Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH:6]([C:8]1[O:9][C:10]2[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:11]=2[CH:12]=1)=O>CCO>[OH:3]/[N:2]=[CH:6]\[C:8]1[O:9][C:10]2[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:11]=2[CH:12]=1
Reactant: COC(=O)c1ccc2cc(C=O)oc2c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1ccc2cc(/C=N\O)oc2c1
Reaction time: 8 h

Procedure:
Hydroxylamine hydrochloride (153 mg, 2.2 mmol) is free based for 5 min in 2N NaOH (1.1 ml, 2.2 mmol) and added drop-wise to a solution of methyl 2-formyl-1-benzofuran-6-carboxylate (408 mg, 2.0 mmol) in EtOH (6 ml). The reaction is stirred overnight and the volatiles are removed in vacuo. The residue is suspended in water (5 ml) and the slurry is filtered. The cake is dried overnight to afford 399 mg (91%) of E/Z-methyl 2-[(hydroxyimino)methyl]-1-benzofuran-6-carboxylate as a light brown solid. HRMS (FAB) calcd for C11H9NO4+H: 220.0610, found 220.0602 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16](O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].CN1CCOCC1.Cl[C:27]([O:29][CH2:30][CH:31](C)C)=[O:28].[N+](=C)=[N-].C(N(CC)CC)C>CCOC(C)=O.CCO>[CH3:4][C:2]([CH3:1])([O:5][C:6]([NH:8][C@H:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:16][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:7])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: CC(C)COC(=O)Cl
Agent: C=[N+]=[N-]
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a stirred solution of N-BOC-D-phenylglycine (5.02 g, 20 mmol), N-methylmorpholine (2.02 g, 20 mmol) in EtOAc (100 mL) at 0° C. was added isobutyl chloroformate (2.73 g, 20 mmol). After 15 minutes the reaction mixture was filtered to remove the amine salts then an ethereal solution of diazomethane (60 mL, 30 mmol) was added. The cooling bath was removed and the reaction mixture stirred at ambient temperature for 2 hours. The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane. The reaction mixture was diluted with EtOAc, washed with 1N HCl, saturated NaHCO3, and dried (MgSO4). Evaporation of the solvent afforded the crude diazoketone which was dissolved in EtOH (100 mL) and then treated sequentially with AgO2CPh (1.6 g, 7 mmol) and triethylamine (6.06 g, 60 mmol). After 20 hours the reaction mixture was concentrated and chromatographed (silica gel, 15% EtOAc/hexanes) affording 4.90 g (85%) of product as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ1.17 (t, J=7 Hz, 3H), 1.43 (s, 9H), 2.73-2.92 (m, 2H), 4.07 (q, J=7 Hz, 2H), 5.10 (m, 1H), 5.48 (m, 1H), 7.22-7.39 (m, 5H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:10]=[C:9]1[C:22]([O:24]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I.O>CN(C)C=O>[CH2:1]([N:8]1[C:9]([CH:22]=[O:24])=[CH:10][C:11]([N:13]([CH3:29])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(NS(=O)(=O)c2cccs2)cn1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cc(C=O)n(Cc2ccccc2)c1)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of ethyl 1-benzyl-4-[(2-thienylsulfonyl)amino]-1H-pyrrole-2-carboxylate (19.5 g) in N,N-dimethylformamide (100 mL) was slowly added sodium hydride (60%, oily, 2.2 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (3.4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). To a solution of the yellow oil in tetrahydrofuran (150 mL) was slowly added lithium aluminum hydride (2.2 g) in small portions. The reaction mixture was stirred at room temperature for 1 hr, and water (2.2 mL), 15% aqueous sodium hydroxide solution (2.2 mL) and water (6.6 mL) were successively added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 1 hr, and the insoluble material was filtered off. The filtrate was concentrated, manganese dioxide (30 g) was added to a solution of the residue in tetrahydrofuran (200 mL), and the mixture was stirred at room temperature overnight. The manganese dioxide was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give N-(1-benzyl-5-formyl-1H-pyrrol-3-yl)-N-methylthiophene-2-sulfonamide (10.3 g, yield 57%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[N:3]1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1)[CH3:10]
Reactant: Cn1ccc(C=O)n1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1ccn(C)n1

