Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:23])[CH2:4][N:5]1[CH2:9][C@@H:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[O:7][C:6]1=[O:22].[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.[BH4-].[Na+]>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[OH:23][C@H:3]([CH2:4][N:5]1[CH2:9][C@@H:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[O:7][C:6]1=[O:22])[CH2:2][NH:1][CH2:35][C:33]1[CH:32]=[CH:31][C:28]2[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=2[N:34]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc([C@@H]3CN(C[C@@H](O)CN)C(=O)O3)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2nccc([C@@H]3CN(C[C@@H](O)CNCc4ccc5c(n4)NC(=O)CS5)C(=O)O3)c2n1
Reaction time: 15 h
Yield: 75.1 %

Procedure:
To (R)-3-((S)-3-Amino-2-hydroxy-propyl)-5-(6-methoxy-[1,5]naphthyridin-4-yl)-oxazolidin-2-one (0.069 g, 0.22 mmol) in CH2Cl2 (7 mL) and MeOH (1.8 mL) was added 3-oxo-3,4-dihydro-2H-pyrido[3,2,b][1,4]thiazine-6-carbaldehyde (SB-735214, 0.043 g, 0.22 mmol) and the reaction mixture was stirred for 15 hours. Sodium borohydride (0.01 g, 0.26 mmol) was added followed by methanol (5 mL). After 1 hour, the reaction mixture was diluted with chloroform and washed with saturated aqueous NaHCO3 solution, dried (MgSO4), filtered and concentrated. Flash chromatography on silica gel using a gradient of 0-10% MeOH/CHCl3 afforded the product as a white solid (0.082 g, 76%) 1H NMR (400 MHz, CDCl3): δ8.80 (d, J=4.6 Hz, 1H); 8.25 (d, J=9.1 Hz, 1H); 7.70 (d, J=4.4 Hz, 1H); 7.55 (d, J=7.6 Hz, 1H); 7.16 (d, J=9.1 Hz, 1H); 6.87 (d, J=7.9 Hz, 1H); 6.32 (dd, J=8.7, 7.2 Hz, 1H); 4.57 (t, J=9.4 Hz, 1H); 4.04 (s, 3H); 3.91 (m, 1H); 3.75-3.84 (overlapping signals, 2H); 3.63 (dd, J=9.2, 6.9 Hz, 1H); 3.47-3.50 (overlapping signals, 2H); 3.46 (s, 2H); 3.22 (dd, J=14.4, 6.8 Hz, 1H); 2.79 (dd, J=12.4, 3.6 Hz, 1H); 2.57 (dd, J=12.4, 8.3 Hz, 1H). MS (ES) m/e 497 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C1COCC1.[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:25]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NCc1ccccc1)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred suspension of 4-chlorobenzoic acid, hydrazide (10.4932 g, 6.1508×10-2 mole) and dry THF (240 mL) was warmed with a heat gun until it was homogenous. To this stirred solution was added benzyl isocyanate (7.8 ml, 6.3×10-2 mole). After stirring overnight at room temperature, the reaction was diluted with ether. The precipitate was collected by filtration, washed with a little ether, and dried by suction Crystallization from ethanol afforded small colorless needles 15.69 g (84%), mp 244°-246° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N(CC)CC)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.[C:71]([C:74]1[CH:79]=[CH:78]C(S(Cl)(=O)=O)=[CH:76][CH:75]=1)(=[O:73])[CH3:72]>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([C:32]4[CH:78]=[CH:79][C:74]([C:71](=[O:73])[CH3:72])=[CH:75][CH:76]=4)(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)=[NH:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cnc3n(c2=O)[C@H](C(=O)NCc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)CC3)cc1
Yield: 42 %

