Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:40][CH2:39]1
Reactant: CN1CCNCC1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(C)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of 3.6 g of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoro-methyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 3.7 ml of 1-methylpiperazine in 80 ml dichloromethane is stirred at 40° C. for 2 hours. The reaction mixture is concentrated to dryness and the resulting residue is purified by flash chromatography [silica gel, eluent: dichloromethane/methanol/triethylamine, elution gradient 99.7/0/0.3 (v/v/v) to 89.7/10/0.3 (v/v/v)]. The obtained product is filtered through a short plug of Flash-NH2 silica gel [eluent: dichloro-methane/methanol, 9/1 (v/v)] in a further purification step. After evaporation of the solvents, the resulting oil is treated with 5 ml diethyl ether, resulting in precipitation of the product. After filtration the title compound is obtained as white solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:3].[H][H].CCOCC>Cl>[NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]1)([CH3:9])[CH3:8])[CH3:3]
Reactant: [H][H]
Reactant: CC(N)CCCC(C)(C)c1ccc(N)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(N)CCCC(C)(C)[C@H]1CC[C@H](N)CC1
Temperature: 25 °C

Procedure:
5.0 Parts of 2-amino-6-(4-aminophenyl)-6-methylheptane dissolved in 68 parts of 1N aqueous hydrochloric acid were shaken at room temperature and atmospheric pressure with hydrogen in the presence of 0.5 parts of Nishimura catalyst (rhodium-platinum oxides). Hydrogen uptake ceased at 105% of theory and the solution was filtered free of catalyst and treated with sodium hydroxide solution to give an oil which was isolated with ether. After removing the ether the residue was distilled to give 4.0 parts of cis and trans-2-amino-6-(4-aminocyclohexyl)-6-methyl-heptane b0.3 120°-9° with the following percentage composition by weight.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[O:18][CH:19]=[N:20][N:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[CH2:26]>>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1/[CH:25]=[CH:26]/[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[O:18][CH:19]=[N:20][N:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)c1ccccc1-c1nnco1
Reactant: C=Cc1ccc(F)cc1F
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)cc1)c1ccccc1-c1nnco1

Procedure:
The title compound was prepared according to the method of preparation of Intermediate 1, Step 2, using 2-{2-[(4-bromophenyl)sulfonyl]phenyl}-1,3,4-oxadiazole (Step 1) in place of 3-[(4-bromophenyl)sulfonyl]propanenitrile and 2,4-difluorostyrene in place of 4-fluorostyrene. δH (500 MHz, d6 DMSO): 9.45 (1H, s), 8.35 (1H, d, J 7.8), 7.97-7.85 (8H, m), 7.47-7.31 (3H, m), 7.17 (1H, t, J 8.6). m/z (ES+) 425 [MH+].
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[CH2:14][CH2:13][C:12]2=[O:28])C.[OH-].[K+].CO>O>[O:28]=[C:12]1[C:11]2[C:15](=[CH:16][C:17]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=3)=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])[CH:10]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)CCCOc1cc2c(cc1-c1ccc(C(F)(F)F)cc1)CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCOc1cc2c(cc1-c1ccc(C(F)(F)F)cc1)CCC2=O

Procedure:
1.2 g (3 mmol) of ethyl4-[3-oxo-6-(4-trifluoromethylphenyl)indan-5-yloxy]butyrate are mixed with 250 mg (45 mmol) of potassium hydroxide, 40 ml of methanol and 10 ml of water. The mixture is heated at reflux for 2 hours and the methanol is then evaporated off. The solution obtained is washed with ether; the aqueous phase is acidified and extracted with dichloromethane. The organic phase is dried (Na2SO4) and the solvents are evaporated off: yellow solid (0.95 g). Purification of the compound by flash chromatography (98/2 dichloromethane/methanol) [lacuna] (0.56 g; 50%).
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:8][CH2:9][C:10](=O)[CH2:11]Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:2]([C:1]1[O:6][CH:11]=[C:10]([CH2:9][Cl:8])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(CCl)co1
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 38.1 %

Procedure:
A mixture of pivalamide (30 g) and 1,3-dichloro-2-propanone (37.66 g) was stirred at 160° C. for 1.5 hrs. Saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the reaction mixture, and insoluble materials were removed by filtration. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:5-1:2, v/v). The obtained oily substance (a mixture (41 g) of 2-tert-butyl-4-chloromethyl-1,3-oxazole and 1,3-dichloro-2-propanone) was dissolved in tetrahydrofuran (500 mL) ethanol (50 mL), sodium borohydride (5 g) was added, and the mixture was stirred at room temperature for 16 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:20, v/v) to give 2-tert-butyl-4-(chloromethyl)-1,3-oxazole as a colorless oil (19.61 g, yield 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[N:21]1([CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][O:31][C:30]2=[O:34])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:17])[N:24]3[CH2:25][CH2:26][N:21]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][O:31][C:30]4=[O:34])[CH2:22][CH2:23]3)[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Agent: Cl
Product: O=C(Nc1nc(CC(=O)N2CCN(CCN3CCOC3=O)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 3-[2-(1-piperazinyl)ethyl]-2-oxazolidinone hydrochloride (CAS 52548-39-7) to give 4-chloro-N-[4-(2-oxo-2-{4-[2-(2-oxo-oxazolidin-3-yl)-ethyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide, using general procedure C. White amorphous solid. MS 478.4 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:24][C:25](=[O:27])[CH3:26]>C1COCC1>[O:27]=[C:25]([CH3:26])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CC(=O)CCl
Reactant: Oc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)COc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.6 %