Procedure:
prepared by reaction of 1-methyl-1H-pyrazole-3-carbaldehyde (prepared according to WO2004/058702) with 2M ethylamine in THF.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])=[CH:5][CH:4]=1.[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[CH3:21][O:20][C:18]([N:9]1[CH2:10][CH2:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][CH:8]1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:23][CH:22]=1)=[O:19]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(C(F)(F)F)cc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(C(F)(F)F)cc1
Yield: 87.3 %

Procedure:
Dimethyl 2-(4-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (10.9 g, 30.33 mmol) was dissolved in acetonitrile (80 mL) and water (1.6 mL), then lithium bromide (21.07 g, 242.67 mmol) and triethylamine (16.82 mL, 121.33 mmol) were added and the resulting yellow suspension was heated at reflux. Water (60 mL) and MTBE were added. The organic phase was extracted with water (×2). To the pooled aqueous layer was added MTBE and the solution was acidified to pH 1 with HCl and then extracted with MTBE (×2). The organic layer was dried Na2SO4, filtered through celite and the solvent evaporated to yield 1-(methoxycarbonyl)-2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (9.14 g, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:6][CH2:7][C:8]([OH:10])=O)[CH3:2].CCN=C=NCCCN(C)C.[CH2:34]([O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH2:39])[CH3:35]>C(#N)C>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:6][CH2:7][C:8](=[O:10])[NH:39][CH:38]([C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:40][OH:41])[CH3:2]
Reactant: CCOC(=O)C(CCC(=O)O)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CCOC(=O)C(CO)NC(=O)CCC(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 118.9 %

Procedure:
A suspension of acid (3) (7.6 g, 24.57 mmol) in dry acetonitrile (80 ml) was stirred under nitrogen at room temperature and Hobt (4 g, 29.6 mmol, 1.2 equiv.) was added. Stirring was continued for 10 min., and EDCI (5.1 g, 26.6 mmol, 1.1 equiv.) was added. The resulting mixture was stirred for 1.5 hrs and serine ethyl ester free base (3.27 g, 24.57 mmol, 1 equiv.) in acetonitrile (20 ml) was added. Stirring was continued at room temperature for 3 hrs. The solvent was removed in a rotary evaporator, the residue was partitioned between water (100 ml) and ethyl acetate (200 ml) and phases were separated. The organic phase was washed successively with water (50 ml), 5% potassium carbonate (2×50 ml) and water (2×50 ml), dried over sodium sulfate and the solvent removed in a rotary evaporator. The residue was dried in a vacuum oven (50° C.) to produce (4) (12.4 g, 85.5%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([O:6][Si](C(C)(C)C)(C)C)[CH3:5].Cl.O.C(OCC)(=O)C>CO>[Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([OH:6])[CH3:5]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of 0.45 g (1.28 mmol) of 1-chloro-2-(2,4-difluorophenyl)-3-(tert-butyldimethylsilyloxy)butan-2-ol ((2R,3S)/(2S,3S)=92/8) in 5 mL of methanol was added 0.25 mL of concentrated hydrochloric acid at room temperature. After the completion of the dropwise addition, stirring was performed at room temperature for 18 hours. Then, 10 mL of water was added to stop the reaction, and extraction was performed with ethyl acetate (20 mL). The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product as a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 6). Thereby, the title compound was obtained in a yield of 75% ((2R,3S)/(2S,3S)=91/9). 1H-NMR (400 MHz, CDCl3) (2R,3S) δ: 0.98 (d, 3H, J=6.6 Hz), 2.48 (brs, 1H), 3.20 (s, 1H), 4.11-4.23 (m, 3H), 6.77-6.80 (m, 1H), 6.91-6.93 (m, 1H), 7.69-7.71 (m, 1H); (2S,3S) δ: 1.93 (dd, 3H, J=6.3, 1.2 Hz), 2.25 (d, 1H, J=5.2 Hz), 3.15 (s, 1H), 3.97 (d, J=11.0 Hz), 4.06 (q, 1H, J=6.3 Hz), 4.35 (d, J=11.2 Hz), 6.75-6.82 (m, 1H), 6.91-6.93 (m, 1H), 7.69-7.71 (m, 1H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH2:4][CH2:5][CH3:6].[C:8]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:18][C:17]3([O:36][C:21]4=[CH:22][N:23]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:30][CH:31]=5)[CH:25]=[C:20]4[CH2:19]3)[CH2:16]2)[CH2:12][CH2:11]1)#N>>[CH3:35][S:32]([N:29]1[CH2:28][CH:27]=[C:26]([C:24]2[CH:25]=[C:20]3[CH2:19][C:17]4([CH2:16][C:13]5([CH2:12][CH2:11][N:10]([C:8]6[O:1][N:2]=[C:3]([CH2:4][CH2:5][CH3:6])[N:7]=6)[CH2:15][CH2:14]5)[CH2:18]4)[O:36][C:21]3=[CH:22][N:23]=2)[CH2:31][CH2:30]1)(=[O:33])=[O:34]
Reactant: CCCC(=N)NO
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(C#N)CC3)C2)CC1
Product: CCCc1noc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)n1

