Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[F:1][C:2]1([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3][CH2:4][CH:5]2[CH:6]([O:23]2)[CH2:7][CH2:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1ncc([N+](=O)[O-])c1C1(F)CCC=CCC1
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1C1(F)CCC2OC2CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (Z)-5-(1-fluorocyclohept-4-enyl)-1-methyl-4-nitro-1H-pyrazole (900 mg, 3.77 mmol) in DCM (30 mL) at 0° C. was added portionwise meta-chloroperoxybenzoic acid (1.0 g, 4.14 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 90 min before being quenched with a saturated solution of sodium hydrogencarbonate (30 mL). The mixture was extracted with DCM (100 mL), washed with aqueous 2 M NaOH (2×50 mL) and brine (30 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to give 5-(4-fluoro-8-oxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-1H-pyrazole as a colourless solid (982 mg, quantitative) as a 2:5 ratio of diastereomers.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=1[NH2:27])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>CC(OC)(C)C>[CH2:24]([O:23][C:21](=[O:22])[C:18]1[CH:19]=[CH:20][C:15]([S:14][CH2:13][C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])[C:3]([OH:28])=[O:2])=[C:16]([NH2:27])[CH:17]=1)[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)c1ccc(SC[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: C=CCOC(=O)c1ccc(SC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c(N)c1
Temperature: 40 °C

Procedure:
200 mg (0.487 mmol) of N-tert-butoxycarbonyl-3-(4-alloxycarbonyl-2-aminophenylthio)-L-alanine methyl ester (96.7%) was added to a system consisting of 5 ml TBME and 20 ml buffer solution (0.1M sodium chloride; 3 mM sodium phosphate pH 7.0) under vigorous stirring at 40° C. 100 μl of Alcalase 2.4 L [a subtilisin Carlsberg from Novo Nordisk] was added and the pH maintained at 7.0 under vigorous stirring at 40° C. by the controlled addition (pH-static) of 0.1N sodium hydroxide solution. After a consumption 5.44 ml of titrating agent (112% of theory; after 17.4 h), the reaction mixture was washed with 25 ml TBME, acidified to pH 2.5 with IN HCl and extracted with 3×25 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, the solvent evaporated and the residue dried on a high vacuum to give 190 mg (0.479 mmol; 98%) of the product acid in 94.5% HPLC-purity (area-%).
Reaction SMILES: OS(O)(=O)=O.[CH:6]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([F:19])=[CH:16][C:17]=2[F:18])=[CH:10][C:9]([C:20]([OH:22])=[O:21])=[C:8]([OH:23])[CH:7]=1.[CH3:24][CH2:25]O>C(Cl)Cl>[F:18][C:17]1[CH:16]=[C:15]([F:19])[CH:14]=[CH:13][C:12]=1[C:11]1[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([C:20]([O:22][CH2:24][CH3:25])=[O:21])[CH:10]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Yield: 78 %

Procedure:
H2SO4 (1 mL, 18.76 mmol) was added to a solution of diflunisal (1.50 g, 5.995 mmol) in EtOH (50 mL). The reaction mixture was refluxed for 2 days, allowed to reach r.t., and diluted with CH2Cl2 (200 mL). The organic layer was washed with Na2CO3 (1 M aqueous solution, 200 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated to furnish 1.30 g of ethyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]#[N:16])=[C:13]([N:17]=[CH:18][N:19]([CH3:21])[CH3:20])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]#[N:16])=[C:13]([N:17]=[CH:18][N:19]([CH3:21])[CH3:20])[NH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: CN(C)C=Nc1[nH]nc(-c2ccc([N+](=O)[O-])cc2)c1C#N
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C)C=Nc1[nH]nc(-c2ccc(N)cc2)c1C#N

