Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:7])[CH2:5][OH:6].CO[C:19](OC)([CH3:21])[CH3:20].B(F)(F)F.O(CC)CC>CC(C)=O>[CH3:1][O:2][C:3]([C:4]1([CH3:7])[CH2:5][O:6][C:19]([CH3:21])([CH3:20])[N:8]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:16]
Reactant: COC(=O)C(C)(CO)NC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)C1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirring solution of 3 (9.342 g, 40 mmol) in acetone (115 mL) in a flame dried round bottom flask under an inert atmosphere was added 2,2-dimethoxypropane (66 mL). To this solution was added BF3-OEt2 (0.30 mL, cat) and stirring was continued at rt for 2 h. The reaction mixture was then concentrated in vacuo to an orange oil which was purified by flash chromatography to provide 4 (9.392 g, 85%) as a white solid. Rf=0.55 (1:3 EtOAc/hexanes). Compound was observed as an uneven mixture of rotomers.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:20])[NH:12][C@@H:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C=O)C>C1COCC1>[CH2:3]([O:10][C:11](=[O:20])[NH:12][C@@H:13]1[CH2:17][C:16](=[O:18])[N:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]1=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1C[C@@H](NC(=O)OCc2ccccc2)C(=O)N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CC(=O)N(Cc2ccccc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
1.2.2 (via two steps; 2nd step): A suspension of 48.4 mg of 60% NaH in 3 ml of THF was treated with 300 mg of (R)-(2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester at 0° C. followed by 161.3 μL of benzyl bromide. After 30 min the resulting precipitate was warmed to rt and treated with 3 ml of DMF to give after 15 min a solution which was stirred for 16 h at rt then quenched with 60 ml of H2O and extracted with 40 ml of toluene. The combined organic layers were dried over MgSO4 and concentrated to give 409 mg (74%) of the (R)-(2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester as white crystals; m.p. 145.1-145.5° C. Overall yield for the two step process: 78%.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9](O)(=[O:11])=[O:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.O=S(Cl)[Cl:18]>CN(C=O)C>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([Cl:18])(=[O:11])=[O:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)O)c([N+](=O)[O-])cc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)Cl)c([N+](=O)[O-])cc1F
Yield: 99 %

