Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([N:9](CC=C)[CH:10]=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH:7]=[CH2:8].NC=CC=C(C#N)C#N>C(O)C>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([NH:9][CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:15])[C:16]#[N:17])[CH:7]=[CH2:8]
Reactant: C=CCN(C=CC=C(C#N)C#N)CC=C
Agent: C=CC(N)=O
Agent: N#CC(C#N)=CC=CN
Solvent: CCO
Product: C=CCNC=CC=C(C#N)C#N

Procedure:
A solution of 120 g of acrylamide and 114 g of 3-diallylaminoallylidenmalononitrile (A) in 500 ml of ethanol was brought to reflux. 3.2 g of 2,2'-azobisisobutyrronitrile (AZBN) were added thereto and the mixture was left to reflux for 1 hour under stirring. A solution of 104 g of acrylamide, 800 ml of ethanol and 3.2 g of AZBN was then introduced therein. The obtained solution was left to reflux for 1 hour under stirring. A solution of 88 g of acrylamide, 400 ml of ethanol and 2.4 g of AZBN was introduced therein and the solution was left to reflux for 1 hour. A solution of 72 g of acrylamide, 400 ml of ethanol and 1.6 g of AZBN was added thereto and the obtained solution was left to reflux for 1 hour. A solution of 56 g of acrylamide, 400 ml of ethanol and 1.6 g of AZBN was finally added thereto and the obtained solution was left to reflux for 2 hours. The so-obtained mixture was cooled, filtered, washed with ethanol and then with ethyl ether and dried under vacuum at 50° C., thus obtaining 478 g of a water soluble product containing about 9% w/w of aminoallylidenmalononitrile moieties.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][C@H:12]1/[CH:24]=[CH:25]\[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O-].[Na+].CO>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1/[CH:24]=[CH:25]\[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](/C=C\c2cccnc2)N(C(=O)OCc2ccccc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1/C=C\c1cccnc1
Reaction time: 3 h
Yield: 149.6 %

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-[(Z)-2-(pyridin-3-yl)vinyl]-pyrrolidine (4.70 g) in methanol (50 ml) was added conc. hydrochloric acid (2.68 ml) at ambient temperature with stirring and the mixture was allowed to stand at the same temperature for 3 hours. To the reaction mixture was added 28% sodium methoxide-methanol solution (6.20 ml) under ice-cooling with stirring and the resulting insoluble material was filtered off. The filtrate was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-1-benzyloxycarbonyl-4-hydroxy-2-[(Z)-2-(pyridin-3-yl)vinyl]-pyrrolidine (5.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:13][CH3:14].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18][N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[CH2:32][CH2:31]1)[CH2:13][CH3:14]
Reactant: CCC1(CCCCCl)C(=O)Nc2cc(F)c(Cl)cc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2cc(F)c(Cl)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 2 from 5-chloro-3-(4-chlorobutyl)-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH3:16])[CH:8]=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18])C.Cl.O>C(O)(C)C>[CH3:16][C:12]1[N:11]([C:9]2[CH:8]=[CH:7][C:6]([N+:17]([O-:19])=[O:18])=[C:5]([CH:10]=2)[CH:4]=[O:3])[CH:15]=[CH:14][N:13]=1
Reactant: CCOC(OCC)c1cc(-n2ccnc2C)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1nccn1-c1ccc([N+](=O)[O-])c(C=O)c1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of 5-(2-methylimidazol-1-yl)-2-nitrobenzaldehyde diethyacetal (735 mg), conc-HCl (2.0 ml), water (4.0 ml) and isopropyl alcohol (4.0 ml) was heated under stirring for 1 hour and cooled. The mixture was extracted with dichloromethane and the extract was dried with Na2SO4 and filtered. The filtrate was distilled to give 494 mg (88%) of the title compound.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].CCCCCC.C([Li])CCC.C(NC(C)C)(C)C.[Cl:27][C:28]1[CH:44]=[CH:43][C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][S:41][CH3:42])=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1.C(I)C>O1CCCC1>[Cl:27][C:28]1[CH:44]=[CH:43][C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH:40]([S:41][CH3:42])[CH2:1][CH3:2])=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Solvent: CC(C)NC(C)C
Product: CCC(SC)c1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran solution (30 ml) of lithium diisopropylamide which was prepared from a 1.6 M n-butyllithium hexane solution (12.5 ml) and diisopropylamine (2.1 g), a tetrahydrofuran solution (10 ml) of 4-chloro-4'-methylmercaptomethylbenzophenone (2.8 g) was added at -78° C., and the mixture was stirred for 30 minutes at the same temperature. Ethyl iodide (3.0 g) was subsequently added thereto at -78° C., and the mixture was stirred for 6 hours while restoring the mixture gradually to room temperature. After completing the reaction, the reaction mixture was washed with aqueous 5% ammonium chloride solution and aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the obtained crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=4:1) to obtain 4-chloro-4'-(1-methylmercaptopropyl)benzophenone (0.3 g) as oily substance.