Procedure:
In the presence of 30 mg of Pd/C (5%), 142 mg (0.50 mmol) of N'-[3-(4-nitro-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine are hydrogenated in 20 ml of THF. Filtering, concentration by evaporation and crystallization from ethyl acetate/diethyl ether/hexane yield N'-[3-(4-amino-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine; TLC: Rf =0.07 (ethyl acetate:hexane=3:1); FAB-MS: (M+H)+ =255.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N+:31]#[C-:32])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CCO>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:31]=[CH:32][O:12][C:11]=2[C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH2:1])[S:3][C:4]=3[CH:10]=2)=[CH:16][CH:15]=1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: Nc1nc2ccc(C=O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1nc2ccc(-c3ocnc3-c3ccc(F)cc3)cc2s1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A solution of 2-aminobenzo[d]thiazole-6-carbaldehyde (0.91 g, 5.11 mmol, 1.0 eq.), 1-((4-fluorophenyl)(isocyano)methylsulfonyl)-4-methylbenzene (2.20 g, 7.60 mmol, 1.5 eq.), and K2CO3 (1.34 g, 9.70 mmol, 1.9 eq.) in EtOH (51 mL) was refluxed for 4 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the residue was taken up in CH2Cl2 and saturated aqueous NaHCO3. After separation of the layers, the aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (40:1) as eluent afforded 6-(4-(4-fluorophenyl)oxazol-5-yl)benzo[d]thiazol-2-amine as a tan solid (1.37 g, 86% yield).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[N:17]=[N:18][CH:19]=[C:20]2[CH:24]=[C:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:21]=12>CN1CCCC1=O>[CH2:1]([O:8][C:16]1[N:17]=[N:18][CH:19]=[C:20]2[CH:24]=[C:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:21]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(Cn2c(C)cc3cnnc(Cl)c32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2c(C)cc3cnnc(OCc4ccccc4)c32)cc1
Yield: 80 %

Procedure:
5.63 g (52 mmol) of benzyl alcohol, 90 ml of N-methylpyrrolidone, 9.75 g (87mmol) of potassium tert-butoxide, 0.46 g (1.74 mmol) of [18]crown-6 and 5.0 g (17 mmol) of 7-chloro-1-(4-methoxybenzyl)-2-methylpyrrolo[2,3-d]pyridazine are reacted at room temperature for 2 h. Purification: crystallization from ethyl acetate, concentration of the mother liquor and chromatography on silica gel (eluent: toluene/dioxane =9:1). Yield: 80%, m.p.: 152°-156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][C:41](Cl)=[O:42]>>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:6][CH:7]=1)=[O:42]
Reactant: COc1ccc(CC(=O)Cl)c(OC)c1
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)CN3C(=O)C(c4ccccc4)(c4ccccc4)N=C3C)cc2)c(OC)c1

Procedure:
Synthesis in analogy to Example 8 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and (2,4-dimethoxy-phenyl)-acetyl chloride to yield 2-(2,4-dimethoxy-phenyl)-N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-acetamide (55 mg, 0.098 mmol) which is dissolved 5 mL dry ethanol. Subsequently LiBH4 (22.5 mg, 0.98 mmol) is added and the reaction mixture is stirred for 4 hour at reflux temperature. The reaction is then diluted with 5 mL water and the solvents evaporated. The residue is purified by preparative HPLC (method 3) to yield 2-(2,4-dimethoxy-phenyl)-N-{4-[1-hydroxy-2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-ethyl]-phenyl}-acetamide (15 mg, 27%). LC/MS at 254 nm; [M+H] 565; Rt=3.006 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([N+:17]([O-])=O)[CH:3]=1>[Zn]>[NH2:17][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C
Agent: [Zn]
Product: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C

Procedure:
The title compound was prepared from the tert-butyl 4,5-dimethyl-2-nitrophenylcarbamate (Example A7; 3 mmol) by reduction with zinc according to the general procedure B. Obtained as a yellow solid (56%), MS (EI) 237 [(M+1)+].
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])([C:7]#[N:8])[C:5]#[N:6]
Reactant: FC(F)(F)C(F)(F)CCI
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 21.1 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.4 g of 1-iodo-3,3,4,4,4-pentafluorobutane were dissolved in 5 ml of dimethyl sulfoxide, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 7 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.45 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,4,4,4-pentafluorobutyl)malononitrile (hereinafter, referred to as the present compound (68)).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.C[CH:21]([OH:23])[CH3:22]>>[CH:6]1([NH:5][C:21](=[O:23])[C:22]2[CH:17]=[CH:18][CH:19]=[CH:14][C:4]=2[NH:3][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[C:4]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:3]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)O
Reactant: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Product: COc1ccc2nc(-c3cccnc3)nc(Nc3ccccc3C(=O)NC3CCCCC3)c2c1

