Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:38])[O:13][C:14]([OH:37])([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:15]=2[CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:15]([CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[C:14]([O:37][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[O:13][C:12]2=[O:38])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1ccc(C2(O)OC(=O)C(c3cc(OC)cc(OC)c3)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reactant: CN(C)CCO
Solvent: ClCCl
Product: COc1ccc(C2(OCCN(C)C)OC(=O)C(c3cc(OC)cc(OC)c3)C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 125 mL dichloromethane was added 3-(3,5-Dimethoxy-phenyl)-5-hydroxy-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 5.0 g (9.57 mmol), giving a suspension. N,N-dimethylethanol-amine 2.66 g (29.8 mmol) was added, and the mixture was purged with anhydrous HCl gas until saturated. After an hour at room temperature, additional N,N-dimethyl-ethanolamine 1.33 g (14.9 mmol) was added, followed by stirring for 24 hours at room temperature. An additional N,N-dimethylethanolamine 2.66 g (29.8 mmol) was then added, followed by stirring for 24 hours at room temperature. The mixture was evaporated in vacuo, and the residue was suspended in ethyl ether. The ether suspension was washed exhaustively with 4 N NaOH, followed by water and saturated sodium chloride solution. The ether phase was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to a crude foam, 2.8 g. The crude material was purified by chromatography on 200 g silica gel eluted with 5% methanol in chloroform. The appropriate fractions were evaporated to a glassy solid, 2.31 g. The product was identified by 1H NMR, MS [M--H]+ =594.4 Da.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[N:15]1([C:21]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CO>[ClH:1].[ClH:1].[O:18]1[CH2:19][CH2:20][N:15]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:22])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCOCC2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCOCC1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 99 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(morpholine-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (20.0 mg, 0.038 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 14.5 mg (99%) of the desired product. LC-MS: RT=1.49 min, [M+H]+=307.1.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][NH2:10]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([NH:9][NH2:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: Clc1ncccc1Br
Solvent: c1ccncc1
Product: NNc1ncccc1Br
Temperature: 60 °C
Reaction time: 24 h
Yield: 60.6 %

Procedure:
To a stirring solution of 3-bromo-2-chloropyridine (8.56 g, 45 mmol) in pyridine (40 mL) was added anhydrous hydrazine (4.0 g, 125 mmol). The resulting mixture was stirred at 60° C. for 24 h. Analysis by HPLC indicated that about 50% of starting material was consumed. Additional hydrazine (4.0 g, 125 mmol) was added and the reaction mixture was stirred at 80° C. for another 16 h (total 40 h). After cooling to room temperature, the resulting white suspension was filtered. The collected solid was washed with water (2×50 mL), and dried in a 50° C. vacuum oven for 16 h to afford 5.13 g (61%) of the title compound as a white solid. HPLC/MS (Method C): retention time=0.38 min, [M+H]+=188.0.
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[NH2:22][CH:23]([CH:39]([CH3:41])[CH3:40])[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25]>C(Cl)Cl.CO>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:29]2[CH2:28][CH2:27][N:26]([C:24](=[O:25])[CH:23]([NH:22][S:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:10])=[O:9])[CH:39]([CH3:41])[CH3:40])[CH2:31][CH2:30]2)=[CH:33][CH:34]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)C(N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(NS(=O)(=O)Cc1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction tube was charged with benzylsulfonyl chloride (14 mg), DIEA (50 μL) and 2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (20 mg) in DCM (0.3 mL). The reaction mixture was shaken overnight at rt. At the conclusion of this period, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 200. MS found: (M+H)+=450.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([C:6]([NH2:9])([CH3:8])[CH3:7])[CH2:2]1.[CH:10]1([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](F)[C:21]=3[O:23][CH3:24])[C:16](=[O:26])[C:15]3[C:27]([OH:32])=[C:28]([C:30]#[N:31])[S:29][C:14]2=3)[CH2:12][CH2:11]1.OC1C2C(=O)C3C(=C(OC)C=CC=3)NC=2SC=1C#N>>[NH2:9][C:6]([C@@H:3]1[CH2:4][CH2:5][N:1]([C:20]2[C:21]([O:23][CH3:24])=[C:22]3[C:17]([C:16](=[O:26])[C:15]4[C:27]([OH:32])=[C:28]([C:30]#[N:31])[S:29][C:14]=4[N:13]3[CH:10]3[CH2:11][CH2:12]3)=[CH:18][CH:19]=2)[CH2:2]1)([CH3:8])[CH3:7]
Reactant: COc1c(F)ccc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12
Reactant: CC(C)(N)[C@@H]1CCNC1
Agent: COc1cccc2c(=O)c3c(O)c(C#N)sc3[nH]c12
Product: COc1c(N2CC[C@@H](C(C)(C)N)C2)ccc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12

