OH:8])=[O:7]
Reactant: CC[O-]
Reactant: COCC(=O)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1C(=O)CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of diethyl oxalate (16 g, 110 mmol) and sodium ethoxide (100 mL, 21% by wt. in ethanol, 300 mmol) was added dropwise a solution of 2-methoxy acetophenone (15 g, 100 mmol) in ethanol (100 mL). The reaction mixture was allowed to stir at ambient temperature overnight. The resulting solution was concentrated to approximately 50 mL on a rotary evaporator, followed by partitioning between diethyl ether (100 mL) and water (250 mL). The aqueous layer was adjusted to pH=3 with conc. HCl to give a suspension with a fine white precipitate, which was heated at 100° C. for 5-10 minutes followed by cooling in an ice bath for 1 h. The precipitate was filtered, washed with water (20 mL), and dried overnight under high vacuum to give 4-(2-methoxyphenyl)-2,4-dioxobutanoic acid. 1H NMR (300 MHz, CDCl3) δ 7.96 (q, J=9.0, 3.0 Hz, 1H), 7.53 (t, J=6.0 Hz, 1H), 7.47 (s, 0.9H keto form), 7.24 (s, 1.1H enol form), 7.06 (t, J=6.0 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 3.97 (s, 3H). ESI-MS m/z 220.9 (M−H)−.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[F:4][C:5]1[CH:6]=[C:7](I)[C:8]([NH2:11])=[N:9][CH:10]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[F:4][C:5]1[CH:6]=[C:7]([C:1]#[C:2][CH3:3])[C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: Nc1ncc(F)cc1I
Reactant: C#CC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC#Cc1cc(F)cnc1N
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Propyne (15.4 g, 0.39 mol) was condensed into a pre-weighed flask cooled to ca. −40° C. containing THF (80 mL). The solution was added via cannula to a cooled (0-5° C.), degassed mixture of 5-fluoro-3-iodo-pyridin-2-ylamine (61.0 g, 0.26 mol), bis(triphenylphosphine)dichloropalladium(0) (9.0 g, 13.0 mmol), copper (I) iodide (2.95 g, 15.6 mmol) and triethylamine (77.7 g, 107 mL, 0.78 mol) in THF (650 mL). The mixture was stirred at 0-5° C. for 30 minutes then for a further 30 minutes at ambient temperature. The solid was removed by filtration and the cake washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (×3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate then extracted with diethyl ether (×3). The combined organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound as a brown solid (32.2 g, 84%). 1H NMR (400 MHz, CDCl3): 7.90 (s, 1H), 7.24 (dd, J=8.4, 2.8 Hz, 1H), 4.84 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:27](#[N:31])[CH2:28][C:29]#[N:30]>C(O)(=O)C>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](=[C:28]([C:27]#[N:31])[C:29]#[N:30])[CH3:25])=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCC#N
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Product: CC(=C(C#N)C#N)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
Hexamethyldisilazane (2.50 mL, 1.937 g, 12.0 mmol) was added to 1-(4-(benzyloxy)phenyl)ethanone (2.263 g, 10 mmol) in acetic acid (6 mL) at a rate to maintain the internal temperature below 74° C. After the addition was over, malononitrile (1.32 g, 20 mmol) in acetic acid (6 mL) was added to the solution. The reaction was heated at 90 C.° for 12 hours. After cooling, the reaction was poured into ice/water, extracted with EtOAc, dried, and concentrated under reduced pressure to give the crude product. The solid was triturated with 1:9 EtOAc/hexanes to provide 2.74 g of the desired product. 1H NMR (DMSO-d6): δ 7.72-7.75 (m, 2H), 7.35-7.49 (m, 5H), 7.18-7.21 (d, 2H), 5.22 (s, 2H), 2.61 (s, 3H). MS (ESI(+)): m/z 291 (M+NH4).
Reaction SMILES: [H-].[Na+].[S:3]([C:7]1[NH:8][CH:9]=[CH:10][N:11]=1)([CH3:6])(=[O:5])=[O:4].Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].O>CN(C)C=O.C(Cl)Cl>[S:3]([C:7]1[N:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][N:11]=1)([CH3:6])(=[O:5])=[O:4]
Reactant: CS(=O)(=O)c1ncc[nH]1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1ccnc1S(C)(=O)=O
Temperature: 20 °C
Yield: 88 %

Procedure:
Sodium hydride (50% suspension in mineral oil) (5.04 g.) is added, under a nitrogen atmosphere, to a solution of 2-mesyl-imidazole (15.3 g.) in dimethylformamide (130 cc.). Ethyl chloroacetate (12.9 g.) is then added. Reaction is allowed to take place for 20 hours, with stirring, at a temperature of about 20° C. The reaction mixture is then poured into water (4 liters) and extraction is effected using methylene chloride (1 liter). The methylene chloride extracts are washed with water, dried over sodium sulphate, treated with decolorising charcoal and then concentrated to dryness under reduced pressure (0.5 mm.Hg) to yield ethyl (2-mesyl-imidazol-1-yl)-acetate (21.4 g.) in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].CI.Cl>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Cl)cc(Cl)cc1Br
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Cl)cc(Cl)cc1Br
Temperature: 0 °C
Yield: 113.1 %

