Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[C:18]([C:20]([NH:22][C:23]3[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:26]([O:28]C)=[O:27])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[C:18]([C:20]([NH:22][C:23]3[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:26]([OH:28])=[O:27])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O)CC3)nc3ccccc23)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)c(C)c1NC(=O)c1cc(N2CCC(O)CC2)nc2ccccc12
Reaction time: 5 h
Yield: 31.1 %

Procedure:
A solution of aqueous 2N NaOH (2.00 ml) is added to a stirred solution of methyl 3-(2-(4-hydroxypiperidin-1-yl)quinoline-4-carboxamido)-2,4-dimethylbenzoate (0.10 g, 0.00023 mol) in THF:MeOH (4 ml:2 ml). After 5 h at 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with aqueous 1N HCl, and extracted with ethyl acetate (2×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with pentane and diethyl ether and filtered to afford the title compound as a light yellow solid (0.03 g, 31%). Mass spectrum (m/z): 420.2 (M+1).
Reaction SMILES: C(C1C=C2C(=CC=1)C(=O)OC2)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:19](=[O:20])[O:18][CH2:17]2.C([Cu])#N>>[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:19](=[O:20])[O:18][CH2:17]2.[NH2:13][C:14]1[CH:15]=[C:16]2[C:17](=[O:18])[NH:2][C:19](=[O:20])[C:21]2=[CH:22][CH:23]=1
Reactant: N#Cc1ccc2c(c1)COC2=O
Agent: N#C[Cu]
Agent: Nc1ccc2c(c1)COC2=O
Product: Nc1ccc2c(c1)C(=O)NC2=O

Procedure:
A method for the preparation of 5-cyanophthalide has previously been described in Bull. Soc. Sci. Bretagne, 26, 1951, 35 and in Levy and Stephen, J. Chem. Soc., 1931, 867. By this method, 5-aminophthalide is converted to the corresponding 5-cyanophthalide by diazotation followed by reaction with CuCN. 5-Aminophthalide was obtained from 4-aminophthalimide by a two step reduction procedure.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7](OC)[N:6]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:4].[CH2:23]([Si](C)(C)C)[CH:24]=[CH2:25].O>C(Cl)Cl.[Cl-].[Na+].O.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:25][CH:24]=[CH2:23])[N:6]1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])=[O:4]
Reactant: C=CC[Si](C)(C)C
Reactant: COC(=O)C1CCCC(OC)N1C(=O)OCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCC1CCCC(C(=O)OC)N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
6-Methoxy-piperidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (Compound 233, 1.04 g, 3.39 mmol) was dissolved in CH2Cl2 (10 mL), and the solution was cooled to −78° C. using dry ice-acetone bath. 1M TiCl4 solution in CH2Cl2 (3.7 mL) was added dropwise over a 1-minute period, followed by allyltrimethylsilane (1.61 mL, 10.14 mmol). The bath was changed to water, and the reaction mixture was stirred for 2 hours. The reaction mixture was poured into brine (50 ml) and extracted with CHCl3 (2×50 mL). The combined organic layers were washed with saturated NaHCO3 solution (50 mL) and finally dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography (1:5 EtOAc/hexanes) to give Compound 234 (0.91 g, 84%). Rf=0.78 (1:2 EtOAc/hexanes).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]1([C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=2[CH:27](O)[CH3:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P([N:44]=[N+:45]=[N-:46])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:44]([CH:27]([C:19]1[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:18]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:28])=[N+:45]=[N-:46]
Reactant: CC(O)c1oc2ccccc2c1-c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(N=[N+]=[N-])c1oc2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
