Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][NH:12]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ncc(OC[C@@H]2CCN2)cc1Br
Reaction time: 0.5 h

Procedure:
To 5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 66a (360 mg, 0.95 mmol) was added TFA in CH2Cl2 at 0° C., and the mixture was stirred for 30 minutes. The volatiles were then removed under vacuum. The residue was neutralized with NaHCO3 to pH 8, then extracted with CH2Cl2, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2:MeOH:NH4OH 10:1:0.1 to afford to give the free base of the title compound. The base was converted to the salt by treatment with hydrogen chloride saturated EtOH to give the title compound (224 mg). mp 168-169° C. MS (CI/NH3) m/z 277/279 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.69 (dd, J=7.0, 8.5, 2H), 4.06-4.20 (m, 3H), 4.43 (d, J=4.5, 2H), 4.91-4.99 (m, 1H), 7.94 (d, J=3.0, 1H), 8.17 (d, J=3.0, 1H). Anal. Calcd for C9H10N2OBrCl.0.9 HCl: C, 34.83; H, 3.54; N, 9.03. Found: C, 34.85; H, 3.56; N, 8.82. [α]25D=−4.81° (c 0.13, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Fc1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(F)cc2)c1
Yield: 67.3 %

Procedure:
Reaction of 4-(4-fluoro-phenyl)-1H-imidazole (573 mg, 3.53 mmol), 95% NaH (100 mg, 4.0 mmol), and SEMCl (650 mg, 3.90 mmol) followed by purification of the crude material on silica gel (50% EtOAc/hexanes) gave the title compound as yellow crystals (695 mg, 67%). 1H NMR (CDCl3) □−0.01 (s, 9H), 0.93 (m, 2H), 3.52 (m, 2H), 5.29 (s, 2H), 7.07 (m, 2H), 7.28 (s, 1H), 7.62 (s, 1H), 7.75 (m, 2H).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[CH:13][C:12]=1[F:31]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:21][CH2:22]2)=[CH:13][C:12]=1[F:31]
Reactant: CCOC(=O)CCCN1CCC(c2ccc(Cl)c(F)c2)CC1
Reactant: ON=C1CCCCCC1
Product: Fc1cc(C2CCN(CCCc3onc4c3CCCCC4)CC2)ccc1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: Cl.N[C:3]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.N([O-])=O.[Na+].[NH2:18][C:19](N)=O.C1(C)C=CC=CC=1.[Cu]C#N.N.[C-]#N.[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2].C1(C)C=CC=CC=1.C(O)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:3]([C:19]#[N:18])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1ccc(Br)c2ncccc12
Reactant: NC(N)=O
Agent: N#C[Cu]
Agent: [Cu+2]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: N#Cc1ccc(Br)c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.60 g of concentrated hydrochloric acid was added dropwise to a mixture of 0.70 g of 5-amino-8-bromoquinoline and 3.15 ml of acetic acid, and the mixture was stirred for 1 hour at room temperature. At 0-5° C., 0.22 g of sodium nitrite in 0.45 ml of water were then added, and the mixture was stirred for 1 hour. After the addition of 20 mg of urea in 0.16 ml of water, stirring was continued at 0-5° C. for a further hour. This solution is added to a two-phase system of toluene/copper(I) cyanide solution which was prepared as follows: a solution of 0.79 g of copper(II) sulfate in 2.2 ml of water was added dropwise to a solution of 1.06 g of 10% strength ammonia solution and 0.77 g of sodium cyanide, and 6 ml of toluene were added to this mixture to form a lower layer. After stirring for 1 hour at room temperature, insoluble particles were filtered off and the solution was extracted with ethyl acetate. The organic phase was dried and the solvent was removed under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:21]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:19])[N:10]=1>C(O)(=O)C>[NH2:21][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C:9]2[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:19])[N:10]=2)=[C:6]([Cl:20])[CH:5]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)nn(C)c1=O
Solvent: CC(=O)O
Product: CC(C)c1cc(Cc2c(Cl)cc(N)cc2Cl)nn(C)c1=O
Temperature: 25 °C
Yield: 68.7 %