Procedure:
The title compound is prepared from N-hydroxy-butyramidine and 1″-cyano-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] following a procedure analogous to that described for Example 23. LC (method 3): tR=0.91 min; Mass spectrum (ESI+): m/z=500 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]([F:44])([F:43])[C:6]1[CH:7]=[C:8]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[N:22]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:23]([CH:26]=O)=[N:24][N:25]=2)[N:12]=[N:11]1.[OH-].[Na+]>ClCCCl>[F:4][C:5]([F:44])([F:43])[C:6]1[CH:7]=[C:8]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[N:22]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:23]([CH:26]=[N:2][OH:3])=[N:24][N:25]=2)[N:12]=[N:11]1
Reactant: NO
Reactant: O=Cc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)n1Cc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: ON=Cc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 35.1 %

Procedure:
Add hydroxylamine hydrochloride (7 mg) to a 0° C. solution 5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-4-(2-chloro-benzyl)-4H-[1,2,4]triazole-3-carbaldehyde (50 mg) in 1,2-dichloroethane (1 mL). Stir 60 hours while allowing reaction to slowly warm to RT. Quench reaction by slowly adding 1 N NaOH (1 mL). Extract with CH2Cl2 (2×2 mL) and dry. Purification via silica gel chromatography using 3:1 to 1:1 hexanes:EtOAc gradient gives the desired product (18 mg, 35%). MS (IS) 606.1 (M+1); Rf=0.52 (1:1 hexanes:EtOAc).
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[O:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[C:15]#[N:16].CC1(C)C(C)(C)OB([C:28]2[CH:45]=[CH:44][C:31]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:30][CH:29]=2)O1>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][C:5]1([CH3:9])[O:4][C:3]([C:10]2[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=2)[C:15]#[N:16])=[C:2]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:44][CH:45]=2)[C:6]1=[O:7]
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Reactant: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1C#N
Yield: 56.4 %