Procedure:
8-Hydroxyquinoline (0.73 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and dry N,N-dimethylformamide (DMF) (40 ml) were stirred at room temperature for 30 min. To this solution was added chloroacetone (0.46 g, 5 mmol) in dry THF (10 ml) in one portion. The resulting mixture was stirred at room temperature for 24 h. (monitored by TLC) and then poured into ice water (100 ml). The pale yellow solid thus obtained was collected and crystallized from dichloromethane and ether to afford 8-(2-oxopropoxy)quinoline (7a) (0.68 g, 67%) as a pale yellow needle crystal. mp: 58°-59° C.; 1H-NMR (CDCl3): δ2.32 (s, 3H, CH3), 4.88 (s, 2H, OCH2), 6.88-8.97 (m, 6H, Ar--H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=3)=[N:10][C:9]=2[N:8]([CH3:36])[C:7]1=[O:37].[C:38](Cl)(=[O:40])[CH3:39]>C1COCC1.O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:12]2[C:13]3[C:14](=[O:15])[N:6]([CH2:5][CH2:4][CH2:3][NH:2][C:38](=[O:40])[CH3:39])[C:7](=[O:37])[N:8]([CH3:36])[C:9]=3[N:10]=[C:11]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:33])[F:35])[CH:26]=2)=[CH:18][CH:19]=1
Reactant: Cn1c(=O)n(CCCN)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
1-(3-Aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.10 g, 0.19 mmol, example 357) and TEA (0.80 mL, 0.57 mmol) were combined in THF (1 mL). Acetyl chloride (0.28 mL, 0.42 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to an oil. The oil was purified using a 2000 micron preparative TLC plate eluted with 5% methanol/DCM. Target band was scraped off plate and eluted off silica gel with eluent to give N-(3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl)acetamide (0.053 g, 49% yield) as a light tan solid. LCMS retention time=3.789 minutes and 99% purity, LCMS MH+ 566. 1H NMR (DMSO-d6) δ 7.78-7.82 (m, 1H), 7.59 (t, 1H, J=8 Hz), 7.44-7.48 (m, 1H), 7.38-7.42 (m, 5H), 7.31 (d, 1H, J=8 Hz), 5.42 (s, 2H), 3.87 (t, 2H, J=8 Hz), 3.28 (s, 3H), 2.04 (dd, 2H, J=4 Hz and 12 Hz), 1.78 (s, 3H), 1.61-1.70 (m, 2H).
Reaction SMILES: C1(C[NH:8][C@@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:11][C@H:10]2[OH:24])C=CC=CC=1.[H][H]>[Pd].CO>[NH2:8][C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]2[N:19]=[CH:20][CH:21]=[CH:22][N:23]=2)[CH2:11][C@H:10]1[OH:24]
Reactant: [H][H]
Reactant: O[C@@H]1CN(CCNc2ncccn2)CC[C@H]1NCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CCN(CCNc2ncccn2)C[C@H]1O
Yield: 86.9 %

