Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([CH:56]=[CH:57][CH:58]=2)[NH2:55])[CH:38]=[CH:37][N:36]=1.[N:60]1[CH:65]=[CH:64][CH:63]=[C:62]([S:66](Cl)(=[O:68])=[O:67])[CH:61]=1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([NH:55][S:66]([C:62]3[CH:61]=[N:60][CH:65]=[CH:64][CH:63]=3)(=[O:68])=[O:67])[CH:56]=[CH:57][CH:58]=2)[CH:38]=[CH:37][N:36]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cccnc1
Yield: 71.5 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14, using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (3 g, 7.7 mmol) and pyridine-3-sulfonyl chloride (1.49 g, 8.4 mmol) the title compound of Step A was obtained (2.9 g, 71.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.55-10.60 (br, 1H), 8.82-8.86 (m, 1H), 8.72-8.76 (m, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.07-8.13 (m, 1H), 7.51-7.52 (m, 1H), 7.39-7.47 (m, 1H), 7.27-7.40 (m, 2H), 6.47 (d, J=5.3 Hz, 1H), 3.47-3.57 (m, 4H), 3.67-3.75 (m, 4H). MS (ES+): 533 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=4[F:36])=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:37][CH3:38])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:36][C:28]1[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:27]=1[O:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[C:17]([O:37][CH3:38])[CH:18]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C)CC1
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
To a solution of 4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (305 mg, 0.58 mmol) in CH2Cl2 (1 mL) was added 0.4 mL of TFA. The reaction mixture was stirred for 1.5 h and the solvents were removed under reduced pressure. The crude product was treated with NaBH(OAc)3 (381 mg, 1.80 μmmol) and formaldehyde (0.5 mL, 37% in H2O). The stirring was continued for 12 h. The reaction was quenched with sat. aqueous NaHCO3. 15% NaOH was added until PH=14. The product was extracted with EtOAc. Removal of the solvent in vacuo gave the crude product, 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinoline, (240 mg, 93%), which was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([N+:12]([O-])=O)=[C:10]([OH:11])[C:5]=2[O:4][CH:3]=1.[C:15]1([CH2:21][CH:22](O)[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC1C(F)=CC=C(Cl)C=1[C@H](OC1C2OC=CC=2C=NC=1[N+]([O-])=O)C>[Fe].Cl>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:12])=[C:10]([O:11][CH:22]([CH3:23])[CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5]=2[O:4][CH:3]=1
Reactant: O=[N+]([O-])c1ncc2c(Br)coc2c1O
Reactant: CC(O)Cc1ccccc1
Agent: [Fe]
Agent: C[C@@H](Oc1c([N+](=O)[O-])ncc2ccoc12)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Product: CC(Cc1ccccc1)Oc1c(N)ncc2c(Br)coc12

Procedure:
3-Bromo-6-nitrofuro[3,2-c]pyridin-7-ol (Intermediate 10) was reacted with racemic 1-phenylpropan-2-ol following the procedure described for Intermediate 8. The resulting intermediate was reacted with iron/HCl as described in Example 2 to give the title compound. MS (ES+): m/z 347.22/349.23 (100/99) [MH+]. HPLC: tR=0.81 min (HPLC-ACQUITY, Analytical). 1H NMR (400 MHz, CD3OD): δ=1.32 (d, J=6.1 Hz, 3H), 2.93 (dd, J=13.5, 6.2 Hz, 1H), 3.10 (dd, J=13.6, 6.6 Hz, 1H), 4.98 (m, 1H), 7.13-7.21 (m, 1H), 7.25 (d, J=4.3 Hz, 4H), 7.70 (s, 1H), 7.82 (s, 1H).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OC([O:23][CH:24]1[CH2:36][CH2:35][C:34]([O:38]C(OCC)C)([CH3:37])[CH:33]([O:44][C:45](=[O:53])[CH2:46][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH:32]=[CH:31][CH:30]([CH3:54])[CH:29](/[C:55](/[CH3:76])=[CH:56]/[CH:57]=[CH:58]/[CH:59]([CH3:75])[CH2:60][CH:61]2[O:74][CH:62]2[CH:63]([CH3:73])[CH:64]([O:67]C(OCC)C)[CH2:65][CH3:66])[O:28][C:26](=[O:27])[CH2:25]1)C)C>CO>[OH:23][CH:24]1[CH2:36][CH2:35][C:34]([OH:38])([CH3:37])[CH:33]([O:44][C:45](=[O:53])[CH2:46][N:47]2[CH2:48][CH2:49][O:50][CH2:51][CH2:52]2)[CH:32]=[CH:31][CH:30]([CH3:54])[CH:29](/[C:55](/[CH3:76])=[CH:56]/[CH:57]=[CH:58]/[CH:59]([CH3:75])[CH2:60][CH:61]2[O:74][CH:62]2[CH:63]([CH3:73])[CH:64]([OH:67])[CH2:65][CH3:66])[O:28][C:26](=[O:27])[CH2:25]1
