Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:27]([O-])([O-:29])=[O:28].[K+].[OH-].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:27]([O-:29])=[O:28])[C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1NCCOc2ccc(F)cc21
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: O=C1NCCOc2c1cc(F)cc2[N+](=O)[O-]

Procedure:
7-Fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (346 mg, 1.91 mmol) in Acetonitrile (10 mL) and Trifluoroacetic anhydride (0.85 mL, 6.0 mmol) was treated with Potassium nitrate (0.203 g, 2.00 mmol) at room temperature for 24 h. Aq. NaOH (15% w/w, 10 mL) was added and the mixture extracted 3×15 mL DCM. The DCM extract was washed with water (20 mL) and brine (20 mL) then dried over sodium sulfate and conc. in vacuo. 1H-, 19F-NMR and HPLC showed a 2-3:1 mixture of 7-Fluoro-9-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one and 7-Fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one, which was chromatographed (ISCO, 40 g, 0-75% EtOAc:Hex) to give 7-Fluoro-9-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one, enriched in the mixture, but still containing 7-Fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one. This mixture was dissolved in Ethanol (10 mL) and added to Palladium on Carbon 10% (0.05 g) wetted with a small amount of water. The mixture was shaken under an atmosphere of Hydrogen (40 psi) for 1.5 h, then filtered through Celite, washing with ethanol. Conc. in vacuo gave a white solid, which was taken up in Et2O with minimal MeOH to solubilize, then extracted with 15 mL 1N HCl. The aq. extract was washed once with ether (10 mL) then basified with 15% NaOH, then extracted 8×10 mL DCM. The organic layers were dried over sodium sulfate and conc. in vacuo to give 9-Amino-7-fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one as a white solid (120 mg, 35% over two steps.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[C:2]1=[N:11][OH:12].[H-].[Na+].Br[CH2:16][CH2:17][OH:18].O>CN(C)C=O>[OH:18][CH2:17][CH2:16][O:12][N:11]=[C:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: OCCBr
Reactant: O=C1C(=NO)Oc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(=NOCCO)Oc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
11.8 g (0.0725 mol) of benzofuran-2,3-dione 2-oxime (XI-1) (Stoermer, Kahlert, B. 35, 1644) are dissolved in 75 ml of dimethylformamide. With cooling, 3 g (0.075 mol) of 60% strength sodium hydride (mineral oil suspension) are added a little at a time and stirring is continued at a temperature of 25° C. for about one hour until the formation of gas has ceased. The mixture is then cooled to 0° C., and at this temperature 9.3 g (0.0744 mol) of 2-bromoethanol are added dropwise and stirring is continued at 25° C. for a further 24 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is recrystallized from a mixture of 150 ml of toluene and 100 ml of cyclohexane. 11.5 g (64% of theory) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] (VII-1) are obtained (content according to HPLC analysis: 83.5%). A sample recrystallized from toluenes has a melting point of 110-111° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].S([NH:23][N:24]=[CH:25][CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(C1C=CC(C)=CC=1)(=O)=O>O.Cl.C(O)C.N1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([N:9]2[N:23]=[N:24][C:25]([CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:1]2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(S(=O)(=O)NN=CC=Cc2ccccc2)cc1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: Clc1cccc(-n2nnc(C=Cc3ccccc3)n2)c1
Temperature: 0 °C
Yield: 19 %

Procedure:
An aqueous (5 mL) solution of sodium nitrite (540.9 mg, 7.839 mmol) was added to a solution of 3-chloroaniline in water (7 mL), concentrated hydrochloric acid (3 mL) and ethanol (7 mL) via dropping funnel. The reaction was allowed to stir at 0° C. for ten minutes. This solution was poured into a dropping funnel and ice was added. This was added dropwise to a solution of cinnamaldehyde tosyl hydrazone (2.3 g, 7.682 mmol) in pyridine (20 mL). This was allowed to stir overnight. An aqueous workup was done extracting with dichloromethane three times. The combined layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (20% EtOAc/hexanes) to yield the title compound as a light purple solid (433.6 mg, 19%). 1H NMR (CDCl3) δ (ppm): 8.21 (m, 1H), 8.09 (d of t, 1H), 7.89 (d, 1H), 7.61 (m, 2H), 7.49 (m, 5H), 7.24 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)(=O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC=CC=1)([O-])=O.C1([S-])C=CC=CC=1.[Na+]>O>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2S(=O)(=O)c2ccccc2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [S-]c1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccccc2Sc2ccccc2-c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