Procedure:
A mixture of 10.6 parts of trans-4-[(phenylmethyl)amino]-1-[2-(2-pyrimidinylamino)ethyl]-3-piperidinol and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The second fraction was collected and the eluent was evaporated, yielding 6.6 parts (86.9%) of trans-4-amino-1-[2-(2-pyrimidinylamino)ethyl]-3-piperidinol as a residue (interm. 19).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([NH2:13])[CH2:11][NH2:12]>CCO.O>[CH:7]1[CH:6]=[CH:5][C:3](=[O:4])/[C:2](=[CH:1]/[NH:12][CH2:11][CH2:10][NH:13]/[CH:1]=[C:2]2/[CH:8]=[CH:7][CH:6]=[CH:5][C:3]/2=[O:4])/[CH:8]=1
Reactant: NCCN
Reactant: O=Cc1ccccc1O
Solvent: O
Solvent: CCO
Product: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of salicylaldehyde (24.42 g, 0.200 mole) in 80 ml of EtOh was added to a stirred solution of ethylenediamine (6.070 g, 0.100, olc) in a mixture of 50 ml EtOH and 50 ml of H2O over a period of 5 minutes. The reaction mixture was refluxed for 1 hour and stirred at room temperature overnight. The yellow crystalline product was separated by filtration and washed with 2×30 ml of cold 60% EtOh and air dried to yield 25.733 g (95.9%) of salen.
Reaction SMILES: C(O[C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])C.[NH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH2:16]>O1CCCC1>[F:6][C:5]([F:8])([F:7])[C:4]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH:16][C:4](=[O:9])[C:5]([F:6])([F:7])[F:8])=[O:9]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCNCCN
Solvent: C1CCOC1
Product: O=C(NCCNCCNC(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
113.3 g (790 mmol) of trifluoroacetic acid ethyl ester is added in drops to a solution consisting of 41.14 g (390 mmol) of 1,4,7-triazaheptane in 350 ml of tetrahydrofuran at 80° C. and under nitrogen. It is allowed to stir overnight at room temperature, concentrated by evaporation in a vacuum. The remaining oil is crystallized from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH:16]1[CH:20]=[C:19]([CH:21]=[O:22])[N:18]=[CH:17]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:16]2[CH:20]=[C:19]([CH:21]=[O:22])[N:18]=[CH:17]2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]cn1
Reactant: C=CC(=O)NC(C)(C)c1ccc(Cl)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(NC(=O)CCn1cnc(C=O)c1)c1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
A mixture of N-[1-(4-chlorophenyl)-1-methylethyl]-acrylamide (22.35 g), imidazole-4-carboxaldehyde (9.6 g), benzyltrimethylammonium hydroxide (2.24 ml of a 40% solution in methanol, Triton®B) and 1,4-dioxane (112 ml) was stirred and heated at 95° C. for 6 hours and then worked up as described in Example 19a to give N-[1-(4-chlorophenyl)-1-methylethyl]-3-(4-formylimidazol-1-yl) propionamide, m.p. 151°-153° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[F-].[K+]>C1COCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccccc1Br
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(Cl)cc1
Yield: 95 %

Procedure:
2-Bromoanisole (97 mg, 0.52 mmol) reacted with 4-chlorophenylboronic acid (102 mg, 0.65 mmol) using 0.5/1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (8.8 mg, 1.57 mmol) in THF (2 ml) at room temperature to give the title compound (108 mg, 95%): 1H-NMR (400 MHz, CDCl3): δ 7.51 (d, 2H, J=8.4 Hz), 7.42 (d, 2H, J=8.0 Hz), 7.46-7.32 (m, 2H), 7.08 (t, 1H, J=7.6 Hz, aryl coupling J=1.2), 7.03 (d, 1H, J=8.0 Hz), 3.85 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 156.27, 136.86, 132.79, 130.81, 130.60, 129.33, 128.94, 128.10, 120.85, 111.16, 55.47. GC/MS(EI): m/z 218 (M+), 220 (M++2, Cl isotope peak), 168, 139. Anal. Calcd for C13H11ClO: C, 71.40; H, 5.07. Found: C, 71.47; H, 5.21.
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]2=[O:23])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCCCCC.C(Cl)(Cl)Cl>[O:23]=[C:8]1[C:9]([CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC1(Cc2ccncc2)C(=O)N(N2CCOCC2)c2ccccc21

Procedure:
The product obtained from Example 20 could be reacted with sodium hydride and ethyl bromoacetate in a manner similar to Example 8 to render the product as a crystalline white solid, m.p. 168°-2/3° C. (hexane-chloroform). High Res. Mass Spec. Calcd. for C22H25N3O4 : 396.1923 (M+H). Found: 396.1922.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH2:25]([O:32][CH2:33][C@H:34]([CH3:37])[CH:35]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCCCCC>C(Cl)Cl>[CH2:25]([O:32][CH2:33][C@@H:34]([CH3:37])[CH:35]=[C:20]([Br:24])[Br:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H](C=O)COCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: C[C@@H](C=C(Br)Br)COCc1ccccc1
Temperature: 2.5 °C