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CN2CCOCC2)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)CN2CCOCC2)/C=C/C1C
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)CN2CCOCC2)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)CN2CCOCC2)C=CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridinium p-toluenesulfonate (2.2 mg, 8.71 μmol) was added to a solution of (8E,12E,14E)-3,6,21-tri(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(morpholin-4-yl)acetoxy-18,19-epoxytricosa-8,12,14-trien-11-olide (7.3 mg, 8.71 μmol) in methanol (1 mL), followed by stirring at room temperature overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate, water and a saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous magnesium sulfate, filtered and then evaporated. The resulting residue was purified by thin layer chromatography (MERCK Silica gel 60 F254, 0.2 mm, developing solution; methanol-dichloromethane=1:19) to obtain the title compound (4.4 mg, 82%) as a colorless oil.
Reaction SMILES: [ClH:1].[CH:2]1([O:7][N:8]=[C:9]([C:32]2[N:33]=[C:34]([NH:37]C=O)[S:35][CH:36]=2)[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3]1>CO>[ClH:1].[CH:2]1([O:7][N:8]=[C:9]([C:32]2[N:33]=[C:34]([NH2:37])[S:35][CH:36]=2)[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=CNc1nc(C(=NOC2CCCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: Cl
Solvent: CO
Product: Nc1nc(C(=NOC2CCCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
Conc. hydrochloric acid (1.8 g) was added to a solution of 7-[2-cyclopentyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.7 g) in methanol (27 ml) and the mixture was stirred for 2 hours at ambient temperature. An insoluble material was filtered off and the filtrate was concentrated to dryness under reduced pressure and the residue was triturated with diethyl ether and dried to give 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (2.9 g). The powder (2.9 g) was dissolved in an aqueous solution of sodium hydroxide to adjust pH 7.5. The solution was adjusted to pH 3.0 and precipitates were collected by filtration and washed with water to give 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.95 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[C:15]([NH2:29])=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)=[N:12][N:11]=[N:10]1.Br[C:31]1[S:46][C:34]2[CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38][C:33]=2[CH:32]=1.C([O-])(O)=O.[Na+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:29][C:15]1[N:16]=[CH:17][C:18]([C:31]2[S:46][C:34]3[CH2:35][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:37][CH2:38][C:33]=3[CH:32]=2)=[CH:19][C:14]=1[C:13]1[N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:10]=[N:11][N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)sc2C1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nnnn3-c3cccc(F)c3F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3cnc(N)c(-c4nnnn4-c4cccc(F)c4F)c3)sc2C1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (250 mg, 0.63 mmol), tert-butyl 2-bromo-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (198 mg, 0.63 mmol), and NaHCO3 (1.56 mL, saturated solution in H2O) in N,N-dimethylformamide (8.3 mL) was degassed with a nitrogen stream for 20 min. To this mixture was added [1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) dichloride (46 mg, 0.06 mmol) and the reaction was stirred in a microwave