An amount of 21.4 g (0.08 mole) of the thus obtained 4-nitrophenylphenyl sulfone was dissolved in a two phase solvent composed of a mixture of 80 g of nitrobenzene and 80 g of water, and was reacted with sodium thiophenolate in the same manner as in Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:26][CH:27]=2)=[O:14])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCOc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCOc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
4-(benzyloxy)benzoic acid (20.0 g, 87.6 mmol), 4-(hexyloxy)phenol (17.0 g, 87.6 mmol), N,N′-dicyclohexylcarbodiimide (21.7 g, 105 mmol) and 4-dimethylaminopyridine (535 mg, 4.38 mmol) were dissolved in 300 mL of methylene chloride. The resulting solution was stirred for 3 hours at room temperature. Then, 300 mL of pure water was added thereto, and then the resulting liquid was filtered to remove insoluble matters. Thereafter, the obtained solution was subjected to separation operation, and the resulting methylene chloride solution was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After methylene chloride was distilled off, the resulting solid matter was washed with methanol. Thereby, a white solid compound, 4-(hexyloxy)phenyl 4-(benzyloxy)benzoate (24.9 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([CH3:12])[C:3]=1[Cl:13].[Cu](C#N)[C:15]#[N:16].C(N)CN.O>CN1CCCC1=O.[Cu](I)I>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[C:3]([Cl:13])[C:4]=1[CH3:12]
Reactant: N#C[Cu]C#N
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1C
Agent: I[Cu]I
Solvent: O
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: Cc1c(N)ccc(C#N)c1Cl
Yield: 79 %

Procedure:
Dissolve N-(4-bromo-3-chloro-2-methyl-phenyl)-acetamide (10 g, 38 mmol) in N-methylpyrrolidinone (60 mL) and sparge with nitrogen. Add copper cyanide (10.2 g, 114 mol) and copper iodide (21.8 g, 114 mol) and stir under nitrogen at 130° C. for 72 h. Cool the reaction and add ethylene diamine (100 mL), along with water (300 mL). Extract the reaction mixture with EtOAc. Separate and dry the organic portion over Na2SO4, filter, and concentrate. Dissolve the resulting residue in 1:1 EtOH/concentrated HCl. Stir at reflux temperature for 30 min, cool and concentrate to half of the volume. Add water (500 mL) and filter. Rinse the filter cake with water and isolate 5.0 g (79%) of the title compound as a white solid. MS: MS (ESI−): 207 (M−1)−. MS (ESI+): 209 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=CC=C[C:33]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>CN(C=O)C>[CH:34]([NH:30][C:21]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23])([CH3:35])[CH3:33]
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC(C)C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (28 mg, 0.085 mmol) in DMF (0.5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (30 mg, 0.085 mmol), N,N-diisopropyl ethyl amine (72 μL, 0.423 mmol) and isopropylamine (8 μL, 0.40 mmol). The resulting reaction mixture was stirred for 1 h. The reaction mixture was then evaporated and purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (24 mg, 74%) as a white solid after trituration from water. MS: m/e=387.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH2:28])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].[NH2:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[N:49]=1>C1COCC1>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH:28][C:34]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:57])[CH3:58])[N:49]=2)=[O:35])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=2)=[CH:13][CH:12]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(C(OCc2cccc(CN)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN)n1
Solvent: C1CCOC1
Product: COc1ccc(C(OCc2cccc(CNC(=O)NCc3cccc(CO[Si](C)(C)C(C)(C)C)n3)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
A suspension of 3-(4,4′-dimethoxytrityloxymethyl)benzylamine (5) (455 mg, 1.04 mmol) and 1,1′-carbonyldiimidazole (170 mg, 1.05 mmol) in THF (52 mL) was stirred for 24 hours at a room temperature under Ar atmosphere. TLC was used to confirm there was no starting material in the reaction mixture. Then, to the suspension was added dropwise a solution of 2-aminomethyl-6-[(tert-butyldimethylsilyloxy)methyl]pyridine (3) (593 mg, 2.35 mmol) in THF (13 mL), and further stirred for 48 hours. The reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=100:1) to give N-[3-(4,4′-dimethoxytrityloxymethyl)benzyl]-N′-{[6-(tert-butyldimethylsilyloxy)methylpyridin-2-yl]methyl}urea (6) (406 mg, 54%) as a colorless oil.