DBU (155 μL, 1.04 mmol) was added dropwise to a solution of 1-(3-phenylbenzofuran-2-yl)ethanol (206 mg, 0.864 mmol) and diphenyl phosphoryl azide (255 μL, 1.04 mmol) in anhydrous THF (7 mL) at 0° C. under a nitrogen atmosphere. After 30 min stirring at 0° C., the mixture was slowly warmed to RT and stirring was continued for 1.5 h. Additional diphenyl phosphoryl azide (255 μL, 1.04 mmol) and DBU (155 μL, 1.04 mmol) were added and stirring was continued for 18 h. Volatiles were removed under reduced pressure and the resulting residues was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) affording the title compound as an oil (186 mg, 82%). LCMS: RT 4.48 min [M+H-N2]+ 236.1.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([Cl:15])=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:16]O>S(=O)(=O)(O)O.CCOC(C)=O>[NH2:1][S:2]([C:5]1[C:6]([Cl:15])=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([O:12][CH3:16])=[O:11])(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(F)cc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1F
Yield: 95 %

Procedure:
5-(Aminosulfonyl)-4-chloro-2-fluorobenzoic acid (507 mg, 2.0 mmol) in CH3OH (3 mL) with 3 drops of concentrated sulfuric acid was heated at 80° C. for 60 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water, brine, and dried (Na2SO4). The solvent was evaporated to afford the product (508 mg, 95%) as a white solid. MS (ES+) m/z 268 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:10]([S-:12])#[N:11].[K+]>C1(C)C=CC=CC=1>[O:9]=[C:3]([CH2:2][S:12][C:10]#[N:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: N#C[S-]
Reactant: COC(=O)CC(=O)CCl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)CSC#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of methyl 4-chloro-3-oxobutanoate (10 g, 66 mmol) in toluene (100 ml) was added a vessel containing KSCN (9.6 g, 99 mmol), the reaction mixture was stirred at rt for 24 h. LCMS showed that the desired product was detected, the mixture was concentrated to give the residue, the residue was purified by a standard method to give the desired product. LC-MS: m/z (M+H)=174.3
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=O)[CH:14]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][NH:26][CH:23]2[CH2:25][CH2:24]2)[CH:14]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C=O)c1)CC(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CNC2CC2)c1)CC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
(4-Chloro-3-formyl-benzyl)-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (563 mg, 1.69 mmol) was dissolved in MeOH (18 mL). Cyclopropylamine (0.181 mL, 2.53 mmol) was added, and the mixture was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (96 mg, 95.7 mg, 2.53 mmol) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. The residue was taken in EtOAc, and the mixture was washed with aq. sat. NaHCO3 (1×) and brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2/MeOH 95:5) yielded the title compound (558 mg, 88%). LC-MS: tR=0.76 min; ES+: 375.15.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH:28]([CH3:32])[NH:27]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:30]3[CH2:29][C@@H:28]([CH3:32])[NH:27][C@@H:26]([CH3:25])[CH2:31]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC1CNCC(C)N1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(N2C[C@@H](C)N[C@@H](C)C2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Stoichiometric amounts (0.04 mol) of methyl proplolate and ethyl 3-aminocrotonate were heated to 140° C. for 1 h. 1 g of the crude (2E,4Z)-methyl-4-(1-aminoethylidene)-5-oxooct-2-enoate in 4 mL of DMF was heated to 230° C. in a sealed microwave reactor for 40 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford crude ethyl 6-hydroxy-2-methylnicotinate. A mixture of 800 mg of crude ethyl 6-hydroxy-2-methylnicotinate in 4 mL of phosphorus oxychloride was heated to 150° C. in a sealed microwave reactor for 15 min. The reaction mixture was poured into ice/water, extracted with diethyl ether. The combined organic layers were dried (MgSO4) and evaporated. Purified by silica gel chromatograph (0-20% ethyl acetate/hexane) to yield ethyl 6-chloro-2-methylnicotinate. 400 mg of ethyl 6-chloro-2-methylnicotinate was hydrolyzed via Procedure M to give 6-chloro-2-methylnicotinic acid. 300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-chloro-2-methylnicotinic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 128 mg of 2,6-dimethylpiperazine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-methylnicotinamide. MS (Q1) 436.3 (M)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:24]([OH:26])=[O:25])[C:15]([CH2:18][C:19]4[S:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N+]=[N-])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.C(OCC)(=O)C>[C:29]1([CH:35]([O:25][C:24]([CH:14]2[N:13]3[C:27](=[O:28])[C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C@H:12]3[S:17][CH:16]=[C:15]2[CH2:18][C:19]2[S:23][CH:22]=[CH:21][CH:20]=2)=[O:26])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)C(Cc3cccs3)=CS[C@H]12