Procedure:
In a similar fashion using route 39 general procedure 96, 4-fluoro-5-methyl-2-nitro-benzenesulfonic acid 452 (1.5 g, 6.38 mmol), SOCl2 (15 ml) and DMF (0.1 ml) gave the title compound (1.6 g, 99%) which was used in the next step without purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][C:23]4([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26]4)[CH2:22][CH2:21]3)=[O:19])=[CH:7][N:8]2[CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:34]C(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:21][CH2:22][C:23]4([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26]4)[CH2:24][CH2:25]3)=[O:19])=[CH:7][N:8]2[CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:34])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C(c1cn(C[C@H]2CCCNC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC[C@H](Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1′-({6-chloro-1-[(3S)-piperidin-3-ylmethyl]-1H-indol-3-yl}carbonyl)-3H-spiro[2-benzofuran-1,4′-piperidine] in MeOH was treated with aq. H2CO (1.5 eq), AcOH (1.1 eq) and stirred for 15 min at room temperature, then treated with NaCNBH3 (1.1 eq) and stirred at room temperature for 1 h. Concentration and purification by preparative HPLC the desired product. ES-MS m/e (%): 478.2 (M+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:19])=[C:6]([OH:18])[C:7]([CH3:17])=[CH:8][C:9]=1[O:10]C(=O)C(C)(C)C.[CH3:20][O:21][CH2:22]Cl>O1CCCC1>[Cl:3][C:4]1[C:5]([CH3:19])=[C:6]([O:18][CH2:20][O:21][CH3:22])[C:7]([CH3:17])=[CH:8][C:9]=1[OH:10]
Reactant: Cc1cc(OC(=O)C(C)(C)C)c(Cl)c(C)c1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c(C)cc(O)c(Cl)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To 20 ml of an anhydrous tetrahydrofuran suspension containing 1.78 g of sodium hydride (55% by weight), 30 ml of a solution of 8.02 g of 3-chloro-2,6-dimethyl-4-pivaloyloxyphenol in anhydrous tetrahydrofuran were added dropwise, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 3.28 g of chloromethyl methyl ether were added and the mixture was stirred at room temperature for 13 hours. The reaction mixture was then concentrated by evaporation. Water was added to the concentrate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. In 30 ml of methanol, 9.30 g of the residue were dissolved. To the resulting solution, 30 ml of a solution of 3.51 g of potassium hydroxide in methanol were added dropwise, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated by evaporation. The concentrate was neutralized with 3N hydrochloric acid and sodium bicarbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was separated and purified by chromatography through a silica gel column (eluting solvent: n-hexane/ethyl acetate=10/1), whereby 5.65 g of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:27][CH:26]=1
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2c(C(=O)c3ccccn3)cnc3c(C(F)(F)F)cccc23)cc1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-methylphenylboronic acid in place of phenyl boronic acid. MS (ESI) m/z 393 ([M+H]+); Anal. Calcd for C23H15F3N2O.0.2H2O: C, 69.76; H, 3.92; N, 7.07. Found: C, 69.73; H, 3.79; N, 6.99.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[C:18]([OH:25])[CH:17]=1.C(=O)(O)[O-].[Na+].[CH2:31](I)[CH3:32]>CN(C)C=O>[CH2:31]([O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=2[OH:1])=[CH:17][C:18]=1[OH:25])[CH3:32]
Reactant: CCI
Reactant: O=C(O)c1ccc(OCCCCCCc2cccc(O)c2O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCCCCc2cccc(O)c2O)cc1O
Reaction time: 6 h
Yield: 74 %

Procedure:
A mixture of 1.0 g (2.9 mmole) of 4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxybenzoic acid, 0.295 g (3.5 mmole) of sodium bicarbonate and 2.4 mL (29 mmole) of ethyl iodide in 10 ml of anhydrous dimethylformamide was stirred at 50° for 6 hours. The solvent was removed on the oil pump and the residue was treated with sodium bicarbonate solution. The product was extracted with ethyl acetate and the dried extract was concentrated at reduced pressure to a solid. Recrystallization from ether-hexane gave 0.8 g, mp 63°-68°, (74% yield) of 4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxybenzoic acid ethyl ester.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:16]([NH:20][NH2:21])([CH3:19])([CH3:18])[CH3:17]>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14](=[S:15])[NH:21][NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=S)NNC(C)(C)C)CCCCC1