Reaction SMILES: ClC1C=C(C(Cl)=O)C=C(Cl)C=1.[Cl:12][C:13]1[CH:19]=[C:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:14]=1[NH2:15].[Cl:35][C:36]1[CH:37]=[C:38]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:39]=[C:40]([Cl:42])[CH:41]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][C:36]1[CH:37]=[C:38]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:39]=[C:40]([Cl:42])[CH:41]=1.[Cl:12][C:13]1[CH:19]=[C:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:14]=1[NH:15][C:46]([NH:45][C:43](=[O:44])[C:38]1[CH:39]=[C:40]([Cl:42])[CH:41]=[C:36]([Cl:35])[CH:37]=1)=[S:47]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C(N=C=S)c1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(Cl)cc(Cl)c4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
3,5-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,5-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,5-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 47%).
Reaction SMILES: CC1CCCO1.[C:7](=[N:10][OH:11])([NH2:9])[CH3:8].C[O-].[Na+].[C:15]12([C:28](OCC)=O)[CH2:20][CH:19]1[CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2>O>[CH3:8][C:7]1[N:9]=[C:28]([C:15]23[CH2:20][CH:19]2[CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[O:11][N:10]=1
Reactant: CCOC(=O)C12CC1CN(C(=O)OC(C)(C)C)C2
Reactant: CC(N)=NO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: Cc1noc(C23CC2CN(C(=O)OC(C)(C)C)C3)n1
Yield: 53.6 %

Procedure:
2-Methyltetrahydrofuran (15 mL), acetamide oxime (2.54 g, 34.3 mmol) and sodium methoxide (3.70 g, 68.6 mmol) were added to 3-tert-butyl 1-ethyl 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylate (103) (3.5 g, 13.72 mmol) and the mixture was heated to reflux for 20 minutes. Upon cooling the suspension was treated with 60 mL of water and extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated sodium chloride and dried over magnesium sulfate. The mixture was concentrated and the residue was chromatographed over 20 g of silica gel with hexanes/ethyl acetate; obtained 1.95 g of 104 as a white solid. MS (ESI) m/z 304.0 [M+K]+. 1H NMR (CDCl3) δ: 1.17 (m, 1H), 1.46 (s, 9H), 1.74 (m, 1H), 2.18 (s, 2H), 2.22 (m, 1H), 2.36 (s, 3H), 3.50 (m, 1H), 3.70 (m, 1H).