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(Cc3cccs3)=CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7β-phenylacetylamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid in 150 ml of methanol is diluted with 200 ml of ethyl acetate, then treated with 9.70 g of diphenyldiazomethane in 20 ml of ethyl acetate. The reaction mixture is stirred at room temperature for 1 hour and evaporated to dryness under reduced pressure. The residue is crystallised from ethyl acetate and chromatographed on 400 g of silica gel. Elution with ethyl acetate yields the 7β-phenylacetylamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid diphenylmethylester, which after recrystallisation from ethyl acetate melts at 166°-167°; [α]D20 = + 359° ± 2° (c = 0.490 in 95% ethanol); thin-layer chromatogram (silica gel): Rf = 0.73 (system: toluene/ethyl acetate 1:1) and Rf = 0.56 (system: toluene/acetone 4:1); ultraviolet absorption spectrum (in 95% alkanol): strong terminal absorption; infrared absorption spectrum (in mineral oil); characteristic bands at 2,97μ, 5,62μ, 5,75μ, 6,03μ and 6,54μ.
Reaction SMILES: [Al].[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:15]([Si:18]([Cl:21])([Cl:20])[Cl:19])[CH2:16]Cl>CCCCCC>[Cl:19][Si:18]([CH2:15][CH:16]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:2]2[C:7]1=[CH:6][CH:5]=[CH:4][CH:3]=2)([Cl:21])[Cl:20]
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: ClCC(Cl)[Si](Cl)(Cl)Cl
Agent: [Al]
Solvent: CCCCCC
Product: Cl[Si](Cl)(Cl)CC1c2ccccc2-c2ccccc21
Yield: 38.9 %

Procedure:
In a 250 ml, three-necked, frame dried, round bottom flask, aluminum 0.40 g (15 mmol), biphenyl 20.0 g (130 mmol), and (1,2-dichloroethyl)- trichlorosilane 7.50 ml (53.5 mmol) were reacted as in Example 1 at 120° C. for 30 min. Freshly distilled hexane (60 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane was distilled, the reaction products were vacuum distilled to give 6.53 g of 9-(trichlorosilyl)methylfluorene (bp; 130°-135° C./0.2 torr, yield; 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([S:51](=[N:55][CH3:56])([NH:53][CH3:54])=[O:52])=[CH:47][CH:46]=1>O1CCOCC1>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:43])[CH3:41])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:46]=[CH:47][C:48]([S:51](=[N:53][CH3:54])([NH:55][CH3:56])=[O:52])=[CH:49][CH:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CN=S(=O)(NC)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Solvent: C1COCCO1
Product: CN=S(=O)(NC)c1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 4-bromo-N,N′-dimethyl-benzenesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3) using 1,4-dioxane as a solvent. LC (method 1): tR=1.01 min; Mass spectrum (ESI+): m/z=686 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[CH3:30][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:29])([CH3:30])[CH3:28])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(-c2nc(-c3ccccc3)n(C)c2Sc2ccc(Cl)cc2)cc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)nc(-c2ccc(C(C)(C)O)cc2)c1Sc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the crude product of Step 1 in 1 mL of THF was added 0.1 mmol of MeMgBr (3M in ether) at −78° C. After stirring at 0° C. for 1 hr, the reaction was quenched with aqueous NH4Cl, and the product was extracted with EtOAc. The combined extracts were concentrated and the crude product was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.04 (d, 2H), 7.68 (m, 2H), 7.54 (d, 2H), 7.53 (m, 3H), 7.26 (d, 2H), 7.06 (d, 2H), 3.67 (s, 3H), 1.61 (s, 6H). LCMS: m/z 435 (M+H)+.