Procedure:
To the crude amide was added the solution of 4-chloro-6-methoxy-2-pyridin-3-yl-quinazoline (20 μmol) in 2-propanol (200 μL). The mixture was refluxed for 8 h. After evaporation, the residue was dissolved in 5% TFA/MeOH-DMF (1:1) and purified by PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:25])[CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:26]([O:30]C)(=[O:29])[CH:27]=[CH2:28]>CO.C(COC)OC>[CH2:12]([C:11]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:10](=[O:25])[CH:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:28][CH2:27][C:26]([OH:30])=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CC(=O)OC
Reactant: O=C(C=Cc1ccc(Cl)cc1)C(Cc1ccccc1)c1ccccc1
Solvent: CO
Solvent: COCCOC
Product: O=C(O)CCC(Cc1ccccc1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 96 h

Procedure:
Triton B (2 ml., 40% in MeOH) is added to a stirred solution of 1-(p-chlorophenyl)-4,5-diphenyl-1-penten-3-one (17.33 g., 0.05 mole) in glyme (200 ml.) followed by addition of methyl acrylate (4.73 g., 0.055 mole) in glyme (50 ml.). The solution is stirred for 96 hours and the solvent is removed under reduces pressure. The residue is dissolved in methanol (500 ml.) and a 20% sodium hydroxide solution (25 ml.) is added. After an additional 24 hours, the methanol is evaporated in vacuo and the residue is dissolved in water. Extraction with ether removes unreacted ketone. Acidification produces 16.18 g., m.p. 160°-170°C. when collected and air-dried. Recrystallization from butyl chloride gives material with m.p. 173°-176°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][C:31]1=[O:36].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:33]2[CH2:34][CH2:35][NH:30][C:31](=[O:36])[CH2:32]2)=[O:18])=[N:14][CH:15]=1
Reactant: O=C1CNCCN1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCNC(=O)C2)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.9 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (114 mg, 0.271 mmol) obtained in Example 12 in methylene chloride (3 ml), piperazin-2-one (33 mg, 0.325 mmol), 1-hydroxybenzotriazole (37 mg, 0.271 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (62 mg, 0.325 mmol) and 4-methylmorpholine (35 μl, 0.325 mmol) were added. The reaction mixture was stirred for 4 days at room temperature, and was concentrated under reduced pressure. Ethyl acetate was added to the resulting concentration residue, and the mixture was washed sequentially with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:30) was concentrated under reduced pressure. The resulting solid was washed with ether, and then was collected by filtration, to obtain the title compound (116 mg, 0.230 mmol, 85%) as a white powder.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:11][N:12]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[S:13]1(=[O:15])=[O:14].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([O:9][CH2:11][N:12]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:13]2(=[O:14])=[O:15])=[O:8])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: O=C(OCN1C(=O)c2ccccc2S1(=O)=O)c1ccncc1
Yield: 35.3 %