Reaction SMILES: C[N:2]([C:4]([C:26](=O)[CH2:27]C)=[CH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:3].O.[CH3:31][NH:32]N>CO>[CH2:26]([C:4]1[N:2]([CH3:3])[N:32]=[CH:31][C:5]=1[S:6]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH3:27]
Reactant: CNN
Reactant: CCC(=O)C(=CS(=O)(=O)c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1)N(C)C
Solvent: CO
Solvent: O
Product: CCc1c(S(=O)(=O)c2ccc(O)cc2)cnn1C
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A mixture composed of 4.3 g (0.01 mole) of 1-(N,N-dimethylamino)-1propionyl 2-(4-tosyloxybenzenesulfonyl)ethene is heated at reflux for 20 hours in 25 ml of methanol and 10 ml of water in the presence of 2.35 g (0.05 mole) of methylhydrazine. The mixture is allowed to cool to room temperature and then cooled in ice for 1 h. It is evaporated to dryness and 4.85 g of residue are thus obtained which are recrystallized from 250 ml of water and decolorized with 0.8 g of active charcoal. The product is filtered off and allowed to crystallize for 2 hours in ice. It is recrystallized again from 50 ml of dichloroethene. In this manner, 1.15 g of 5-ethyl 4-(4-hydroxybenzenesulfonyl)1-methyl pyrazole is obtained which represents a yield of 43.2%. M.p.: 188.5°-190° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][CH2:7][O:8][C:9]1[CH:35]=[CH:34][C:12]2[C@:13]3([OH:33])[C@@H:18]([OH:19])[CH2:17][C@@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@:14]3([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[O:15][C:11]=2[CH:10]=1>CN(C=O)C>[N:1]([CH2:6][CH2:7][O:8][C:9]1[CH:35]=[CH:34][C:12]2[C@:13]3([OH:33])[C@@H:18]([OH:19])[CH2:17][C@@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@:14]3([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[O:15][C:11]=2[CH:10]=1)=[N+:2]=[N-:3]
Reactant: O[C@H]1C[C@@H](c2ccccc2)[C@]2(c3ccc(Cl)cc3)Oc3cc(OCCCl)ccc3[C@]12O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1ccc2c(c1)O[C@@]1(c3ccc(Cl)cc3)[C@H](c3ccccc3)C[C@H](O)[C@@]21O
Temperature: 100 °C

Procedure:
56.9 mg (0.87 mmol) of sodium azide are added to 200 mg (0.44 mmol) of (1S*,3S*,3aR*,8bS*)-6-(2-chloroethoxy)-3a-(4-chlorophenyl)-3-phenyl-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran-1,8b-(1H)-diol (Example 48A) in 4 ml of DMF under argon, and the mixture is heated at 100° C. overnight. After cooling and concentration, the residue is taken up in water and dichloromethane, the phases are separated, the aqueous phase is extracted twice with dichloromethane, and the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Gradient chromatography on silica gel 60 (mobile phase: toluene/ethyl acetate) results in 190 mg (94% of theory) of the product.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:20][C:21]1([CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH2:24][O:23][CH2:22]1>>[CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:20][C:21]3([CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH2:24][O:23][CH2:22]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: CNC(=O)CC1(N)COC1
Product: CNC(=O)CC1(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 2-(3-aminooxetan-3-yl)-N-methyl-acetamide (example 231a) as starting materials and isolated (25 mg, 43%); MS (ESI, m/z): 402.6 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8](COCC[Si](C)(C)C)[CH:7]=2)[CH:3]=[N:2]1.FC(F)(F)C(O)=O.N>>[NH:1]1[CH:5]=[C:4]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[NH:8][CH:7]=2)[CH:3]=[N:2]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cn[nH]c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cn[nH]c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 66.4 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (23 mg, 0.04 mmol) was treated with trifluoroacetic acid (460 μl, 5.97 mmol) and a solution of ammonia (7N in methanol, 460 μl, 3.22 mmol) according to the method described in Example 27 to give 12 mg (66% yield) of the title compound. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:28][NH:29][O:30][CH3:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][O:30][N:29]([CH3:28])[C:10](=[O:11])[C@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC[C@H](C(=O)N(C)OC)c1ccc(Cl)c(Cl)c1