Reaction SMILES: [SH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][O:29][C:27]([C:26]1[CH:25]=[CH:24][C:23]([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][S:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[N:18]=2)=[CH:32][CH:31]=1)=[O:28]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CSC3CCN(C(=O)OC(C)(C)C)CC3)c(C)o2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A mixture of the crude tert-butyl 4-mercaptopiperidine-1-carboxylate (2.34 g, 10.78 mmol, 1.20 equiv), methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.33 g, 8.79 mmol, 1.00 equiv) and potassium carbonate (1.74 g, 12.39 mmol, 1.50 equiv) in N,N-dimethylformamide (23.4 mL) was stirred overnight in a 100-mL round-bottom flask at 50° C. The reaction mixture was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The organic layer was washed with 2×40 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted with ethyl acetate/petroleum ether (1:30-1:5) on a silica gel column to give 920 mg (23%) of tert-butyl 4-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methylthio)piperidine-1-carboxylate as a yellow solid. LC-MS: (ES, m/z): 447 [M+H]+, 347, 271, 146, 105.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22](O)=[O:23])=[O:19])=[CH:12]2>>[CH2:25]([CH:21]([NH:20][C:18]([C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=2)=[O:19])[C:22](=[O:23])[N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C1CCNCC1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(NC(Cc1ccccc1)C(=O)N1CCCCC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Piperidine hydrochloride (0.34 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.30 mmol) were coupled according to procedure A (0-25° C. reaction temperature). The crude product was chromatographed on silica gel eluted with 20%, 30%, 40%, 50%, 75% and 100% ethyl acetate in hexane giving partial separation. The pure fractions were pooled giving 31 mg (25%) of the title substance: HPLC (60/40) 9.38 minutes (94%); PBMS 410/412 (MH+, 100%);
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.O>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 72.4 %

Procedure:
A solution of 61 g (0.5 mole) of 4-hydroxybenzaldehyde in 20 mL of dry DMF was added to a suspension of 0.5 mole of sodium hydride (from 24 g of 50% sodium hydride washed free of oil with hexane) in 500 mL of DMF. When the sodium hydride had completely dissolved, a solution of 53 mL (0.55 mole) of 4-fluoronitrobenzene was added and the reaction mixture was heated to 70°-80° C. for 2 hr. The mixture was then poured into water, the solid collected and recrystallized from iso-propanol. The solid was recrystallized again from ethanol to give 88 g (85% yield) of the title compound as a yellow solid, mp=101°-104° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[C:3]=1[OH:13].O[C:15]1C=C(C(C)C)C=C(O)[C:20]=1C.C1(C)CC(=O)C(C(C)C)C(=O)C1.C(OC(OCC)OCC)C.OS(O)(=O)=O>CO.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH:10]([C:4]1[C:3]2[O:13][C:15]([CH3:20])=[N:1][C:2]=2[C:7]([CH3:8])=[CH:6][C:5]=1[OH:9])([CH3:11])[CH3:12]
Reactant: Cc1c(O)cc(C(C)C)cc1O
Reactant: Cc1cc(O)c(C(C)C)c(O)c1N
Agent: [Ti+4]
Agent: CC1CC(=O)C(C(C)C)C(=O)C1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOC(OCC)OCC
Product: Cc1nc2c(C)cc(O)c(C(C)C)c2o1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a flask charged with 4-amino-2-isopropyl-5-methyl-benzene-1,3-diol (250 mg, 1.4 mmol) (Treibs and Albrecht, “The dihydroxycymenes. IV. Isocymorcin (3,5-dihydroxycymene) from 3,5-menthanedione by dehydrogenation and total synthesis,” Journal fuer Praktische Chemie (1961), 13, 291-305), purged with argon, and cooled to 0° C., was sequentially added triethylorthoformate (0.53 mL, 4.2 mmol), MeOH (2.5 mL), and a 10% v/v solution of H2SO4 in MeOH (25 μL). The reaction was allowed to warm to room temperature slowly, stirred overnight, quenched with saturated NaHCO3, and concentrated. The residue was partitioned between water and methylene chloride. The combined organic phases were dried with Na2SO4 and concentrated. Purification via flash chromatography afforded 175 mg of 7-isopropyl-2,4-dimethyl-benzooxazol-6-ol.