Procedure:
An oven dried three-necked 2 L round bottom flask was equipped with a mechanical stirrer, a thermometer, an N2 inlet, and a septum. The flask was charged with 180.71 g (0.689 mol) of triphenyl- phosphine and 925 mL of CH2Cl2. The reaction mixture was stirred under an N2 atmosphere and cooled to 0-5° C. with an external ice-water bath. The septum was then removed and 114.25 g (0.344 mol) of carbon tetrabromide was added in portions through the open neck of the flask at a rate that maintained the temperature of the reaction mixture below 20° C. After the addition was complete the reaction was stirred for 1 h and then a solution of the (S)-3-benzyloxy-2-methylpropanal from the previous step dissolved in 150 mL of CH2Cl2 was added via cannula over a 5 min period. The reaction mixture was stirred under N2 for an additional 1 h and allowed to warm to room temperature. A separate 10 L three-necked round bottom flask was equipped with a mechanical stirrer and charged with 4 L of hexane. The stirrer was started and the crude reaction mixture was introduced as a slow stream which resulted in formation of a granular precipitate. After the transfer was complete the reaction mixture was filtered and the solids were carefully washed with hexane. The filtrate was evaporated in vacuo and additional solids were deposited. The residue was resuspended in hexane, filtered and the filtrate reevaporated. The resulting oil was purified by Kugelrohr distillation to afford 46.54 g of the title compound as an oil.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH2:11][C:12](=[O:14])[N:13]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>C1COCC1>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]2([CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:12](=[O:14])[N:13]=1
Reactant: O=C1CSC(N[C@H]2C[C@@H]3CC[C@H]2C3)=N1
Reactant: BrCCOCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC12CCOCC2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To the mixture of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)thiazol-4(5H)-one (840 mg, 4.0 mmol) in THF (5.0 mL) was added LDA (2.0 M, 20 mL) at −78° C. The resulting mixture was stirred for 10 min at −78° C., and then 1-bromo-2-(2-bromoethoxy)ethane (3.71 g, 16 mmol) was added. The mixture was allowed to warm to room temperature and then stirred overnight. A sat'd solution of NaH2PO4 was added, and it was extracted with EtOAc. The organic layer was washed with sat'd NH4Cl, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified through flash chromatography (4:1:0.05; CH2Cl2/EtOAc/MeOH) to give the title compound as off-white solid. MS (ES+): 281 (M+H)+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH3:34])[CH:18]=[CH:17][C:16]([S:19]([O:22][CH2:23][C@@H:24]([OH:33])[CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:54](O)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>O1CCCC1>[C:13]1([CH3:34])[CH:18]=[CH:17][C:16]([S:19]([O:22][CH2:23][C@H:24]([O:33][C:54](=[O:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCc2cccnc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)OC(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 64.7 %

Procedure:
Diethyl azodicarboxylate (0.61 ml) was added to a solution of (2S)-2-hydroxy-4-(3-pyridyl)-1-butyl para-toluenesulfonate (1.4 g), triphenylphosphine (1.31 g) and benzoic acid (0.61 g) in tetrahydrofuran (30 ml) at 0° C. and the resulting solution stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue obtained purified by column chromatography over silica eluting with diethyl ether to give the sub-title compound as a white solid (1.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8](/[C:10](=N/[S@@](C(C)(C)C)=O)/[CH2:11][CH2:12][CH3:13])[CH:9]=1)([O-:3])=[O:2].[C:21]([O:24][CH3:25])(=[O:23])[CH3:22]>>[CH3:25][O:24][C:21](=[O:23])[CH2:22][CH:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCC/C(=N\[S@](=O)C(C)(C)C)c1cccc([N+](=O)[O-])c1
Reactant: COC(C)=O
Product: CCCC(CC(=O)OC)c1cccc([N+](=O)[O-])c1

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(5-nitro-phenyl)-(E)-butylidene]-amide and methyl acetate, the product (S)-3-(R)-2-methyl-propane-2-sulfinylamino)-3-(3-nitro-phenyl)-hexanoic acid methyl ester was obtained as a white solid. MS (ESI): m/z=371.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=3)[N:15]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12]>CO.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[N:15]([C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12]
Reactant: COCCOc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)cc1F
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: COCCOc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(N)cc23)cc1F
Reaction time: 6 h
Yield: 98 %

Procedure:
A suspension of 3-[3-fluoro-4-(2-methoxy-ethoxy)-phenyl]-1-trityl-5-nitro-1H-indazole 4 (2.8 g, 4.88 mmol) and catalytic amount of Pd on carbon (5 wt %, 0.5 g) in 120 mL of methanol/toluene (1:1) was stirred under a hydrogen atmosphere for 6 h and filtered through Celite. The filtrate was concentrated to provide 3-[3-fluoro-4-(2-methoxy-ethoxy)-phenyl]-1-trityl-1H-indazol-5-ylamine 5 (2.6 g) as an off-white solid.
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]2=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[O:26]=O>>[OH:26][C:9]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]1=[O:23]
Reactant: O=O
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: O=C1N(N2CCCCC2)c2ccccc2C1(O)Cc1ccncc1
Yield: 25 %

Procedure:
1,3-dihydro-1-(1-piperidinyl)-3-(4-pyridinyl methyl)-2H-indol-2-one could be reacted with sodium hydride and oxygen as reported in Example 22. After column chromatography, the product was recrystallized from hexane-chloroform to give the product as a brown solid, m.p. 156°-158° C. in 25% yield. High Res. Mass Spec. Calcd. for C19H21N3O2 : 324.1712(M+H). Found: 324.1709.