Procedure:
To 8.7 grams (.0376 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane cooled to 5° C. and stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added dropwise 4.36 grams (.0376 moles) of a 76% aqueous solution of t-butylhydrazine. The reaction was very exothermic and rapid and was complete almost immediately after the addition was complete. Pentane was added to slurry up the solids and the mixture stirred for 1 hour at room temperature. The pentane was stripped from the reaction mixture to leave a yellow solid weighing 11.3 grams (94.5% crude yield). The product melted at 120°-122° C. and the infrared spectrum of the product had sharp strong bands at 1540 and 1520 cm-1 and sharp NH bands at 3150 and 3280 cm-1.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9](N)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N([O-])=O.[Na+].C(N)CN.[BrH:21]>[Cu]Br>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([Br:21])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Br
Reactant: Nc1ccc(-n2cncn2)cc1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: NCCN
Product: Brc1ccc(-n2cncn2)cc1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
4-(1,2,4-Triazol-1-yl)aniline (400 mg, 2.5 mmol) in 48% HBr (10 ml) at -5° C. was stirred while sodium nitrite (173 mg, 2.5 mmol) was added portionwise over 5 minutes. The brown sludge was left stirring for 15 minutes and then added portionwise over 5 minutes to a refluxing mixture of copper (I) bromide (358 mg, 2.5 mmol) in 48% HBr (2 ml). The mixture was then heated at reflux for 1 minute, allowed to cool slightly, and poured into 10% ethylene diamine solution (20 ml). The aqueous solution was extracted with ethyl acetate, dried (Na2SO4), and evaporated to dryness under reduced pressure. The resulting mixture was purified by column chromatography on silica eluting with n-pentane/ethyl acetate (4-10%) to afford the title compound as a white solid (344 mg, 61%).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C=O)C>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: BrCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Following a literature procedure (Asso, V.; Ghilardi, E.; Bertini, S.; Digiacomo, M.; Granchi, C.; Minutolo, F.; Rapposelli, S.; Bortolato, A.; Moro, S. Macchia, M. Chem Med Chem, 2008, 3, 1530-1534) powdered KOH (0.103 g, 1.85 mmol) was added to a solution of 3,6-dibromocarbazole (0.500 g, 1.54 mmol) in DMF (1.5 mL) at ambient temperature and stirred for 30 min until dissolved. Epibromohydrin (0.32 mL, 3.8 mmol) was added via syringe and the reaction was stirred at room temperature overnight. Upon completion, the solution was partitioned between EtOAc and H2O. The aqueous layer was washed 3× with EtOAc, and the combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was recrystallized from EtOAc/Hexane to afford the desired product (389 mg, 66%).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[CH3:25][C:26]([NH2:33])([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[CH3:27]>>[CH3:25][C:26]([NH:33][C:22]([C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)=[CH:4][CH2:5]3)=[O:23])([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[CH3:27]
Reactant: CC(C)(N)c1cccs1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(C)(C)c4cccs4)[C@@]3(C)CC[C@@H]12
Yield: 50 %

Procedure:
The title compound was prepared in a yield of 50% in a similar manner to that described in Example 2 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 1-methyl-1-(2-thienyl)ethylamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=2)[CH:3]=[N:2]1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1C1C2C(=CC(C=O)=CC=2)NN=1>>[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:3]1[C:4]2[C:9](=[CH:8][C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1
Reactant: O=Cc1ccc2c(-c3nccs3)n[nH]c2c1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(-c3nccs3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-one, except substituting 3-(thiazol-2-yl)-1H-indazole-6-carbaldehyde (4.6 mg, 0.02 mmol), the title compound was prepared as a yellow solid (2.3 mg, 36%). 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br. s, 1H), 10.64 (br. s, 1H), 8.44 (d, J=8.5 Hz, 1H), 8.03 (d, J=3.3 Hz, 1H), 7.96 (s, 1H), 7.80-7.78 (m, 2H), 7.60 (d, 7.3 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.25 (td, J=7.5, 1.0 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.85 (td, J=7.5, 1.0 Hz, 1H); MS ESI 345.1 [M+H]+, calcd for [C19H12N4OS+H]+ 345.07.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:23]([O-])=[O:24])=[C:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)[S:11][C:5]=2[N:4]([CH2:26][CH2:27][CH3:28])[C:3]1=[O:29].[Na+].Cl.[O:32]1[CH2:36][C@@H:35]([OH:37])[CH2:34][NH:33]1>>[OH:37][CH:35]1[CH2:36][O:32][N:33]([C:23]([C:9]2[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:29])[N:4]([CH2:26][CH2:27][CH3:28])[C:5]=3[S:11][C:10]=2[CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[O:24])[CH2:34]1
Reactant: O[C@H]1CNOC1
Reactant: CCCn1c(=O)n(C)c(=O)c2c(C(=O)[O-])c(Cc3ccnc4ccccc34)sc21
Agent: Cl
Agent: [Na+]
Product: CCCn1c(=O)n(C)c(=O)c2c(C(=O)N3CC(O)CO3)c(Cc3ccnc4ccccc34)sc21