Procedure:
A solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-isoindole-1,3-dione (93) (300 mg, 0.66 mmol) in glacial acetic acid was heated to 110° C. for 3 h. At this time, the reaction was cooled to 25° C. and was poured onto water (100 mL). This mixture was extracted with ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum to a brown oil. Recrystallization from diethyl ether and hexanes followed by flash chromatography (Merck Silica gel 60, 230-400 mesh, 30:70 ethyl acetate/petroleum ether) afforded 6-(4-amino-2,6-dichloro-benzyl)-4-isopropyl-2-methyl-2H-pyridazin-3-one (94) (148 mg, 69%) as an off-white solid; ES_HRMS m/e calcd for C15H17Cl2N3O (M+H)+ 326.0822, found 326.0822. Exact Mass=325.0749; Molecular Weight=326.2282.
Reaction SMILES: Br.Cl[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:17])[S:14][C:15]=2[CH3:16])=[CH:7][CH:6]=1.[C:18]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl>C(OCC)(=O)C.C(OCC)(=O)C.CO.CCOCC.C(O)C>[C:18]1([N:28]2[CH2:33][CH2:32][N:31]([CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][C:8]([C:11]4[N:12]=[C:13]([NH2:17])[S:14][C:15]=4[CH3:16])=[CH:7][CH:6]=3)[CH2:30][CH2:29]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1sc(N)nc1-c1ccc(CCCl)cc1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CO
Solvent: CCO
Product: Cc1sc(N)nc1-c1ccc(CCN2CCN(c3cccc4ccccc34)CC2)cc1

Procedure:
To a 35 ml round-bottomed flask equipped with condenser and N2 inlet were added 0.81 g (2.80 mmol) of 4-(4-(2-chloroethyl)phenyl)-2-amino-5-methylthiazole hydrobromide, 0.59 g (2.80 mmol) of N-(1-naphthyl)piperazine, 0.78 ml (5.60 mmol) of triethylamine, 0.30 g (2.80 mmol) of sodium carbonate, 2 mg of sodium iodide, and 10 ml of ethanol. The reaction was heated at reflux for 5 days, cooled, and the reaction taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to an oil. The oil was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent to give a white solid. The solid was taken up in ethyl acetate/methanol, ether saturated with HCl added, the precipitate filtered, washed with ether, and dried to give a white solid, 0.82 g (54%), m.p. 160°-165° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH:19]1[N:23]=[CH:22][N:21]([C:24](N2C=NC=C2)=[O:25])[CH:20]=1>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:18])[N:11]([C:24]([N:21]2[CH:20]=[CH:19][N:23]=[CH:22]2)=[O:25])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C)c(/C=C2\C(=O)Nc3ccccc32)[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole (1.0 gram, 4.2 mmol) and CDI (1.36 gram 8.4 mmol) in DMF was stirred at room temperature for 2 h and filtered. The precipitate was washed with DMF and dried in a high vacuum oven to give 1.25 gram (89%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indol-2-one as an orange solid. 1HNMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H, NH-1′), 8.45 (s, 1H), 7.94 (m, 1H), 7.79 (m, 1H), 7.73 (s, 1H, H-vinyl), 7.46 (m, 1H), 7.25 (m, 2H), 7.13 (m, 1H), 6.14 (d, J=1.95 Hz, 1H, H-4′), 2.36 (s, 3H, CH3), and 2.32 (s, 3H, CH3). MS m/z (relative intensity, %) 332 (100, M+.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([O:21]C)=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([NH2:29])=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: N
Product: NC(=O)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (137c, 75 mg, 200 μmol) in methanolic NH3 (7 M, 1 ml) was stirred at r.t. overnight to give a clear solution. Then the solvent was removed in vacuo, and the crude product was freeze-dried go give white solid material, 60 mg (83%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][C@@H:44]1[CH2:49][CH2:50][OH:51])=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.C(N(CC)CC)C>[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])[CH2:45][C@@H:44]1[CH2:49][CH2:50][OH:51])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(O)c1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3cccnc23)C[C@@H]1CCO
Reaction time: 8 h

Procedure:
8-Quinoline carboxylic acid (1.00 g, 5.78 mmol), EDC.HCl (1.22 g, 6.38 mmol), HOBT (1.77 g, 13.1 mmol) in DMF at pH 7 (adjusted with triethylamine) was stirred at 20° C. for 15 min. 1-tert-Butoxycarbonyl-2(S)-(2-hydroxyethyl)piperazine (1.33 g, 6.71 mmol) was added and the reaction stirred overnight. DMF was removed in vacuo, and the residue taken up in 1:1:1 THF, methanol, and 5% aqueous sodium hydroxide. This was stirred at 20° C. for 72 h. The volatiles were removed in vacuo, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated sodium chloride solution, then dried over magnesium sulfate. The title compound was obtained as a foam (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]([OH:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS([C:21]1[N:26]=[CH:25][C:24]2=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]2[N:22]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[OH:17][C@H:15]([CH3:16])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]4[N:22]=3)=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: C[C@@H](O)CN1CCN(c2ccc(N)cc2)CC1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)cc2)CC1
Yield: 41.7 %