Temperature: 22 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of 306 mg (1.25 mmol) of (2S)-(3,4-dichlorophenyl)-4-pentenoic acid (prepared according to the procedure of Hale, J. J.; Finke, P. E.; MacCoss, M. Bioorganic & Medicinal Chemistry Letters 1993,3, 319-322) and 202 mg (1.50 mmol) of 1-hydroxybenzotriazole hydrate in 10 mL of methylene chloride was cooled to 0° C. and treated with 287 mg (1.50 mmol) of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide. The cooling bath was removed and after 45 min. a solution of 365 mg (3.75 mmol) of N,O-dimethyl-hydroxylamine hydrochloride and 522 μl (3.75 mmol) of triethylamine in 10 mL of methylene chloride was added via cannula. The mixture was then stirred at 22° C. for 4 hours and then quenched with 10 mL of water and diluted with 8 mL of methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride (2×10 mL). The combined organic layers were washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 75 g of silica gel using 1:9 v/v ethyl acetate/hexane as the eluant afforded 319 mg (89%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ 2.40 (pentet, 1H), 2.75 (pentet, 1H), 3.13 (s, 3H), 3.52 (s, 3H), 3.99-4.01 (m, 1H), 4.96-5.05 (m, 2H), 5.63-5.70 (m, 1H), 7.15 (dd, 1H), 7.35 (d, 1H), 7.41 (d, 1H). Mass Spectrum (FAB): m/z 290 (M+H, 37Cl+35Cl isotope, 50%), 288 (M+H, 37Cl+37Cl isotope, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14]C(=O)C(C)(C)C)[CH:7]=1.[OH-].[Na+].CCOC(C)=O>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1-c1ccncc1NC(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1-c1ccncc1N

Procedure:
A solution of N-[4-(5-chloro-2-methyl-phenyl)-pyridin-3-yl]-2,2-dimethyl-propionamide (1 g, 3.3 mmol) in 3M aqueous HCl (50 mL) was stirred at 90° C. for 18 hours. The reaction mixture was poured on 200 mL 1M aqueous NaOH solution and 150 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 150 mL EtOAc. The combined organic layers were washed with 150 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Light brown viscous oil (720 mg, 99%). MS (ESI): m/z=219.068 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:38]([NH:41][CH:42]([C:48](O)=[O:49])[CH2:43][S:44][C:45](=[O:47])[CH3:46])(=[O:40])[CH3:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:48](=[O:49])[CH:42]([CH2:43][S:44][C:45](=[O:47])[CH3:46])[NH:41][C:38](=[O:40])[CH3:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)NC(CSC(C)=O)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(=O)NC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of L-proline tert-butyl ester (0.85 g.) and hydroxybenzotriazole (0.67 g.) in methylene chloride (10 ml.) chilled in an ice bath, dicyclohexylcarbodiimide (1.03 g.) and N,S-diacetyl-D,L-cysteine (1.7 g.) are added in that order. After fifteen minutes, the ice bath is removed and the mixture is stirred at room temperature overnight. The precipitate is filtered off and the filtrate is washed with 10% potassium bisulfate, water, saturated sodium bicarbonate, and water. The organic phase is dried and concentrated to dryness in vacuo to give N,S-diacetyl-D,L-cysteinyl-L-proline tert-butyl ester as an oil. Rf =0.25 (silica gel, ethylacetate).