Procedure:
A solution of 5-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.15 g, 0.465 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.17 g, 0.465 mmol), and Cs2CO, (0.75 g, 2.32 mmol) in toluene (6 mL) and water (3 mL) was degassed. Then, Pd(dppf)Cl2 (0.76 g, 0.090 mmol) was added under an inert atmosphere and the solution was again degassed. The reaction was then refluxed for 2 h, filtered through a pad of Celitc® and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (125 mg, 58%) as a pale yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.43 (d, J=8.5 Hz, 1H), 8.02 (t, J=7.9 Hz, 2H), 7.90 (s, 1H), 7.81-7.77 (m, 2H), 7.70 (d, J=8.2 Hz, 1H), 7.62 (t, J=8.2 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.19 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 5.40 (s, 2H), 3.95 (s, 3H), 1.46 (s, 6H). MS: [M+Na]: m/z=499.3, [M+H]: m/z=477.2. HPLC: 98%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH3:15])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].C1(P(Cl)([Cl:25])=O)C=CC=CC=1>>[Cl:25][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:15])[N:5]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccccc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Product: Cc1nc(Cl)c(C#N)cc1-c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of 100.34 g 3-cyano-6-methyl-5-phenyl-1H-pyridin-2-one [Walker and Weaver, J. Org. Chem. 26, 4441 (1961)]and 192 ml phenylphosphonic dichloride (C6H5POCl2) was warmed to 160-170° C. and kept at that temperature for about 16 hours. The reaction mixture was cooled and poured into ice water. The solid product was collected, dried in a vacuum oven and extracted with ether. The ether solution was concentrated, and the residue was washed with hexane and extracted with 300 ml 15% aqueous potassium bicarbonate. The resulting solid was dried in a vacuum oven to give 92.71 g (85%) 2-chloro-3-cyano-6-methyl-5-phenylpyridine, m.p. 134-135° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CCN(C(C)C)C(C)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:5])[NH2:6]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cccc(C(N)=O)c1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)Nc1c(C)cccc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To a solution of 2-amino-3-methylbenzamide (1.50 g, 10.0 mmol) and DIEA (2.61 mL, 15 mmol) in THF (50 mL) at 0° C. was added ethyl chlorooxoacetate (1.23 mL, 11.0 mmol). The solution was allowed to warm to rt and stir for 16 h, then was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20-100% EtOAc/hexanes to afford ethyl 2-(2-carbamoyl-6-methylphenylamino)-2-oxoacetate as a solid (490 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=7.1 Hz, 3H), 2.17 (s, 3H), 4.30 (q, J=7.1 Hz, 2H), 7.28 (t, 1H), 7.33-7.57 (m, 3H), 7.82 (s, 1H), 10.67 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[S:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
The title compound was prepared from 1-Chloro-2-nitro-4-trifluoromethyl-benzene (250 mg, 1.10 mmol), N-(4-Mercapto-phenyl)-acetamide (185 mg, 1.10 mmol), and K2CO3 (268 mg, 1.94 mmol) heated in DMF at 100° C. for 16 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate (350 mg, 88%).
Reaction SMILES: [Br:1]Br.[S:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]1[CH:10]=[O:11]>C(Cl)(Cl)Cl>[Br:1][C:7]1[S:3][C:4]([CH:10]=[O:11])=[C:5]([CH:8]=[O:9])[CH:6]=1
Reactant: BrBr
Reactant: O=Cc1ccsc1C=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(Br)sc1C=O
Reaction time: 8 h

Procedure:
Bromine (6.0 mL, 116.3 mmol) was added drop wise at room temperature to a solution of 2,3-thiophenedicarboxaldehyde (5.1 g, 36.38 mmol) in 100 mL of CHCl3. The reaction mixture was stirred overnight and then excess bromine was quenched with a saturated solution of Na2S2O3. The organic layer was extracted with CHCl3, dried over Na2SO4 and volatiles were removed in vacuo to obtain 1 as a brown solid. Spectroscopically pure compound was isolated by column chromatography using silica gel as stationary phase and a 4:1 mixture of CH2Cl2:hexanes. 1H NMR (500 MHz, CDCl3): δ1 0.37 (s, 1H), 10.26 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[C:25]1[C:29]([NH2:30])=[CH:28][NH:27][N:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O>[NH:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:16]=[C:17]1[C:25]1[C:29]([NH:30][C:13]([C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:15])=[CH:28][NH:27][N:26]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: ClCCCl
Product: Cc1onc(-c2ccccc2)c1C(=O)Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.6 %