Procedure:
Following a procedure similar to that for the preparation of 16a, intermediate 3a (50 mg, 0.117 mmol) and 4-acetylbenzene sulfonyl chloride (30.6 mg, 0.14 mmol) yielded 30.0 mg (42.0%) of 35a. MS (ESI) 609.1 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([S:57][CH2:58][C:59]3C=CC=CC=3)[CH:52]=2)[C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23]([N:26]([C:41]4C=CC(CCCC)=C[CH:42]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([S:33]CC5C=CC=CC=5)[CH:28]=4)=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[F:65][C:66]([F:73])([F:72])[S:67]([O:70]C)(=[O:69])=[O:68]>C(Cl)Cl.C(=O)=O.CC(C)=O>[O-:70][S:67]([C:66]([F:73])([F:72])[F:65])(=[O:69])=[O:68].[CH2:21]([C:20]1[CH:19]=[CH:18][C:41]([N:26]([C:23]2[CH:24]=[CH:25][C:20](/[CH:19]=[CH:18]/[C:15]3[CH:16]=[CH:17][C:12]([N:11]([C:8]4[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([SH+:57][CH2:58][CH2:59][C:14]5[CH:15]=[CH:16][CH:17]=[CH:12][CH:13]=5)[CH:52]=4)=[CH:13][CH:14]=3)=[CH:21][CH:22]=2)[C:27]2[CH:28]=[C:29]([SH+:33][CH2:2][CH2:1][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:42][CH:25]=1)[CH2:22][CH2:23][CH3:24].[O-:70][S:67]([C:66]([F:73])([F:72])[F:65])(=[O:69])=[O:68]
Reactant: CCCCc1ccc(N(c2ccc(/C=C/c3ccc(N(c4ccc(CCCC)cc4)c4cccc(SCc5ccccc5)c4)cc3)cc2)c2cccc(SCc3ccccc3)c2)cc1
Reactant: COS(=O)(=O)C(F)(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCc1ccc(N(c2ccc(/C=C/c3ccc(N(c4ccc(CCCC)cc4)c4cccc([SH+]CCc5ccccc5)c4)cc3)cc2)c2cccc([SH+]CCc3ccccc3)c2)cc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: -78 °C

Procedure:
Trans-4,4′-di[(4-n-butylphenyl)(3-benzylthiophenyl)amino]stilbene (16) (0.96 g, 1.103 mmol) was dissolved in 20 ml of dry methylene chloride and cooled at −78° C. in dry ice-acetone bath. To this solution was added, via syringe, methyl trifluoromethanesulfonate (276 μl, 2.437 mmol) and the mixture stirred for 30 min while the temperature was maintained at −78° C. The resultant mixture was then stirred two days at room temperature. After removal of some solvent under reduced pressure, the mixture was then poured into 20 ml of ether. The product was precipitated as a yellow solid, that was washed three times with ether and isolated in 80.9% (1.07 g) yield. 1H NMR (CD3COCD3, 500 MHz) δ ppm: 6.9-7.8 (m, 34 Ar—H, 2 ═CH), 5.27 (d, 2J=12.5 Hz, 2H, SCH2), 5.02 (d, 2J=12.5 Hz, 2H, SCH2), 3.53 (s, 6H, CH3), 2.63 (t, J=7.7 Hz, CH2, 4H), 1.61 (m, CH2, 4H), 1.36 (m, CH2, 4H), 0.95 (t, J=7.2 Hz, CH3, 6H)13C NMR (CD3COCD3, 125.7 MHz) δppm: 149.4, 145.6, 143.6, 139.9, 133.5, 131.8, 130.7, 130.1, 129.8, 129.3, 127.9, 127.7, 127.1, 126.5, 125.7, 124.5, 123.8, 123.4, 121.7, 51.0, 34.7, 33.5, 24.5, 22.1, 13.3. (One CF3 carbon was not observed).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][NH:22][C:23](=[O:36])[C@@H:24]([NH:28]C(OCCCC)=O)[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.Cl.[OH-].[Na+]>C(OCC)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][NH:22][C:23](=[O:36])[C@@H:24]([NH2:28])[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1
Reactant: CCCCOC(=O)N[C@H](C(=O)NCCc1ccc(OCC#Cc2ccc(Cl)cc2)c(OC)c1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(CCNC(=O)[C@@H](N)C(C)C)ccc1OCC#Cc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
5.8 g of (S)-2-(butoxycarbonyl-amino)-3-methyl-butyric acid N-[2-{3-methoxy-4-(3-(4-chlorophenyl)-2-propyn-1-yloxy)-phenyl}-ethyl]-amide and 5 g of concentrated hydrochloric acid are stirred for 10 minutes in a mixture of 20 ml of diethyl ether and 20 ml of dichloromethane at 0° C. Stirring is continued overnight at room temperature. The reaction mixture is introduced into 100 ml of 2N hydrochloric acid and extraction is carried out twice using 150 ml of diethyl ether each time. The aqueous phase is adjusted to pH 11 with 5M sodium hydroxide. Extraction is then carried out twice using 150 ml of ethyl acetate each time. The organic phases are washed twice with 50 ml of saturated sodium chloride solution each time, dried over sodium sulfate and concentrated, yielding (S)-2-amino-3-methyl-butyric acid N-[2-{3-methoxy-4-(3-(4-chlorophenyl)-2-propyn-1-yloxy)-phenyl}-ethyl]-amide, which is recrystallised from ethyl acetate/n-hexane, m.p. 115-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([N:14]1[CH2:15][CH2:16][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:21])=[O:22])[CH2:18][CH2:19]1)=[O:13]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(COc1ccc(Cl)cc1Cl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 85.9 %