Reaction SMILES: [Cl-].C([N+]1C=CC(C(=O)NCC(C2C=CC=CC=2)COCC2C=CC(C(F)(F)F)=C(C(F)(F)F)C=2)=CC=1)C1C=CC=CC=1.[CH3:43][N:44]([CH3:54])[C:45]1[CH:53]=[CH:52][C:48]([C:49]([OH:51])=O)=[CH:47][CH:46]=1.Cl.[F:56][C:57]([F:81])([F:80])[C:58]1[CH:59]=[C:60]([CH:73]=[C:74]([C:76]([F:79])([F:78])[F:77])[CH:75]=1)[CH2:61][O:62][CH2:63][CH:64]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH2:65][NH2:66].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:56][C:57]([F:80])([F:81])[C:58]1[CH:59]=[C:60]([CH:73]=[C:74]([C:76]([F:77])([F:79])[F:78])[CH:75]=1)[CH2:61][O:62][CH2:63][CH:64]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH2:65][NH:66][C:49](=[O:51])[C:48]1[CH:47]=[CH:46][C:45]([N:44]([CH3:43])[CH3:54])=[CH:53][CH:52]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(NCC(COCc1ccc(C(F)(F)F)c(C(F)(F)F)c1)c1ccccc1)c1cc[n+](Cc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)NCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)cc1
Yield: 82.4 %

Procedure:
In the same manner as in the case of synthesis of Compound 30, a residue was given from 4-dimethylaminobenzoic acid (0.43 g, 2.5 mmol), the compound produced in Example 17 (1.03 g, 2.5 mmol), triethylamine (0.36 mL, 2.6 mmol), WSC.HCl (0.50 g, 2.6 mmol) and CH2Cl2 (25 mL). The oily residue was crystallized from petroleum ether to give the Compound 58 (1.08 g, 82%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[Li+].CC([N-]C(C)C)C.F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: OCCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OCCCl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
In a round bottom flask under nitrogen, 2-chloro-ethanol (8.3 mL, 120 mmoles) in THF (40 mL) was cooled to 0° C. LDA (60 mL, 120 mmoles) was added dropwise, while maintaining the temperature constant at 0° C. The mixture was stirred at this temperature for 15 minutes, followed by the addition of 2,4-difluoronitrobenzene (11 mL, 100 mmoles). The mixture was stirred at room temperature overnight. Reaction mixture was diluted with water, extracted with EtOAc, washed with brine (1×), dried over Na2SO4, and concentrated under vacuum, to afford the title compound as an off-white solid (20.0 g, 91 mmoles).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>ClCCl>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[O:6][C:2]([CH3:1])=[C:3]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:4]=2)=[CH:12][CH:11]=1)=[O:30]
Reactant: Cc1oc(-c2ccc(N)cc2)nc1-c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1oc(-c2ccc(NC(=O)c3ccc(Cl)cc3Cl)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
to a solution of 4-(5-methyl-4-phenyloxazol-2-yl)benzenamine (311 mg, 1243 μmol) and pyridine, anhydrous (1013 μl, 12425 μmol) in 4 mL dichloromethane at room temperature was added all at once by metered pipet 2,4-dichlorobenzoyl chloride (192 μl, 1367 μmol). The reaction was stirred at room temperature for 1 hour then concentrated under reduced pressure, triturated with heptane and concentrated under reduced pressure. The residue was triturated with ethyl acetate and the isolated solid (170 mg) was purified by reversed phase preparative HPLC. Fractions containing product were combined and concentrated under reduced pressure. The concentrate was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution and the organic separation dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless solid (100 mg, 19%). ESI+ m/z=423.0 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.C([O-])(=O)C.[NH4+:17].O.[OH-].[Na+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH2:17])[CH2:7][CH2:6][CH2:5]2