Procedure:
(R)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (129.1 mg, 0.5488 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (100.0 mg, 0.2744 mmol) and N,N-Diisopropylethylamine (0.1434 mL, 0.8232 mmol) were dissolved in 1-Methoxy-2-propanol (1.00 mL, 10.2 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The mixture was then reduced under nitrogen and the product was isolated and purified by Gilson prep HPLC to afford 61.36 mg of N-[2-(2-{4-[4-((R)-2-Hydroxy-propyl)-piperazin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a lyophilized powder. (M+H)=536.1. 1H NMR (400 MHz, DMSO, d6) δ 9.51 (s, 1H), 9.24 (s, 1H), 8.95 (s, 1H), 8.01 (d, 1H, J=7.52 Hz), 7.65 (d, 1H, J=7.65 Hz), 7.50 (m, 4H), 6.97 (m, 2H), 6.85 (m, 2H), 4.12 (m, 1H), 3.66 (m, 4H), 3.17 (m, 3H), 3.08 (s, 3H), 2.95 (m, 3H), 2.89 (s, 3H), 1.13 (d, 3H, J=5.08 Hz).
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([CH2:18]O)[CH:9]=1.C(#N)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:45]>>[Cl:45][CH2:18][C:10]1[CH:9]=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:21])([CH3:20])[CH3:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: C[Si](C)(C)CCOCOc1cc(CO)cc2ccccc12
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[Si](C)(C)CCOCOc1cc(CCl)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
23.72 g (77.91 mmol) of [4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-yl]-methanol were dissolved in 350 ml of carbon tetrachloride and the solution was cooled to 0° C. Thereupon, 350 ml of acetonitrile and 26.54 g (1.012 mmol) of triphenylphosphine were added. The light yellow solution was stirred at 0° C. for 30 minutes, warmed to room temperature and stirred for a further 2 hours. A further 10.14 g (38.7 mmol) of triphenylphosphine were added and the reaction mixture was stirred at room temperature for 90 minutes. Subsequently, the mixture was partitioned between methylene chloride and water, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was chromatographed on silica gel using a 3:7 mixture of methylene chloride and hexane as the eluent. There were obtained 15.81 g (63% of theory) of 2-chloromethyl-4-(β-trimethylsilylethoxymethoxy)-naphthalene as a light yellow oil; MS: 322, 324 (M)+.
Reaction SMILES: O.[C:2]1(C)[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13](OC(=O)C)C>>[C:4]1([CH3:13])[C:5]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
The present invention is to provide a compound (I') which comprises (d) reacting the produced compound (I) with p-toluenesulfonic acid monohydrate in the presence of ethylacetate to produce toluenesulfonic acid 1,1-dioxppenicillanoyl oxymethyl D-6-[(α-methyleneamino) phenylacetamido]-penicillanate (I') in accordance with the present invention.
Reaction SMILES: OO.NC(N)=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:20][C:21]1[CH:34]=[CH:33][C:32]2[O:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[N+:35]([O-:37])=[O:36])[C:24](=[O:38])[C:23]=2[CH:22]=1>C(Cl)Cl>[Br:20][C:21]1[CH:34]=[CH:33][C:32]2[O:31][C:30]3[C:25](=[N+:26]([O-:5])[CH:27]=[CH:28][C:29]=3[N+:35]([O-:37])=[O:36])[C:24](=[O:38])[C:23]=2[CH:22]=1
Reactant: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])ccnc12
Reactant: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc[n+]([O-])c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of urea hydrogen peroxide (58.6 mg, 0.623 mmol) in 5 mL of CH2Cl2 at 0° C. was added dropwise trifluoroacetic anhydride (87 μL, 0.623 mmol). After stirring for 5 min at 0° C., a solution of 8-bromo-4-nitro-10H-chromeno[3,2-b]pyridin-10-one (80 mg, 0.249 mmol) in CH2Cl2 (5 mL) was added and the resulting reaction was stirred at rt for 1.5 h. The mixture was carefully quenched with saturated NaHCO3 and extracted with ethyl acetate (5×5 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification of the crude residue by column chromatography (CH2Cl2 to CH2Cl2/EA=10:1 to 5:1) gave 8-bromo-4-nitro-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide as an light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([S:11](Cl)(=O)=O)=[C:4]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH:3]=1.BrC1C(C(CC)C)=CC(S(Cl)(=O)=O)=C(C(CC)C)C=1>>[Br:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([SH:11])=[C:4]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH:3]=1
Reactant: CCC(C)c1cc(Br)c(C(C)C)cc1S(=O)(=O)Cl
Agent: CCC(C)c1cc(S(=O)(=O)Cl)c(C(C)CC)cc1Br
Product: CCC(C)c1cc(Br)c(C(C)C)cc1S