Procedure:
2,4-dichloro phenol (138 mg, 0.85 mmol), 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) and anhydrous potassium carbonate (0.293 g, 2.125 mmol) were stirred for over night in dry acetonitrile (20 mL). The mixture was poured into a large volume of water and the solution extracted with diethyl ether. Un-reacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (350 mg, 87.5% yield) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:32])([CH3:31])[CH:4]([NH:23][C:24](=O)[O:25]C(C)(C)C)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][C:16]3=[CH:18][N:19]=[C:20]([CH3:21])[N:15]3[C:14]2=[O:22])[CH2:9][CH2:8]1)=[O:6].[ClH:33].C(O[CH2:38][CH3:39])(=O)C>>[Cl:33][C:39]1[CH:38]=[CH:11][C:10]([NH:13][C:24]([NH:23][CH:4]([C:5]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][C:16]4=[CH:18][N:19]=[C:20]([CH3:21])[N:15]4[C:14]3=[O:22])[CH2:9][CH2:8]2)=[O:6])[C:3]([O:2][CH3:1])([CH3:31])[CH3:32])=[O:25])=[CH:9][CH:8]=1
Reactant: CCOC(C)=O
Reactant: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Reactant: Cl
Product: COC(C)(C)C(NC(=O)Nc1ccc(Cl)cc1)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Yield: 71 %

Procedure:
tert-Butyl 2-methoxy-2-methyl-1-((4-(5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperidinyl)carbonyl)propylcarbamate (0.36 g) obtained in Example 73d) was added a 4 N solution of hydrogen chloride in ethyl acetate (2.6 ml), mixed at room temperature for 5 minutes, and then concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 ml), triethylamine (0.14 ml) and 4-chlorophenyl isocyanate (0.08 g) were added thereto, and mixed at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=10/1). The product was crystallized from ethyl acetate-diethyl ether to obtain the title compound as colorless powder (0.28 g, 71%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OCC)(=[O:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:36](=[O:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@@H](C)O1
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@H](C)C2)c(F)c1F

