Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(NC(C(C1C=CC(O)=C(O)C=1)=O)C)(C)(C)C.C([Cl:25])(=O)C(C)(C)C.FC(F)(F)C(O)=O.Cl.Cl.[C:35]([NH:39][CH:40]([C:42]([C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])=[C:46]([O:57][C:58](=[O:63])[C:59]([CH3:62])([CH3:61])[CH3:60])[CH:45]=1)=[O:43])[CH3:41])([CH3:38])([CH3:37])[CH3:36]>[Pd]>[ClH:25].[C:58]([O:57][C:46]1[CH:45]=[C:44]([CH:49]=[CH:48][C:47]=1[O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[CH:42]([OH:43])[CH:40]([NH:39][C:35]([CH3:36])([CH3:37])[CH3:38])[CH3:41])(=[O:63])[C:59]([CH3:60])([CH3:61])[CH3:62]
Reactant: CC(NC(C)(C)C)C(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Pd]
Agent: CC(NC(C)(C)C)C(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(C)(C)C)C(O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1

Procedure:
3,4-Dihydroxyphenyl 1-(tert-butylamino)ethyl ketone hydrochloride (8 g.) was reacted with 18 ml. of pivalyl chloride in 35 ml. of trifluoroacetic acid, the resulting ester-amine salt was converted to the ester-amine, and the ester-amine was treated with hydrochloric acid to yield 10.5 g. of 3,4-bis(pivalyloxy)phenyl 1-(tert-butylamino)ethyl ketone hydrochloride, m.p. 200°-202° C. (uncorr.). This ketone was catalytically hydrogenated in the presence of palladium-on-charcoal catalyst to yield 3,4-bis(pivalyloxy)-alpha-[1-(tert-butylamino)ethyl]benzyl alcohol hydrochloride as a white crystalline solid which melted at 205°-207° C. (uncorr.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]3[C:19]4[C:14](=[CH:15][C:16]([C:20]5[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=5)=[CH:17][CH:18]=4)[CH2:13][N:12]([CH3:27])[CH2:11]3)[CH:8]=[CH:9][C:2]1=2.O.NN>CO.[Pd]>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]3[C:19]4[C:14](=[CH:15][C:16]([C:20]5[N:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:17][CH:18]=4)[CH2:13][N:12]([CH3:27])[CH2:11]3)[CH:8]=[CH:9][C:2]1=2
Reactant: CN1Cc2cc(-c3ccc(Cl)nn3)ccc2C(c2ccc3sccc3c2)C1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: CN1Cc2cc(-c3cccnn3)ccc2C(c2ccc3sccc3c2)C1
Yield: 70.6 %

Procedure:
To a solution of the product obtained in Step B (2.02 g, 5.15 mmol) and hydrazine hydrate (8 mL) in MeOH (100 mL), was added 10% Pd/C (0.25 g). The reaction mixture was heated to reflux 8 h, then, the reaction mixture was filtered through a short pad of celite. The filtrate was concentrated to dryness under reduced pressure. The residue was diluted with CH2Cl2 (60 mL), then, washed with H2O (1×40 mL). The aqueous phase was extracted with additional amount of CH2Cl2 (3×20 mL). The combined organic phases were dried (Na2SO4) and concentrated to dryness under reduced pressure. The residue was purified using medium pressure chromatography (eluent: EtOAc/MeOH 9:1) to afford (+/−)-4-benzo[b]thiophen-5-yl-2-methyl-7-pyridazin-3-yl-1,2,3,4-tetrahydroisoquinoline (1.3 g, 71%, >99% AUC HPLC) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.14 (dd, J=1.6, 4.9 Hz, 1H), 7.94 (d, J=1.5 Hz, 1H), 7.84-7.79 (m, 2H), 7.71-7.67 (m, 2H), 7.51 (dd, J=8.6, 4.9 Hz, 1H), 7.44 (d, J=5.4 Hz, 1H), 7.28-7.26 (m, 1H), 7.20 (dd, J=8.3, 1.6 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.46 (m, 1H), 3.90 (d, J=14.6 Hz, 1H), 3.76 (d, J=14.6 Hz, 1H), 3.15-3.10 (m, 1H), 2.71-2.65 (m, 1H), 2.48 (s, 3H); ESI-MS m/z 358 [M+H]+.
Reaction SMILES: Cl[C:2]([N:4]([C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1)[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12])=[O:3].[NH3:21]>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[N:4]([C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1)[C:2]([NH2:21])=[O:3]
Reactant: Cc1cc(C)nc(N(C(=O)Cl)c2cc(Cl)ccc2Cl)n1
Reactant: N
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)nc(N(C(N)=O)c2cc(Cl)ccc2Cl)n1