Procedure:
The title compound is prepared from (R)-2-(pyrrolidin-3-yl)propan-2-amine (Fedji, et al., 1994) and 9-cyclopropyl-7-fluoro-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carbonitrile using the method described above for the preparation of 9-cyclopropyl-6-fluoro-7-((R)-3-(S)-1-(2-fluoroethylamino)ethyl)pyrrolidin-1-yl)-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carbonitrile.
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1.Cl.[CH2:26]([OH:30])[CH2:27]CC>CO>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21][O:22][CH2:27][CH2:26][OH:30])=[CH:19][CH:18]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Reactant: Nc1ccc(CO)cc1
Reactant: CCCCO
Agent: Cl
Solvent: CO
Product: OCCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 19 %

Procedure:
4-Anilino-5-bromo-2-chloropyrimidine (Method 1, 2.0 g, 7.03 mmol) was dissolved in n-butanol (40 ml) and methanol (10 ml). 4-Aminobenzyl alcohol (778 mg, 6.33 mmol) and ethereal hydrogen chloride (1.0M; 6.33 ml, 6.33 mmol) were added and the solution was heated at 100° C. for 20 hours. Volatile material was removed by evaporation and the residue as dissolved in ethylene glycol (20 ml). The solution was heated at 100° C. for 6 hours and volatile material was removed by evaporation. The residue was purified by column chromatography, eluting with 0-4% methanol solution in DCM containing 0.5% aqueous ammonia solution, to give the product as a white solid (550 mg, 19%). NMR: 3.40 (t, 2H), 3.50 (dt, 2H), 4.37 (s, 2H), 4.57 (t, 1H), 7.09 (d, 2H), 7.10 (s, 1H), 7.15 (t, 1H), 7.36 (dd, 2H), 7.54 (d, 2H), 7.60 (d, 2H), 8.09 (s, 1H), 8.54 (s, 1H), 9.29 (s, 1H); MS (MH+): 415.2, 417.2.
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][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][NH:19]2)=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1.N1C=CC=CC=1>[F:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][N:19]2[S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc2c(c1)NCC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2CCc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
4-Toluenesulfonyl chloride (460 mg, 2.4 mmol) was slowly added to a solution of 6-fluoro-2,3-dihydro-1H-indole (220 mg, 1.6 mmol) in THF (6 mL) and pyridine (260 μL). The reaction mixture was stirred at room temperature overnight. Upon the completion of the reaction, the mixture was cooled to 0° C., neutralized with aq. sat. NH4Cl (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3×10 mL), brine (10 mL) and dried (MgSO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc/hexanes=1/3) gave 283 mg (0.98 mmol) of the title product. Yield: 61%, colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.67 (d, J=8.2 Hz, 2H), 7.35 (dd, J=10.0, 2.3 Hz, 1H), 7.23 (d, J=8.2 Hz, 2H), 6.97 (m, 1H), 6.62 (m, 1H), 3.90 (t, J=8.4 Hz, 2H), 2.84 (t, J=8.4 Hz, 2H), 2.35 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 162.5 (d, J=241.4 Hz), 144.5, 143.3 (d, J=11.7 Hz), 133.6, 129.8, 127.2, 127.0 (d, J=2.6 Hz), 125.7 (d, J=9.8 Hz), 110.0 (d, J=22.6 Hz), 102.8 (d, J=28.4 Hz), 50.7, 27.1, 21.5 ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)([O-:3])=[O:2].[S:19]([O:24]C)([O:22][CH3:23])(=[O:21])=[O:20]>C(OCC)(=O)C>[CH3:23][O:22][S:19]([O-:24])(=[O:21])=[O:20].[CH3:23][N+:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][O:6][C:5]1[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1OCCc1ccccn1
Reactant: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: COS(=O)(=O)[O-]
Product: C[n+]1ccccc1CCOc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.88 g (20 mmol) of the compound from Step 3.1 was dissolved with agitation in 60 mL of ethyl acetate and to the solution was added 2.78 g (20 mmol) of dimethyl sulfate. A colorless precipitate formed gradually. The mixture was allowed to agitate for an additional 4 hours at room temperature after which it was filtered, and the filter cake was washed with a small amount of ethyl acetate and then dried at 40° C. under vacuum.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15]([SH:17])[CH3:16].[OH-].[K+]>C(O)C.C(OCC)(=O)C>[CH2:15]([S:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH3:16]
Reactant: CCS
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCSCCCCCCCCCCC(=O)O
Yield: 8.2 %