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][C@:13]1([NH:39][CH:40]=[O:41])[C:37](=[O:38])[N:15]2[CH:16]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[C:17](=[CH2:20])[CH2:18][S:19][C@H:14]12.[Br:42]C(Br)(C(OCC)=O)C(OCC)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[NH2:12][C@:13]1([NH:39][CH:40]=[O:41])[C:37](=[O:38])[N:15]2[C:16]([C:21]([O:23][CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:17]([CH2:20][Br:42])[CH2:18][S:19][C@H:14]12
Reactant: C=C1CS[C@H]2N(C(=O)[C@]2(N)NC=O)C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: N[C@]1(NC=O)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@@H]21
Yield: 69.5 %

Procedure:
A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (24 mg) in dry tetrahydrofuran (5 ml) was added over 5 min to a solution of diphenylmethyl 7β-amino-7α-formamido-3-methylenecepham-4-carboxylate (prepared above)(739 mg) in dry tetrahydrofuran (30 ml) containing diethyl dibromomalonate (999 mg) at -70° C. under argon. After 25 min the mixture was added to a mixture of ethyl acetate (150 ml) and 5% (w/v) aqueous citric acid (100 ml). The phases were separated and the organic phase washed with water (3×100 ml), brine (100 ml), then dried (anhyd. MgSO4), filtered and the filtrate evaporated to give a yellow solid. Trituration with dichloromethane (15 ml) followed by filtration provided the title compound (609 mg) as a white solid, m.p. 151°-153° C. (decomp.) (Found: C, 52.33; H, 4.00; N, 8.37; S, 6.50; Br, 15.59%. C22H20N3O4SBr requires C, 52.59; H, 3.98; N, 8.37; S, 6.38; Br, 15.94%). υmax (KBr) 3370, 3280, 3150, 1795, 1720, and 1670 cm-1 ; δH (250 MHz, d8 -THF) (major rotamer) 2.70 (2H, broad s, exch. D2O), 3.46 and 3.58 (2H, ABq, J 16.8 Hz), 4.34 and 4.42 (2H, ABq, J 10.0 Hz), 5.21 (1H, s), 6.95 (1H, s), 7.1-7.6 (10H, m), 8.15 (1H, d, J 1.0 Hz, becomes s on D2O exch.), and 8.17 (1H, broad s, exch. D2O); m/z (positive xenon F.A.B.; 3-nitrobenzyl alcohol-NaOAc) MNa;, 524.
Reaction SMILES: [CH3:1][C:2](=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=1[N:29]=[C:30]=[O:31].C([N-]C(C)C)(C)C.[Li+]>>[O:16]=[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:1][C:30]([NH:29][C:20]1[C:19]([O:18][CH3:17])=[CH:24][C:23]([O:25][CH3:26])=[CH:22][C:21]=1[O:27][CH3:28])=[O:31]
Reactant: CCCCCCCCCCCCCC(C)=O
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCCCCC(=O)CC(=O)Nc1c(OC)cc(OC)cc1OC

Procedure:
The title compound was prepared from 2-pentadecanone (0.54 g, 0.0023 mol), 2,4,6-trimethoxyphenyl isocyanate (prepared from 2,4,6-trimethoxyaniline hydrochloride and phosgene (2.5 eq)) and lithium diisopropylamide (0.0023 mol) using the procedure described in Example 1.
Reaction SMILES: [OH:1][C:2]1[C:10]([Br:11])=[C:9]([Cl:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[CH:4]=[N:5]O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>O1CCCC1>[OH:1][C:2]1[C:10]([Br:11])=[C:9]([Cl:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)c1cc(C=NO)c(O)c(Br)c1Cl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C#N)c(O)c(Br)c1Cl
Yield: 86.8 %

Procedure:
A mixture of 2.20 g (7.18 mmol) of 2-hydroxy-3-bromo-4-chloro-5-(1,1-dimethylethyl)benzaldehyde oxime and 3.12 g (14.72 mmol) of trifluoroacetic anhydride in 15 ml of tetrahydrofuran was cooled in an ice-water bath. A solution of 2.18 g (21.54 mmol) of triethylamine in 10 ml of tetrahydrofuran was added After refluxing for 2 hours, the solvent was evaporated and the residue was partitioned between saturated aqueous sodium bicarbonate solution and ether. The organic phase was washed with 1N hydrochloric acid, followed by water and brine. The organic phase was dried and evaporated. The residue was chromatographed on 100 g of silica gel using a gradient from 5:95 to 50:50 (v/v) ether:hexane as eluent. There was obtained 1.80 g (6.23 mmol, 87%) of 2-hydroxy-3-bromo-4-chloro-5-(1,1-dimethylethyl)benzonitrile; mp 105°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([NH2:12])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH:21]([O:24][C:25]1[CH:34]=[C:33](OC)[CH:32]=[CH:31][C:26]=1[C:27](OC)=O)([CH3:23])C.C[Al](C)C.