for 10 min at 120° C. The resulting crude mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate washed with H2O (2×15 mL) and brine (1×15 mL), concentrated under reduced pressure, and purified via silica gel chromatography to provide tert-butyl 2-(6-amino-5-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate. This material (137 mg, 0.27 mmol) was treated with HCl (4 mL, 4.0 N in dioxane) for 1 hr, and solvent was removed under reduced pressure. The residue was dissolved in MeOH (500 mL) and treated with cold diethyl ether (15 mL). The resulting precipitate was collected and dried in vacuo to provide the hydrochloride salt of 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)pyridin-2-amine as a bright yellow solid (103 mg, 37% yield over two steps); 1H NMR (DMSO-d6): 9.50 (s, 2H), 8.44 (d, J=2.4 Hz, 1H), 7.85-7.46 (m, 4H), 7.05 (s, 1H), 4.29 (s, 2H), 3.39-3.25 (m, 2H), 2.85-2.81 (m, 2H); ES-MS: m/e=412.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[F:14][C:15]([F:30])([F:29])[C:16]1[CH:17]=[C:18]([N:26]=[C:27]=[O:28])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1>C(OCC)(=O)C>[F:14][C:15]([F:29])([F:30])[C:16]1[CH:17]=[C:18]([NH:26][C:27]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=3)[N:6]=2)=[O:28])[CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Nc1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To a stirred solution of 2-amino-4-(4-chlorophenyl)thiazole (0.647 g, 3.07 mmol) in ethyl acetate (50 mL) was added 3,5-bis(trifluoromethyl)phenyl isocyanate (0.53 mL, 3.1 mmol). The mixture was refluxed for 16 hours, cooled to room temperature, and washed with 10% aqueous hydrochloric acid solution, water and brine. The mixture was dried (magnesium sulfate), filtered, and concentrated to provide a white solid. Flash chromatography over silica (hexanes/ethyl acetate) provided 0.850 g (59%) of the product as a white solid: 1H NMR (NMR (DMSO-d6) δ9.62 (br s, 1H), 8.18-8.17 (m, 2H), 7.92-7.88 (m, 2H), 7.72-7.66 (m, 2H), 7.49-7.46 (m, 2H) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C@@H:13]([CH2:21][CH3:22])[CH2:14][C@H:15]1[CH2:19][O:18][C:17]([NH2:20])=[N:16]1)C1C=CC=CC=1>CO.[Pd]>[NH2:20][C:17]1[O:18][CH2:19][C@H:15]([CH2:14][C@@H:13]([O:12][C:11]2[CH:10]=[C:9]([OH:8])[CH:25]=[CH:24][CH:23]=2)[CH2:21][CH3:22])[N:16]=1
Reactant: CC[C@@H](C[C@H]1COC(N)=N1)Oc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CC[C@@H](C[C@H]1COC(N)=N1)Oc1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-4-[(S)-2-(3-benzyloxy-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine (60 mg) in methanol (3 ml) at room temperature was added 10% palladium on charcoal (19 mg). The mixture was stirred under an atmosphere of hydrogen (1 atm) at room temperature for 1 h. The catalyst was removed by filtration through decalite, washing with methanol and with dichloromethane, and the filtrate was concentrated in vacuo to yield 3-[(S)-1-((S)-2-amino-4,5-dihydro-oxazol-4-ylmethyl)-propoxy]-phenol as a white solid (44 mg, quant.); MS (ISP): 251.2 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:17]([C:13]1[S:14][CH:15]=[CH:16][C:12]=1[CH3:11])=[O:18]
Reactant: Nc1nc2ccccc2s1
Reactant: Cc1ccsc1C(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccsc1C(=O)Nc1nc2ccccc2s1

Procedure:
Using 2-amino-benzothiazole and 3-methyl-thiophene-2-carboxylic acid chloride in pyridine the title compound was obtained as a yellow solid (69% yield), MS: m/e=275.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O1CCOCC1.O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N(c2ccc([N+](=O)[O-])cc2)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: NN