Procedure:
A mixture of isonicotinic acid (0.98 g, 0.008 mol), 2-bromomethylsaccharin (2.11 g, 0.008 mol), triethylamine (0.81 g, 0.008 mol) and xylene (25 ml) were refluxed for 1 hour. The solvent was removed in vacuo and the residue was partitioned between water and methylene chloride. The organic layer was separated and the solvent removed in vacuo. The solid residue was recrystallized from CH3CN to afford 0.9 g (37%) of 2-saccharinylmethyl pyridine-4-carboxylate as a yellow solid, m.p. 145°-146° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[N:7][CH:8]=1.OS(O)(=O)=O.[CH3:18]O>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:18])=[O:11])=[N:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(Br)cn1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2-(5-Bromopyridin-2-yl)acetic acid hydrochloride (example 42e) (2.34 g, 9.3 mmol) was dissolved in MeOH (18 mL) and conc. H2SO4 (1.5 mL). The mixture was stirred at 80° C. overnight. The solvent was removed under reduced pressure and the mixture was treated with sat. NaHCO3 then extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated to give methyl 2-(5-bromopyridin-2-yl)acetate as a yellow oil (1.97 g, 92%). 1H NMR (400 MHz, dMSO): δ 3.60 (s, 3H), 3.83 (s, 2H), 7.34-36 (d, 1H), 7.99-8.02 (dd, 1H), 8.60-8.61 (d, 1H); MS+H (230, 231).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]1[C:7]([NH2:13])=[N:8][CH:9]=[C:10]([CH3:12])[N:11]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:13]([C:7]1[C:6]([CH3:5])=[N:11][C:10]([CH3:12])=[CH:9][N:8]=1)=[C:1]=[S:2]
Reactant: Cc1cnc(N)c(C)n1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(N=C=S)c(C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
Thiophosgene (1.59 mL, 20.9 mmol) was added dropwise to a stirred mixture of 3,5-dimethylpyrazin-2-amine (1.98 g, 16.1 mmol) in tetrahydrofuran (20 mL) and saturated aqueous sodium hydrogen carbonate (20 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a brown solid (866 mg, 5.24 mmol, 33%).
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.CCN(C(C)C)C(C)C>CCO>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[CH2:13][CH2:12][O:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Temperature: 100 °C
Yield: 96.2 %

Procedure:
EtOH (12.00 mL) was added to a microwave vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (2.05 g, 7.02 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 1.489 g, 7.435 mmol) and DIPEA (1.836 g, 14.20 mmol). The vial was sealed and the mixture was heated at 100° C. under microwave irradiation for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a yellow solid (2.46 g, 96%). LCMS calc. for C17H25N4O5 (M+H)+: m/z=365.2. found 365.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=O)=[C:8]([CH3:15])[CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[NH2:27])[C:21]([OH:23])=[O:22]>CS(C)=O>[CH3:1][O:2][C:3]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:18]3[CH:19]=[C:20]([C:21]([OH:23])=[O:22])[CH:24]=[CH:25][C:26]=3[N:27]=2)=[C:8]([CH3:15])[CH:7]=1)=[O:16]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: COC(=O)COc1cc(C)c(C=O)c(C)c1
Solvent: CS(C)=O
Product: COC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Reaction time: 8 h

Procedure:
To a solution (4-formyl-3,5-dimethylphenoxy)-acetic acid methyl ester (2.4 g) (from Example 6-9) and 3,4-diaminobenzoic acid (2.0 g) in DMSO (30 mL) under air at ambient temperature was added FeCl3 (150 mg) and the resulting brown reaction mixture was stirred at the same temperature overnight. The reaction was monitored by LC/MS which indicated completion. The reaction mixture was then decanted into 400 mL of stirred water and the resulting precipitate was collected by filtration and washed with water. The crude product was dried in the suction funnel for 4 h to give 2-(4-methoxycarbonylmethoxy-2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid. MS (ESI) m/z 355.04 (M+H); Retention time=0.79 min (Method 10).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([OH:28])[CH2:15][S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:33])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[C@H:14]([OH:28])[CH2:15][S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CSCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3[C@H](O)CSCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using (S)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-trifluoromethyl-benzylsulfanyl)-ethanol and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[CH:22]1[CH2:24][CH:23]1[CH:25]([NH:27][O:28][CH3:29])[CH3:26].C1N2CCN(CC2)C1>C(#N)C>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[C@@H:22]1[CH2:24][C@H:23]1[CH:25]([N:27]([O:28][CH3:29])[C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:26]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)C1CC1c1c(Cl)cc(Cl)cc1Cl
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (24 mg; 0.12 mmol) in acetonitrile (1 ml) was added dropwise to a stirred mixture of N-{1-[2-(2,4,6-trichlorophenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine (24 mg; 0.08 mmol), prepared as described in example P16 and DABCO (14 mg; 0.12 mmol) in acetonitrile (1 ml) at ambient temperature. The reaction mixture was stirred for 2 hours at ambient temperature. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (4 g) (eluent: n-hexane/ethyl acetate 1:2).