[C:41]([Cl:44])(Cl)=[O:42]>C(N(CC)CC)C>[C:5]([C:33]1[CH:32]=[CH:31][C:26]([C:27]2[NH:20][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)([CH2:10][CH3:11])[N:12]=2)=[C:25]([O:24][CH2:21][CH3:23])[CH:34]=1)([CH3:8])([CH3:6])[CH3:4].[C:5]([C:33]1[CH:32]=[CH:31][C:26]([C:27]2[N:20]([C:41]([Cl:44])=[O:42])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)([CH2:10][CH3:11])[N:12]=2)=[C:25]([O:24][CH2:21][CH3:23])[CH:34]=1)([CH3:8])([CH3:6])[CH3:4]
Reactant: CCC(N)(c1ccc(Cl)cc1)C(N)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(OC)cc1OC(C)C
Reactant: O=C(Cl)Cl
Agent: C[Al](C)C
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(CC)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(CC)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-ethyl-4,5-dihydro-1H-imidazole was prepared from rac-(1R*,2S*)-1,2-bis-(4-chloro-phenyl)-butane-1,2-diamine (prepared from 3,4-bis-aryl-1,2,5-thiadiazole-1,1-dioxide and ethylmagnesium bromide as described in example 170) and methyl 2-isopropoxy-4-methoxy-benzoate in the presence of trimethylaluminum using the procedure as described in example 2. It was then reacted with phosgene in the presence of triethylamine to give rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-ethyl-4,5-dihydro-imidazole-1-carbonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:5]=2[O:4][N:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:22]([C:21]4[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=4[Cl:19])=[O:23])=[N:15][CH:16]=3)=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1cc2c(C)noc2cc1-c1ccc(N)nc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(C)noc2cc1-c1ccc(NC(=O)c2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 5-(3,5-dimethylbenzo[d]isoxazol-6-yl)-2-pyridylamine (105) (14.5 mg, 0.06 mmol) in 1 ml DCM was added 2-chlorobenzoyl chloride (16 μl, 0.12 mmol) followed by addition of DIEA (63 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (120 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished N-[5-(3,5-dimethylbenzo[d]isoxazol-6-yl)(2-pyridyl)](2-chlorophenyl)carboxamide (106) (17.1 mg, yield: 75.4%, purity>95%) as off-white solid.
Reaction SMILES: [ClH:1].Cl.Cl.S1C2C(=NC=CC=2)C=C1N.[F:14][C:15]1[CH:57]=[CH:56][C:18]([O:19][C:20]2[C:21]([NH:36][C:37]3[S:41][N:40]=[C:39]([CH2:42][CH:43]4[CH2:48][CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44]4)[N:38]=3)=[N:22][CH:23]=[C:24]([S:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[CH:33]=[CH:34][S:35][C:28]=34)[CH:25]=2)=[CH:17][CH:16]=1.CO.Cl>O1CCOCC1.C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[C:21]([NH:36][C:37]3[S:41][N:40]=[C:39]([CH2:42][CH:43]4[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]4)[N:38]=3)=[N:22][CH:23]=[C:24]([S:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[CH:33]=[CH:34][S:35][C:28]=34)[CH:25]=2)=[CH:56][CH:57]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccc(F)cc3)n2)CC1
Agent: Cl
Agent: Nc1cc2ncccc2s1
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Fc1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(CC3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Preparation of 3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-2-amine trihydrochloride: A 10 mL round-bottomed flask was charged with tert-butyl 4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidine-1-carboxylate (52.2 mg, 0.0802 mmol) and a 1:1 mix of methanol and CH2Cl2 (4 mL). 4N HCl in dioxane (2 mL) was added and the reaction stirred at room temperature for 10 minutes. The solvent was removed to afford crude 3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride (52.9 mg, 100%).