Procedure:
Prepared as the method of example 1, part g) using the product of step f) and (S)-isoxazolidin-4-ol hydrochloride. δ 1H DMSO 0.84 (3H, td), 1.60 (2H, septet), 3.21 (3H, d), 3.56 (1H, d), 3.73 (3H, m), 3.81 (1H, d), 3.90 (1H, m), 4.61 (2H, dd), 4.79 (1H, s), 5.52 (1H, m), 7.46 (1H, dd), 7.63 (1H, m) 7.79 (1H, m), 8.05 (1H, d), 8.27 (1H, dd), 8.87 (1H, d). MS (APCI) 481.1 (M++H)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=O>N1C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: CCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCOc1nc2ccc(C)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.9 %

Procedure:
A solution of 2-amino-5-methylbenzoic acid (302 mg, 2 mmol) in pyridine (10 ml) was cooled to 0° C. and treated dropwise with octyl chloroformate (1.15 ml, 6 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 4 h. The pyridine was removed under vacuum and the residue dissolved in ethyl acetate (50 ml). This solution was washed with 1M HCl (10 ml) and brine (5 ml), dried (MgSO4) and the solvent removed in vacuo to afford a pale orange oily solid. Recrystallisation from hexane afforded the desired product as an off-white solid (144 mg, 25%); δH (400 MHz, DMSO-d6) 0.68 (3H, t, J 7, CH2CH3), 1.26-1.40 (10H, m, 5×CH2), 1.73 (2H, tt, J, J′7, OCH2CH2), 2.35 (3H, s, CH3), 4.35 (2H, t, J 7, OCH2), 7.34 (1H, d, J 8, Ph), 7.65 (1H, d, J 8, Ph), 7.83 (1H, s, Ph); m/z (ES+) 290 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1>C(O)C>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=2)=[CH:19][CH:18]=1)#[N:27]
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: N#Cc1ccccc1-c1ccc(N)cc1
Solvent: CCO
Product: CCc1cc(Nc2ccc(-c3ccccc3C#N)cc2)n2nccc2n1

Procedure:
1.4 g (7.7 mmol) of the chloride from Example 1, Step B and 1.5 g (7.7 mmol) 4-Amino-2'-cyanobiphenyl were heated in 30 ml dry ethanol for 5 h. After removal of the solvent in vacuo the nitrile was obtained in colorless crystals from ethanol, m.p. 247°-248° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[S:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[S:36][N:35]=[CH:34][N:33]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(O[C@H]2CCCCC[C@@H]2c2ccccc2)cc1F
Yield: 79.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (140 mg, 0.227 mmol) prepared in Example 7a, triethylsilane (0.3 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (84.4 mg, 80%) as a colorless solid.
Reaction SMILES: [ClH:1].F[C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10](F)[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28]C(=O)C)([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][NH:23][CH2:22]3.Cl>CO.O1CCOCC1>[ClH:1].[OH:34][C@@H:4]1[C@H:3]2[C@@H:8]([CH2:9][CH2:10][C:11]3[C@:16]2([CH3:17])[CH:15]=[CH:14][C:13](=[O:18])[CH:12]=3)[C@@H:7]2[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][OH:28])([C@@:6]2([CH3:33])[CH2:5]1)[CH2:24][NH:23][CH2:22]3
Reactant: CC(=O)OCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@H]1CNC[C@]12C(=O)CO
Temperature: 25 °C
Reaction time: 240 h
Yield: 100 %