Procedure:
4-Bromo-2-sec-butyl-5-isopropylbenzenethiol was prepared using the procedure of Example 2B except that 4-bromo-2-sec-butyl-5-isopropylbenzenesulfonyl chloride was substituted for the 4-bromo-2,5-di-sec-butylbenzenesulfonyl chloride. The resulting product had a boiling point of 110°C at 0.35 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[NH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=3)=[CH:10][C:11]([O:18][CH3:29])=[N:12][C:13]=2[C:14]([F:15])([F:17])[F:16])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(-c2cc(=O)[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c(C(F)(F)F)n1
Reaction time: 3 h
Yield: 102.5 %

Procedure:
A mixture of 0.16 g (0.39 mMol) of the sulfone of Step 5, 0.2 g of potassium carbonate and 4.0 g of iodomethane, and 5 mL of DMF was stirred for 3 hours, poured into water and extracted with ether. The ether extract was washed with brine, dried over MgSO4 and filtered through silica gel. The filtrate was concentrated in vacuo and the residue was crystallized from hexane to give 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine as a white solid (0.17 g): mp 166.5°-168 ° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[C:10]=2[CH:11]=1.[CH:27](=O)[CH2:28][CH3:29]>>[CH2:27]([N:15]([C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:9]([CH3:12])=[CH:8][CH2:7][C:6]([CH3:14])([CH3:13])[C:5]=2[CH:4]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH2:28][CH3:29]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Reactant: CCC=O
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1cc2c(cc1C)C(C)=CCC2(C)C
Yield: 41.5 %

Procedure:
Following General Procedure D, ethyl 4-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 39, 0.085 g, 0.24 mmol) was reacted with propionaldehyde (180 μL, 2.4 mmol) to give 0.039 g (41%) of the title compound as a clear oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:50][C:51]1[CH:52]=[C:53]([CH:61]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:63]=1)[O:54][CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[F:50][C:51]1[CH:52]=[C:53]([CH:61]=[C:62]([C:64]([F:66])([F:65])[F:67])[CH:63]=1)[O:54][CH:55]1[CH2:56][CH2:57][N:58]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:59][CH2:60]1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Reactant: Fc1cc(OC2CCNCC2)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)cc(C(F)(F)F)c2)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 54 %

Procedure:
DIPEA (97 mg, 0.75 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (61 mg, 0.25 mmol) in DMF (2 mL) followed by HOBt (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol). After 2 minutes of stirring, 4-(3-fluoro-5-trifluoromethyl-phenoxy)-piperidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (75 mg, 0.25 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure The residue obtained was purified by column chromatography (using silica gel 60-120 and 40% EtOAc in hexane as eluent) to afford 66 mg (54% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(3-fluoro-5-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 491, 96%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (m, 1H), 8.3 (m, 1H), 8.03 (m, 1H), 7.78 (m, 2H), 7.58 (m, 2H), 7.4 (m, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 4.8 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1S(O)(=O)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: Cn1c(S(=O)(=O)O)nc2ccccc21
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)nc2ccccc21
Temperature: 155 °C
Yield: 16.6 %

Procedure:
A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (150 mg, 0.47 mmol), 1-methylbenzimidazole-2-sulfonic acid (83.4 mg, 0.39 mmol) and N,N-diisopropylethylamine (175 μl, 0.98 mmol) in acetonitrile (1.5 ml) was heated at 155° C. in the Smith Personal Synthesiser for 2400 seconds and then a further 900 seconds. The reaction mixture was partitioned between dichloromethane (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 95:5:0.5 by volume) to provide the title compound (29 mg, 14%). 1H NMR (400 MHz, CD3OD) δ 1.83-1.86 (m, 4H), 1.96-2.02 (m, 4H), 2.19 (d, 2H), 2.63-2.66 (m, 4H), 2.70 (t, 2H), 3.41 (s, 3H), 3.50 (t, 2H), 3.57 (s, 2H), 3.79-3.82 (m, 2H), 3.97 (t, 2H), 6.91 (d, 2H), 6.97-7.02 (m, 2H), 7.08 (d, 1H), 7.22 (d, 1H), 7.36 (d, 2H). LRMS APCI+ m/z 449 [MH]+.