Reaction SMILES: CS(O[CH:6]([CH2:14][F:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.O.[Cl-].[Na+].O>[N:16]([CH:6]([CH2:14][F:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC(CF)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(CF)Cc1ccccc1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
To a stirred solution of 1-fluoromethyl-2-phenylethyl methanesulfonate (1.1 g) in anhydrous DMF (15 mL) under nitrogen was added sodium azide (0.53 g) followed by heating at 80° C. overnight. The cooled reaction mixture was diluted with equal parts of water and brine and extracted with EtOAc. The extracts were washed with water and brine, dried over Na2SO4, and concentrated to an oil which was chromatographed over silica gel with a mixture of EtOAc and hexane to give 0.70 g of the title compound. MS ES (M++H−N2) 151.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:12][CH2:11][C@:10]2([CH3:16])[C:13]([CH3:15])([CH3:14])[C@H:6]1[CH2:7][C:8]1[C:20](OC)=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=[CH:17][C:9]=12)=[O:4].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([NH:35][C:20]1[C:8]2[CH2:7][C@@H:6]3[C:13]([CH3:14])([CH3:15])[C@:10]([CH3:16])([C:9]=2[CH:17]=[CH:18][C:19]=1[N+:23]([O-:25])=[O:24])[CH2:11][CH2:12][N:5]3[C:3](=[O:4])[C:2]([F:1])([F:26])[F:27])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: COc1c([N+](=O)[O-])ccc2c1C[C@H]1N(C(=O)C(F)(F)F)CC[C@]2(C)C1(C)C
Product: CC1(C)[C@H]2Cc3c(ccc([N+](=O)[O-])c3NCc3ccccc3)[C@]1(C)CCN2C(=O)C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2,2,2-Trifluoro-1-[(2R,6S)-10-methoxy-6,11,11-trimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (0.41 g) is combined with benzylamine (0.7 mL) and the resulting mixture is stirred at 70° C. overnight. After cooling to room temperature, the mixture is purified by HPLC on reversed phase (MeCN/H2O/F3CCO2H) to give the product as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]1[N:25]=[C:16]2[CH:17]=[CH:18][C:19]3[C:24]([N:15]2[N:14]=1)=[CH:23][CH:22]=[CH:21][N:20]=3>[OH-].[Na+].CO.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]1[N:25]=[C:16]2[CH:17]=[CH:18][C:19]3[C:24]([N:15]2[N:14]=1)=[CH:23][CH:22]=[CH:21][N:20]=3
Reactant: C(=C/c1nc2ccc3ncccc3n2n1)\c1cnc2ccccc2n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc2nc(CCc3nc4ccc5ncccc5n4n3)cnc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of (E)-2-(2-(quinoxalin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridine (32 mg, 0.099 mmol) in 1 N sodium hydroxide aqueous solution (1 mL) and methanol (2 mL) was added Pd/C (10%, 5 mg). The mixture was stirred under hydrogen at room temperature for 16 h. The mixture was filtered and the filtrate was concentrated, and purified by reverse phase prep-HPLC to give 15 mg of 2-(2-(quinoxalin-2-yl)ethyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridine as a yellow solid.