Procedure:
In a closed vessel compound 20 (300 mg, 0.600 mmol) is dissolved in MeOH, HCl (0.045 ml, 0.180 mmol) in dioxane is added and the mixture is stirred at room temperature for 10 days, then further HCl (0.045 ml, 0.180 mmol) is added and the reaction mixture is stirred for further 2 days. The reaction mixture is concentrated to dryness affording the title compound (253 mg, 0.600 mmol, 100% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:25][C:24]2[C:4](=[CH:5][C:6]3[N+:11]([O-:12])=[N:10][C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[N:8][C:7]=3[CH:23]=2)[CH2:3]1.C[OH:27].C(Cl)Cl>>[CH3:1][CH:2]1[CH2:25][C:24]2[C:4](=[CH:5][C:6]3[N+:11]([O-:12])=[N:10][C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[N+:8]([O-:27])[C:7]=3[CH:23]=2)[CH2:3]1
Reactant: CC1Cc2cc3nc(NCCCN4CCOCC4)n[n+]([O-])c3cc2C1
Reactant: CO
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C1)[n+]([O-])c(NCCCN1CCOCC1)n[n+]3[O-]

Procedure:
H2O2 (70%, 0.72 mL, ca. 14.3 mmol) was added dropwise to a stirred solution of TFAA (2.0 mL, 14.3 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 98 (490 mg, 1.4 mmol) and TFA (0.55 mL, 7.1 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 98 (280 mg, 57%) and (ii) 1,4-dioxide 99 (88 mg, 17%) as a red solid: mp (MeOH/DCM) 161-163 DC; 1H NMR δ 8.30 (br s, 1H, NH), 8.08 (br s, 2H, H-5, H-9), 3.82 (br t, J=4.5 Hz, 4H, 2×CH2O), 3.58-3.63 (m, 2H, CH2N), 3.15-3.25 (m, 2H, CH2), 2.61-2.74 (m, 3H, CH, CH2), 2.57 (br t, J=6.1 Hz, 2H, CH2N), 2.47-2.53 (m, 4H, 2×CH2N), 1.83-1.90 (m, 2H, CH2), 1.18 (d, J=6.2 Hz, 3H, CH3); 13C NMR δ 155.2, 149.5, 145.2, 138.1, 129.5, 115.8, 111.7, 66.9 (2), 57.7, 53.8 (2), 41.6, 41.4, 40.4, 34.9, 24.5, 20.2. Anal. calcd for C18H25N5O3: C, 60.2; H, 7.0; N, 19.5. Found: C, 60.6; H, 7.0; N, 18.3%.
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:32])[N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].[CH2:33]([O:35][C:36](=[O:45])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](Cl)=[O:43])[CH3:34]>CC#N>[O:31]=[C:25]1[CH:24]([N:17]2[C:16](=[O:32])[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][NH:12][C:42]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:45])=[O:43])[C:18]2=[O:23])[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCOC(=O)CCCCCC(=O)Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 50 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.26 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrocbloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 6-(chloroformyl)hexanoic acid ethyl ester (0.46 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give ethyl 6-(N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}carbamoyl)hexanoate (0.43 g, 50%) as a white solid: mp 82–84° C.; 1H NMR (DMSO-d6) δ d 11.11 (s, 1H), 8.41 (t, J=5.6 Hz, 1H), 7.86–7.65 (m, 3H), 5.18–5.11 (dd, J=5.4 and 12.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 4.05 (q, J=7.1 Ha, 2H), 2.97–2.83 (m, 1H), 2.64–2.48 (m, 2H), 2.30–2.15 (m, 4H), 2.08–2.04 (m, 1H), 1.56–1.47 (m, 4H), 1.32–1.23 (m, 2H), 1.17 (t, J=7.1 Hz, 3H), 13C NMR (DMSO-d6) δ d 172.80, 172.71, 172.52, 169.77, 167.45, 166.92, 139.49, 134.67, 133.13, 131.49, 127.04, 121.78, 59.60, 48.84, 37.57, 35.02, 33.38, 30.91, 28.08, 24.83, 24.16, 21.96, 14.09; Anal. Calcd. For C23H27N3O7: C, 60.39; H, 5.95; N, 9.18. Found: C, 60.10; H, 5.82; N, 8.82.