Procedure:
A mixture of 5-methyl-3-phenylisoxazole-4-carboxylic acid (57 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (41 mg, 0.30 mmol) in DMSO (2 ml) was stirred at ambient temperature for 24 h. The reaction mixture was partitioned between EtOAc and water and the organic portion dried (MgSO4), filtered and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-petrol (1:2, 1:1, 2:1)] affording 5-methyl-3-phenyl-isoxazole-4-carboxylic acid [3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide as a cream solid (15 mg, 16%). (LC/MS: Rt 3.73, [M+H]+ 385.14).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH2:7]([C:14]1[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][CH:17]=[C:16]([CH2:24][CH2:25][C:26](OCC)=[O:27])[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>CCOCC>[CH2:7]([C:14]1[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][CH:17]=[C:16]([CH2:24][CH2:25][CH2:26][OH:27])[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCc1ccc(OCOC)c(Cc2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COCOc1ccc(CCCO)nc1Cc1ccccc1
Reaction time: 1 h

Procedure:
205 mg of aluminum lithium hydride was suspended in 20 ml of anhydrous ether. A solution of 10 ml of anhydrous ether containing 1.3 g of 2-benzyl-6-(2-ethoxycarbonylethyl)-3-methoxymethyloxypyridine was added dropwise under ice-cooling. After stirring for one hour as it was, 0.2 ml of water, then 0.2 ml of an aqueous 5N sodium hydroxide solution and then 0.6 ml of water were added thereto under ice-cooling. The reaction solution was filtered through filter paper to remove insoluble matters. After washing with ether, the organic phase was evaporated. The residue was subjected to silica gel column chromatography using 40% ethyl acetate/hexane as an eluent for separation and purification, to give 1.0 g of the target compound.
Reaction SMILES: [C:1]([C:5]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][CH:7]([C:13]([O:15]C)=[O:14])[CH2:6]2)([O:3]C)=[O:2].O.[OH-].[Li+]>O1CCCC1.C(O)(C)C.O>[C:1]([C:5]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][CH:7]([C:13]([OH:15])=[O:14])[CH2:6]2)([OH:3])=[O:2]
Reactant: COC(=O)C1CC2CCC(C(=O)OC)(C2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: O=C(O)C1CC2CCC(C(=O)O)(C2)C1
Yield: 86.4 %

Procedure:
A stirred solution of 1,3-dicarbomethoxybicyclo[3.2.1]octane (8.26 g, 36.5 mmol) in tetrahydrofuran (50 mL) and isopropanol (16 mL) was treated with a solution of lithium hydroxide hydrate (4.20 g, 100 mmol) in water (50 mL), and the mixture was heated to 60°-70° C. for 2 h with stirring. The organic solvents were removed in vacuo, and the alkaline aqueous solution was cooled on an ice bath and acidified with concentrated hydrochloric acid (10 mL). The solid was filtered, rinsed with cold water, and partially air dried overnight, then further dried under vacuum, triturated from acetonitrile, and redried in vacuo to afford 6.25 g (86%) of subject material as a white solid. No MS could be obtained. 1H NMR (CDCl3+drop d6-DMSO) δ 2.15-2.25 (m, 1H), 1.95-2.05 (m, 2H), 1.40-1.70 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[N+:20]([O-])=O.C(O)(=O)C.COCCOC.[Sn](Cl)Cl>O.CCO>[NH2:20][C:11]1[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: COCCOC
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(N)c1
Temperature: 60 °C
Yield: 100 %

Procedure:
To a stirred solution of T10.2 (1.00 g, 3.3 mmol) in acetic acid (2.00 mL, 35 mmol) at 23° C. was added DME (15.00 mL, 144 mmol), EtOH (10.00 mL), followed by tin(II) chloride (4.7 g, 25 mmol). The mixture was heated at 60° C. for 17 hours. After which, the reaction was cooled to room temperature. The reaction was diluted with water and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure to give the product T10.3 (0.90 g, 100% yield).