Procedure:
11-Bromoundecanoic acid (1 g, 3.77 mmol, Aldrich) was added to a solution of ethanethiol (0.279 mL, 3.77 mmol, Aldrich) and potassium hydroxide (0.486 g, 8.66 mmol) in absolute ethanol (40 mL) and refluxed for 5 hr under a nitrogen atmosphere. After cooling and acidification with HC1, solvent was removed under reduced pressure to give a white solid. The solid was dissolved in ethyl acetate and extracted with water. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by silica column chromatography using increasing concentrations of ethyl acetate in hexane for elution. The product eluted at 25% ethyl acetate/hexane. Solvent was removed under reduced pressure to yield 11-(ethylthio)-undecanoic acid (76 mg, 8%), mp 58-61° C.; 1H NMR (300 MHz, CDC13) δ 1.24 (t, 3H, J=7.4, CH3), 1.20-1.40 (bm, 12 H, methylene envelope), 1.48-1.67 (bm, 4H, S-CH2 -CH2COO-CH2 -CH2), 2.33 (t, 2H, J=7.5, CH2 -COOH), 2.49 (t, 2H, J=7.4, S-CH2 -CH2), 2.51 (q, 2H, J=7.4, S-CH2 -CH2), 10.5 (br, 1H, COOH); 13C NMR (75.4 MHz, CDC13) δ 14.88, 24.70, 25.98, 28.97, 29.08, 29.24*, 29.38, 29.48, 29.69, 31.73, 34.11, 180.05; MS, m/z 246 (M+, 50), 217 (COOH(CH2)10S+, 7), 199 (100), 181 (7), 167 (7), 149 (6), 117 (7), 101 (9), 97 (9), 87 (14), 83 (18), 75 (54), 69 (29), 62 (18), 55 (37).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[N:3]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[N:3]=[C:4]([CH2:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1CS(=O)(=O)c1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)nc1CS(=O)(=O)c1ccccc1
Yield: 96 %

Procedure:
A stirred mixture of 2-chloro-5-nitro-6-[(phenylsulfonyl)methyl]pyridine (1.41 g, 4.50 mmol), 1-benzylpiperazine (0.873 g, 4.95 mmol), and K2CO3 (0.683 g, 4.95 mmol) in ethanol is heated at reflux temperature for 1.5 h, cooled, diluted with water and extracted with CH2Cl2. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, EtOAc as eluent) to afford the title compound as an orange-yellow solid, 1.96 g (96% yield), mp 175-176° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=4)[N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.[OH-].[Na+].Cl>C1COCC1.O>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=4)[N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CNc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CNc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2)cc1
Temperature: 40 °C

Procedure:
To a solution of 20 (1.9 g, 4.2 mmol) in a mixture of THF (8 mL), MeOH (8 mL) and water (4 mL) was added NaOH (373 mg, 9.3 mmol). The mixture was heated at 40° C. for 16 h, then acidified to pH 6 by adding 1N HCl, concentrated, and dried under high vacuum to afford the title compound 21, which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][Se:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:2]=1.C(N(CC)CC)C.[NH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C.[Cl:33]CCl>O>[ClH:33].[ClH:33].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][Se:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[O:13])[CH:2]=1
Reactant: Nc1ccncc1
Reactant: ClCCl
Reactant: O=C(O)c1ccccc1[Se]Cc1cccnc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cl
Product: O=C(Nc1ccncc1)c1ccccc1[Se]Cc1cccnc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4 g (0.0132 mol) 2-(3-picolylseleno)benzoic acid (from Example 2) and 4.4 ml triethylamine in 40 ml dichloromethane, that has been cooled to 0° C., is added in one portion 3.5 g (0.0132 mol) bis(2-oxo-3-oxazolidinyl)-phoshoryl chloride. After 15 minutes 1.3 g (0.0138 mol) 4-aminopyridine is added and the mixture stirred at 0° C. for 3.5 hours. It is then extracted twice with 100 ml portions of water, the organic phase dried over sodium sulfate and the solvent removed. The residue is taken up in 60 ml 2-propanol and treated with 10 ml 15% HCl in 2-propanol. The solid product that results is dissolved in 50 ml H2O and treated with 1 g active charcoal, stirred at room temperature for 15 minutes and then filtered. Acetone is added dropwise to the filtrate until the solution remains turbid. The crystals that are formed are filtered off after 2 hours and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.Cl.[NH2:17][OH:18]>>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[N:17][OH:18])[CH2:7][CH2:6]1
Reactant: O=C1CCN(Cc2ccccc2Cl)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(Cc2ccccc2Cl)CC1