Procedure:
Starting materials: (2R,6R)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (11.96 g, 24.13 mmol) (Intermediate 43) and diethyl oxalate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=2)=[N:10][C:9]([Br:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:25]=[N+:26]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=2)=[N:10][C:9]([Br:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2cccc(CO)c2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)nc(-c2cccc(C=O)c2)c1N=[N+]=[N-]
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Methyl 3-amino-6-bromo-2-(3-(hydroxymethyl)phenyl)isonicotinate (1.35 g, 4.00 mmol) was dissolved in TFA (20 mL) and the yellow solution was cooled in an ice bath. Solid sodium nitrite (0.553 g, 8.01 mmol) was added with stirring to give a yellow solution with gas evolution. After 30 min, sodium azide (2.60 g, 40 0 mmol) was added over 5 min followed immediately by Et2O (20 mL). A precipitate formed and, after 0.5 hr, water was added and the mixture was extracted with EtOAc. The organic phases were washed with water (3×), brine (1×), and then saturated Na2CO3 solution (until the aqueous phase was basic) and brine (1×). After drying with sodium sulfate, the solvent was removed. Flash chromatography (step gradient elution with DCM containing 20% hexane, DCM and DCM containing 5% EtOAc) afforded methyl 3-azido-6-bromo-2-(3-formylphenyl)isonicotinate (0.90 g, 2.5 mmol, 63% yield) as a tan solid. 1H NMR (400 MHz, chloroform-d) δ ppm 10.09 (1H, s), 8.27 (1H, t, J=1.51 Hz), 8.01-8.07 (1H, m), 7.98 (1H, ddd, J=7.68, 1.51, 1.38 Hz), 7.84 (1H, s), 7.65 (1H, t, J=7.68 Hz), 4.02 (3H, s).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:27]1[N:28]([CH2:35][C:36]2([CH3:39])[CH2:38][O:37]2)[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[N:31]=1>CN(C=O)C>[CH3:38][C:36]1([CH2:39][O:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=4)[CH2:10][CH2:11]3)=[CH:16][CH:17]=2)[O:37][C:27]2=[N:31][C:30]([N+:32]([O-:34])=[O:33])=[CH:29][N:28]2[CH2:35]1
Reactant: Oc1ccc(N2CCN(c3ccc(C(F)(F)F)cc3)CC2)cc1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COc2ccc(N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
4-[4-(4-Trifluoromethylphenyl)piperazin-1-yl]phenol (296 mg, 0.92 mmol) was dissolved in DMF (10 ml). To the solution, sodium hydride (44 mg, 1.1 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (200 mg, 0.92 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and then crystallized from methylene chloride/ethyl acetate to afford 2-methyl-6-nitro-2-{4-[4-(4-trifluoromethylphenyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (178 mg, yield 38%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NC1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CCOCC1
Temperature: 120 °C
Yield: 90.9 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.137 mmol) in DMF (10 mL) was added tetrahydro-2H-pyran-4-amine (1.108 g, 10.964 mmol) and TEA (2.772 g, 27.410 mmol). The reaction mixture was heated at 120° C. in microwave reactor for 30 mins. The reaction mixture was diluted with H2O then extracted with EA. The combined organic layers were dried over sodium sulfate, filtered and concentrated to yield a crude product (2.5 g) which was used in next step without further purification. LCMS (m/z): 301.0 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.N1C=CN=C1.[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)Cl)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.CN(C1C=CN=CC=1)C.O>[Si:18]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NC[C@@H](CO)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OC[C@@H]1CNC(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 79 %

Procedure:
(S)-5-(hydroxylmethyl)oxazolidin-2-one (1.61 g, 13.7 mmol) was dissolved in dried N,N-dimethyl formamide. Imidazole (1.87 g, 27.4 mmol) and DMAP (168 mg, 1.37 mmol) were added. The resulting mixture was cooled to 0° C., and then tert-butyldiphenylchlorosilane (5.66 g, 20.6 mmol) was added. The mixture was raised to room temperature to react for 4 hrs. The reaction was measured by TLC. After the reaction completed, the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was combined, washed sequentially with water and saturated saline solution, dried over anhydrous sodium sulfate, and filtered. Column chromatography afforded 3.85 g of white solid (compound 25a), yield 83%.
Reaction SMILES: [Cl:1][C:2]1([Cl:19])[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:17][CH3:18])[CH2:15][CH3:16].[N+](=[CH2:22])=[N-].CN(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+]>CCOCC.C(O)C.C(O)(=O)C>[Cl:19][C:2]1([Cl:1])[C:8](=[O:9])[CH2:22][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:17][CH3:18])[CH2:15][CH3:16]
Reactant: CCC(CCCCC1CCC2C1C(=O)C2(Cl)Cl)OC
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCC(CCCCC1CCC2C1CC(=O)C2(Cl)Cl)OC

Procedure:
The starting material, 6,6-dichloro-2-(5-methoxyhept-1-yl) bicyclo[3.2.0]heptan-7-one {7,7-dichloro-4-(5-methoxyheptyl)bicyclo [3.2.0]heptan-6-one} (5 g), is dissolved in 100 ml of ether and transferred to a 500 ml, round-bottomed flask. An excess of diazomethane is generated in situ by reacting N-methyl-N-nitroso-p-toluene sulfonamide (60 g) with potassium hydroxide in ethanol. The diazomethane is allowed to react for 50 minutes, after which time acetic acid is added to destroy any remaining diazomethane. The solution is extracted with ether and dried over anhydrous sodium sulfate and yields the crude product as an orange oil.
Reaction SMILES: [C:1](OO)(=[O:3])C.[CH3:6][O:7][C:8]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:9].COC(CCCC1C=C[N+]([O-])=CC=1)=O.[CH3:33][O:34][S:35]([O:38]C)(=[O:37])=[O:36]>C1(C)C=CC=CC=1>[CH3:33][O:34][S:35]([O-:38])(=[O:37])=[O:36].[CH3:6][O:7][C:8]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][N+:16]([O:3][CH3:1])=[CH:15][CH:14]=1)=[O:9]
Reactant: CC(=O)OO
Reactant: COC(=O)CCCc1ccncc1
Reactant: COS(=O)(=O)OC
Agent: COC(=O)CCCc1cc[n+]([O-])cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCCc1cc[n+](OC)cc1
Product: COS(=O)(=O)[O-]