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: Nc1ccc(N(c2ccc(N)cc2)c2ccc(N)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a 300-mL, 3-necked flask equipped with a reflux tube were added 1.52 g (4.00 mmol) of tri(4-nitrophenyl)amine and 5% Pd/C (200 mg), and the inside was replaced with argon. Dioxane (50 mL) and ethanol (25 mL) were added thereto, and the resulting mixture was stirred at a temperature of 80° C., and hydrazine monohydrate (8.0 mL) was added dropwise thereto over 3 hours and further stirred at 80° C. for 20 hours. The catalyst was separated by filtration, and then the reaction mixture was added to ice water (400 mL). The obtained gray solid was obtained by filtration, washed with water and then vacuum-dried, whereby a desired product was obtained (Quantity: 1.02 g, 3.51 mmol, Yield: 88%).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: O=C(O)c1ccncc1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccncc3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and isonicotinic acid, the title compound was prepared. MS: m/e=386(M+H+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12]
Reactant: O=Cc1c(Br)ccc2c1OCO2
Reactant: OB(O)c1ccccc1Cl
Product: O=Cc1c(-c2ccccc2Cl)ccc2c1OCO2

Procedure:
The process described in Method B was followed. 5-Bromo-1,3-benzodioxole-4-carbaldehyde (0.458 g, 2.00 mmol) and 2-chlorophenylboronic acid (0.469 g, 3.00 mmol) were used to obtain the title compound. The crude product was purified by column chromatography with a mixture of hexane:ethyl acetate (4:1) as the eluent.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25]([N:30]([CH3:31])[CH3:29])=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: CNC
Product: CN(C)c1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Example 141, from 42 mg (0.092 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one and 1 mL 2 M dimethylamine solution. Yield: 17 mg of a yellow powder. LC-MSD, m/z for C23H19BrN4O2 [M+H]+=463.0, 465.0; HPLC retention time: 0.6 min.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][SH:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:20].[K+]>C(O)C>[NH:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][S:18][CH2:17][CH2:16][C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[O:20])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: O=C(CCS)Nc1ccc(Nc2ccccc2)cc1
Agent: [K+]
Solvent: CCO
Product: O=C(CCSCCC(=O)Nc1ccc(Nc2ccccc2)cc1)Nc1ccc(Nc2ccccc2)cc1
Reaction time: 2 h

Procedure:
To a suspension of 20.4 grams of N-4(anilinophenyl)acrylamide in 200 milliliters of ethanol was added 23.3 grams of N-(4-anilinophenyl)-3-mercaptopropionamide. A solution of one gram of potassium hydroxide in 10 milliliters of ethanol was added at 17.5°C. Within a few minutes the temperature began to rise, reaching a maximum of 28°C. Simultaneous with the increase in temperature, product began to precipitate. The reaction mixture was stirred for 2 hours. The solid product was filtered off and allowed to dry. There was obtained 41 grams (94 percent of theory) of product which melted at 199°-203°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[Cl:8].CCOCC>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCCCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 141.8 %

Procedure:
To a solution of Intermediate 1A (8.0 g, 36.7 mmol) in THF (35 mL) was added LAH (40.4 mL, 2 M in THF, 81 mmol) dropwise for 40 min at 0° C. under Ar. The colorless solution turned yellowish brown, and a precipitate formed after stirring at rt for 30 min. The suspension was stirred at rt for 6 h. The reaction mixture was cooled to 0° C. and quenched by careful addition of H2O (3 mL), 15% NaOH (3 mL) and then H2O (9 mL). Et2O (ca. 100 mL) was added. The mixture was stirred at rt for 20 min then filtered through Celite® and rinsed with Et2O (ca. 150 mL). The filtrate was concentrated. The residue was dissolved in Et2O (100 mL) and CH2Cl2 (10 mL), dried over Na2SO4, filtered and concentrated to give a light tan oil after drying under vacuum. 3-(3,4-Dichlorophenyl)propan-1-amine was taken to the next step without further purification. LC-MS: 203.9 (M+H), RT=2.76 min (Method A). TEA (8.36 mL, 60.0 mmol) was added to 3-(3,4-dichlorophenyl)propan-1-amine (6.8 g, 33.3 mmol) in THF (100 mL) followed by the addition of di-tert-butyl dicarbonate (8.22 g, 37.6 mmol) and the reaction mixture was stirred at rt overnight. The solvent was removed under vacuum and Et2O was added. The organic solution was washed with H2O and then brine. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography using Hexanes/EtOAc to give the product tert-butyl 3-(3,4-dichlorophenyl)propylcarbamate (6.9 g, 23 mmol, 68% yield) as a colorless oil. LC-MS (ESI) 248.0 (M−tBu+H), RT=3.85 min (Method A). tert-Butyl 3-(3,4-dichlorophenyl)propylcarbamate (3.48 g, 11.44 mmol) was stirred in 4N HCl in dioxane (20 mL) at rt for 2 h. The volume of the mixture was reduced under reduced pressure, and Et2O was added. The reaction mixture was stirred at rt for 30 min. The resulting precipitate was filtered and rinsed with Et2O to give Intermediate 1 (1.95 g, 8.11 mmol, 70.9% yield). LCMS=203.9 [M+1], RT=1.51 min (Method B).
Reaction SMILES: C([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])C1C=CC=CC=1.C[N:20](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([NH2:20])=[O:11])=[CH:8][CH:16]=1
Reactant: COc1ccc(C(=O)O)c(Cc2ccccc2)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-benzyl-4-methoxybenzoic acid (14.2 g) in 600 mL CH2Cl2 was added a catalytic amount of DMF, followed by a solution of oxalyl chloride (8.7 g) in 100 mL of CH2Cl2. The reaction was stirred at room temp overnight, then concentrated and azeotroped with toluene (2×). The residue was dissolved in 700 mL CH2Cl2 and cooled to 0 C. Tert-butyl amine (13.9 g) was added, and the reaction was warmed to room temp. After 1.5 h, the reaction was quenched with 5% aqueous KHSO4. The organic solution was separated, washed once with saturated aqueous sodium bicarbonate, dried (Na2SO4) and concentrated to give 15.9 g of 2-benzyl-N-tert-butyl)-4-methoxybenzamide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.[CH2:28]([Sn:32](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C(OCC)C>[CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][C:12]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc(COCn2ncnn2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(COCc2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
In a flame-dried three-neck flask, a solution of 2-(benzyloxymethyl)-2H-tetrazole (2.01 g, 10.57 mmol) and tetramethylethylenediamine (3.16 mL, 21.4 mmol) in diethyl ether (30 mL) was cooled to −78° C. and then treated with the dropwise addition of n-butyllithium (1.6 M in hexanes, 7.3 mL, 11.62 mmol), causing the color of the solution to turn dark red. Upon completion of addition, the mixture was stirred for 10 minutes, then transferred via cannula to a solution of tributyltin chloride (2.9 mL, 10.57 mmol) in diethyl ether (20 mL) which had been pre-cooled to −78° C. The resulting reaction was stirred for 45 min, then quenched with a saturated ammonium chloride solution. The reaction mixture was allowed to come to room temperature, and the layers were separated. The aqueous phase was extracted 3× with ethyl acetate, and the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield a residue. The residue was purified over silica gel, eluting with 1% then 5% then 10% ethyl acetate/hexanes to yield the title compound (3.0 g, 60% yield) as a colorless oil.