Procedure:
1-(2-Chlorobenzyl)-4-piperidone oxime is prepared from 1-(2-chlorobenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl.Cl[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.[OH-].[K+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccccc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccccc1OCc1ccc2ccccc2n1
Temperature: 8 °C
Yield: 52.5 %

Procedure:
To a solution of 2-fluorophenol (7.8 g, 70 mmol) in 20 mL ethanol is added 2-(chloromethyl)quinoline hydrochloride (15.0 g, 70 mmol) followed by a solution of potassium hydroxide (7.86 g, 140 mmol) in 50 mL ethanol. The reaction mixture is refluxed overnight. After filtering while still hot, the reaction mixture is cooled to 8° C. to afford 9.3 g (53%) of brown crystals, m.p. 84°-86° C.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[C:18]([F:29])[C:14]3[N:15]=[N:16][S:17][C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[N+]1([O-])CC[O:34]CC1.[OH2:38]>C1COCC1.[Os](=O)(=O)(=O)=O>[OH:38][CH:2]([CH2:3][OH:34])[CH2:1][C:4]1([S:7]([NH:10][C:11]2[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[C:18]([F:29])[C:14]3[N:15]=[N:16][S:17][C:13]=3[CH:12]=2)(=[O:8])=[O:9])[CH2:5][CH2:6]1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCC1(S(=O)(=O)Nc2cc3snnc3c(F)c2Nc2ccc(I)cc2F)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc2snnc2c(F)c1Nc1ccc(I)cc1F)C1(CC(O)CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of 1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide (50 mg, 0.09 mmol) in THF (5 mL) was added N-methylmorpholine-N-oxide (12 mg, 0.09 mmol) followed by osmium tetraoxide (5 mg, 0.02 mmol) and water (0.5 mL). The resultant was stirred at room temperature overnight. The mixture was concentrated and then diluted with ethyl acetate. The organic layer was washed with water, saturated NaHCO3 (aq.) and brine sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel to give the product as white solid (30 mg, 56.5% yield). 1H NMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 7.67-7.64 (d, 2H), 7.32 (m, 1H), 7.03 (s, 1H), 6.85 (s, 1H), 4.40-4.26 (m, 2H), 4.20-4.10 (m, 1H), 3.75-3.60 (m, 1H), 3.60-3.50 (m, 1H), 2.62-2.50 (m, 2H), 0.92-0.82 (m, 4H). MS APCI (+) m/z: 583.5, [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)=[C:2]([CH:9]=1)[NH2:1]
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1cc(Cl)ccc1-c1nnn[nH]1
Temperature: 100 °C
Yield: 85 %

Procedure:
2-Amino-4-chlorobenzonitrile (1000 mg, 6.6 mmol), sodium azide (555 mg, 8.5 mmol) and triethylamine hydrochloride (1175 mg, 8.5 mmol) were taken up in 15 mL of toluene. The suspension was heated to 100° C. overnight. After cooling, the reaction mixture was washed 3 times with 5 mL portions of water. The combined aqueous fractions were acidified with concentrated hydrochloric acid. The desired 5-Chloro-2-(1H-tetrazol-5-yl)aniline precipitated from aqueous solution and was isolated by filtration (1090 mg, 85% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.73 (d, 1H), 6.97 (d, 1H), 6.74 (dd, 1H); MS (electrospray) m/z 196 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=2)[C:22]([CH3:33])([CH3:32])[CH2:21][C:20]1=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[OH-].[Na+].CO>[CH2:13]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29](=[O:31])[CH:30]=[CH:1][C:3]3[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:26][CH:27]=2)[C:22]([CH3:33])([CH3:32])[CH2:21][C:20]1=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCN1C(=O)CC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.3 %

Procedure:
Methyl 4-formylbenzoate (22 mg, 13.4 mmol) was added to a solution of N-hexyl-6-acetyl 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (Intermediate 6a, 40 mg, 13.3 mmol) in 2 mL of 1 N NaOH and 4 mL of methanol. After stirring at room temperature for 18 h, the reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chormatography (50:49:1 hexane/ethyl acetate/acetic acid) gave the title compound as a light yellow solid (18.9 mg, 33% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]1)=[O:22].[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[C:37]2[CH:36]=[CH:35][N:34]=[C:33]([Cl:32])[CH:38]=2)=[CH:4][C:3]=1[C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]1)=[O:22]
Reactant: CC(C)N1CCN(C(=O)c2cc3cc(C(=O)N4CCC(F)(F)CC4)[nH]c3cc2Cl)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2cc3cc(C(=O)N4CCC(F)(F)CC4)n(-c4ccnc(Cl)c4)c3cc2Cl)CC1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 66, from [6-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 227), 2-chloropyridine-4-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (19%).