Procedure:
Peracetic acid (40%, 2.9 ml) is added to 4-(3-methoxycarbonylpropyl)pyridine (3.20 g) at room temperature. The mixture is heated at 80° for 1 hour and the acetic acid is evaporated after a test for peroxide is negative. The residue is taken up in methylene chloride (50 ml), filtered, and the solvent evaporated. The resulting 4-(3-methoxycarbonylpropyl)pyridine-N-oxide is treated with dimethylsulfate (2.8 g, 22.2 mmol) in 12 ml of toluene at 80° C. for 1 hour. The solvent is evaporated to yield 5.45 g of the 4-(3-methoxycarbonylpropyl)-1-methoxypyridinium methyl sulfate salt which is added at 0° to a solution of 89.75 g potassium cyanide in 20 ml of water. The reaction is stirred at 0° for l hour and 25° for 3 hours and then extracted with methylene chloride (1×30 ml). The aqueous phase is reextracted, after standing for 24 hours, with methylene chloride (1×30 ml), and the combined extracts are dried over sodium sulfate and evaporated to yield a red oil. Chromatography on 70 g of silica gel with ether as the eluent yields 2-cyano-4-(3-methoxycarbonylpropyl)pyridine as an oil; NMR (CDCl3) 3.67 (s, 3 H), 7.42 (d, 1 H), 7.60 (s, 1 H), 8.60 (d, 1 H); IR (CH2Cl2) 1725 cm-1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=3)[O:10][C:3]=12.[CH3:19][C:20]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2>>[CH3:19][C:20]1[C:28]([NH:29][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=4)[O:10][C:3]=23)=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: OCc1ccc(-c2cc3nccc(Cl)c3o2)cc1
Product: Cc1c(Nc2ccnc3cc(-c4ccc(CO)cc4)oc23)ccc2[nH]ccc12

Procedure:
The title compound was prepared by procedure E using [4-(7-chlorofuro[3,2-b]pyridin-2-yl)phenyl]methanol (20.40 mg; 0.08 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (12.06 mg; 0.08 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (8 mg, 28%). (HPLC (method F): 97%, RT: 3.30 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.14 (s, 1H), 8.54 (s, 1H), 7.94 (d, J=5.4, 1H), 7.91 (d, J=8.2, 2H), 7.42 (d, J=8.1, 2H), 7.40-7.35 (m, 2H), 7.30 (d, J=8.3, 1H), 7.00 (d, J=8.4, 1H), 6.52 (s, 1H), 6.09 (d, J=5.4, 1H), 5.26 (s, 1H), 4.55 (d, J=5.6, 2H), 2.36 (s, 3H); MS (m/z) 370 [M+H]+, RT: 3.2 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.[C:11](#[N:17])[CH:12]([CH2:14][C:15]#[N:16])[OH:13].N1CCCCC1>CCO>[CH3:10][C:2]1([CH3:1])[CH2:3][C:4](=[O:5])[CH2:6][C:7](=[C:14]([C:15]#[N:16])[CH:12]([OH:13])[C:11]#[N:17])[CH2:9]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: N#CCC(O)C#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CC1(C)CC(=O)CC(=C(C#N)C(O)C#N)C1
Yield: 70.7 %

Procedure:
To a stirred solution of dimedone (98.0 g, 700.0 mmol) and malonitrile (46.2 g, 700.0 mmol) in EtOH (400 mL) at r.t. was added piperidine (8.5 g, 9.9 mL, 100.0 mmol) dropwise over 15 minutes. The reaction mixture was then heated to reflux for 3 days before cooling. The solvent was removed in vacuo and the residue was re-dissolved in EtOAc (500 mL) and dried (MgSO4). Filtration and concentration in vacuo gave a black oil that was purified by column chromatography (SiO2, 1:6 MeOH/DCM) to give the title compound as a yellow solid (108.0 g, 82%). δH (DMSO-d6) 8.31 (2H, br. s), 2.51 (2H, t, J 1.8 Hz), 2.30 (2H, s), 1.04 (6H, s). LCMS (ES−) 187.3 (M−H)−.