Reactant: [NH4+]
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: NC1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
6-Bromo-3,4-dihydro-2H-naphthalen-1-one (9.5 g, 42.2 mmol) was suspended in 2-propanol (250 ml); then, NaBH3 CN (13.3 g, 211 mmol) was added, followed by ammonium acetate (65.1 g, 844 mmol). The reaction mixture was then stirred at RT for 4 hours. It was subsequently heated up to reflux and stirring was continued for 22 hours. The reaction mixture was then cooled down to RT and poured into cold H2O (500 ml); the pH was adjusted to >10 with sodium hydroxide solution and the mixture was extracted with CH2Cl2 (2×25 ml). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (9.842 g) which was purified by flash chromatography (silica gel, 100 g, 2% to 10% MeOH in CH2Cl2) to yield the title compound (8.08 g, 85%) as light red oil. MS: 226.0 (MH+, 1Br).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:12])[N:7]=[N:8][C:9]=1[CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[C:6]([O:12][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[N:7][NH:8][C:9]=1[CH2:10][OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)C1=C(CO)N=NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2n[nH]c(CO)c2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.5 %

Procedure:
To a suspension of 4-tert-butyl-5-hydroxymethylpyrazol-3-one (6.25 g, 0.037 mol) in dry dichloromethane (200 ml) was added p-toluene sulfonyl chloride (9.8 g, 0.051 mol) followed by triethylamine (6.14 ml, 0.044 mol) dropwise. The solution was stirred at room temperature for 3 days. Dichloromethane (250 ml) was then added to dilute and the solution was washed with brine (250 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with 0%→30% ethyl acetate/dichloromethane as eluent to give the title compound (7.5 g). Data for the title compound: 1H NMR (400 MHz, DMSO) δ 1.28 (9H, s), 2.43 (3H, s), 4.49 (2H, m), 5.32 (1H, m), 7.47 (2H, m), 7.86 (2H, m), 12.28 (1H, s); MS (ES+) m/e 325 [MH]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][OH:17])[C:13](=[O:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:26]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][CH3:26])[CH:13]([OH:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(CO)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: ClCCl
Product: COCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1O
Temperature: 0 °C
Yield: 81.4 %

Procedure:
To a stirred solution of Intermediate 117 (7.3 g, 19.65 mmol) in DCM (180 mL) was added N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (25.3 g, 117.89 mmol). Then it was cooled to 0° C. and trimethyloxonium tetrafluoroborate (8.72 g, 58.94 mmol) was added. The reaction was then stirred at rt for several hours until LCMS showed the starting material was all consumed. Then it was concentrated under reduced pressure. The residue was then taken up in 100 mL Et2O and filtered, washed with 100 mL Et2O. The organic layer was then washed with 10% citric acid, aq NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was then taken up in MeOH (180 mL), cooled to 0° C. and cerium(III) chloride (7.32 g, 19.65 mmol) was then added to give a clear solution. Then NaBH4 (0.743 g, 19.65 mmol) was added as solid, and the mixture was stirred from 0° C. to rt for 1 hr. The reaction mixture was concentrated in vacuo. The white solid was redissolved in 200 mL Et2O and washed with 10% citric acid, NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column (20-80% Hex/EA, 80 g) to afford the title compound (6.20 g, 81%) as a colorless oil (−3.8:1 mixture of 2 diastereomers).