Procedure:
2-Bromo-4,6-dichlorophenol (Preparation 24, 4.6 g, 19 mmol), potassium carbonate (4.5 g, 32.3 mmol) and methyl iodide (1.8 ml, 20.5 mmol) were combined in 46 ml acetone and heated to reflux for 18 hours. The reaction was cooled to 0° C., 1N HCl (aqueous) was added to give pH 3, and the reaction was extracted into 50 ml ethyl acetate. The organic layer was washed with brine (2×20 ml), dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown solid (5.5 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Brc1ccccn1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ccccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 2-bromopyridine
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[O:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[O:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:3]=1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: Clc1cc(N2CC3CCC(C2)O3)nc(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3CC4CCC(C3)O4)n2)cc1
Temperature: 100 °C
Yield: 77.5 %

Procedure:
In a 0.5-2 mL microwave vial was placed 3-(6-chloro-2-iodopyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (16, 50 mg, 0.142 mmol) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (35.4 mg, 0.142 mmol) in DME (1.5 ml) to give an orange solution. Na2CO3 (2M solution in water) (0.284 ml, 0.569 mmol) was added. The mixture was degassed by bubbling nitrogen through the solution. Pd(PPh3)4 (16.43 mg, 0.014 mmol) was added and the mixture was heated under microwave irradiation for 60 min at 100° C. The mixture was diluted with ethyl acetate and washed with a saturated solution of NaHCO3. The organic phase was dried (MgSO4) and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (10-25%). Collected fractions were concentrated to give 39 mg (0.11 mmol, 79%) of the title compound as an off-white/yellow solid. The thus obtained compound was identical to the same compound prepared according to Scheme 5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:40](OC(=O)C)([F:42])[F:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:40]([F:42])[F:41])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: COC(=O)COc1ccc(F)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(F)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC(F)F)c12
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of [3-(4-chlorobenzyl)-8-fluoro-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.29 g), N,N-dimethylformamide (10 mL), potassium carbonate (0.62 g) and acetic acid chlorodifluoromethyl ester (0.31 mL) was stirred at 70° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (4:1 by volume) gave title compound, 0.18 g.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.S=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1>C(O)C>[CH3:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5][NH:6][C:17]1[CH2:21][S:20][C:19](=[O:22])[N:18]=1
Reactant: O=C1NC(=S)CS1
Reactant: CN(C)C(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
To a solution of N,N-dimethylglycinamide hydrochloride (5 g) and triethylamine (5.03 mL) in ethanol (20 mL) was added 4-thioxo-1,3-thiazolidin-2-one (4.81 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/THF) to give the title compound (4.68 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[S:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=1.C(N(C(C)C)CC)(C)C>>[NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[S:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CCC(N)CC2)nc1C
Yield: 87.6 %

Procedure:
The same operation as in Example (237a) was performed using 4-aminopiperidine (0.19 mL, 1.80 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (300 mg, 1.20 mmol) and diisopropylethylamine (0.42 mL, 2.40 mmol), to obtain 283 mg of the title compound as a pale yellow oily substance (88%).
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:21][CH:22]([CH3:24])[CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:25].CCOCC.O>CO.[OH-].[OH-].[Pd+2]>[ClH:25].[CH:22]([NH:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:17][NH:14][CH2:15]1)([CH3:24])[CH3:23]
Reactant: CC(C)NC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CC(C)NC1(C(N)=O)CNC1

Procedure:
To a solution of 1-benzhydryl-3-isopropylaminoazetidine-3-carboxylic acid amide (I-3A-1b; 2.28 g, 7.05 mmol) in methanol (100 ml) was added 1M HCl in ether (14.8 ml, 14.8 mmol) and then water (10 ml). After the addition of 20% Pd(OH)2 on carbon (60% water; 1.43 g), the mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature overnight. The mixture was filtered through a pad of Celite®, and then concentrated, in vacuo. The residue was then concentrated, in vacuo, from toluene (2×), acetonitrile (2×) and then methanol to give I-3A-1c (1.59 g, 98%) as a tan solid: +APcI MS (M+1) 158.1; 1H NMR (400 MHz, CD3OD) δ 4.71 (d, J=13.3 Hz, 2H), 4.60 (d, J=13.3 Hz, 2H), 3.49 (septuplet, J=6.6 Hz, 1H), 1.34 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:17])[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([CH3:4])[CH3:3].O[C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>>[CH3:4][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([O:17][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23])[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([CH3:1])[CH3:3]
Reactant: N#Cc1ccc(Cl)cc1O
Reactant: CC(C)(C)OC(=O)NCCCC(O)c1nccs1
Product: CC(C)(C)OC(=O)NCCCC(Oc1cc(Cl)ccc1C#N)c1nccs1

Procedure:
The subtitle compound was prepared according to the method of Example 19 step (b) using the product of step (c) above and 2-hydroxy-4-chlorobenzonitrile.