Procedure:
4.0 g (0.012 mole) of N-chlorocarbonyl-N-(4,6-dimethylpyrimidin-2-yl)-2,5-dichloroaniline are dissolved in 50 ml of chloroform. An excess of ammonia gas is introduced into the solution. When the exothermic reaction has subsided, the reaction mixture is washed twice with water, dried with magnesium sulfate and concentrated by evaporation.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([OH:3])=[O:2].[Cl:15][S:16](O)(=[O:18])=[O:17].ClS(C1C=CC(OC)=C(C=1)C(O)=O)(=O)=O>>[C:1]([CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([OH:3])=[O:2]
Reactant: O=C(O)COc1ccccc1C(=O)O
Reactant: O=S(=O)(O)Cl
Agent: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Product: O=C(O)COc1ccc(S(=O)(=O)Cl)cc1C(=O)O

Procedure:
2-(Carboxymethoxy)-5-chlorosulfonyl-benzoic acid was synthesized by the reaction of 2-carboxymethoxy benzoic acid with chlorosulfonic acid using a method similar to the synthesis of Intermediate 6.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([CH:38]=[CH:37][CH:36]=1)[O:17][CH2:16][CH:15]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=1)=[O:33]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1
Reactant: Oc1cccc(Cl)c1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccc(Cl)c2)NS(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (310 mg) was reacted with 3-chlorophenol (125 μl) to obtain (RS)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)propanamide (257.24 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:30][C:12]2=[CH:13][C:14]3[C:15](=[O:29])[N:16]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:31][C:32]1[C:37]([F:38])=[CH:36][C:35]([F:39])=[C:34]([F:40])[C:33]=1[CH2:41][CH:42]([NH2:44])[CH3:43]>C(O)CCC>[CH3:20][C:19]1[C:18]2[C:17](=[O:21])[N:16]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:15](=[O:29])[C:14]=2[CH:13]=[C:12]2[NH:30][C:9]([C:3]3[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=3[NH:44][CH:42]([CH3:43])[CH2:41][C:33]3[C:34]([F:40])=[C:35]([F:39])[CH:36]=[C:37]([F:38])[C:32]=3[F:31])=[N:10][C:11]=12
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Solvent: CCCCO
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Yield: 78.5 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 2.35 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.54 g, 2.58 mmol), Hunig,s base (1.52 g, 0.011 mol), and 20 mL of anhydrous 1-butanol was heated at reflux for 14-15 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 1.10 g of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ 13.35 (s, 1H, NH), 11.35 (d, J=6.0 Hz, 1H, NH), 11.02 (d, J=8.5 Hz, 1H, NH), 7.93 (s, 1H, ArH), 7.81-7.77 (m, 1H, ArH), 7.42 (t, J=7.0 Hz, 1H, ArH), 6.22 (d, J=8.0 Hz, 1H, ArH), 4.34-4.29 (m, 1H, CH), 4.12 (m, 1H, CH), 3.17 (m, 2H, CH2), 3.08 (d, J=5.5 Hz, 2H, CH2), 2.72 (s, 3H, CH3), 2.48 (s, 3H, CH3), 1.77-1.76 (m, 2H, CH2), 1.37 (d, J=6.5 Hz, 3H, CH3), 1.29-1.24 (m, 6H, 2×CH2); Mass (ESI, positive) m/z 597.2 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+].O>CC(O)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([O-:10])=[O:9]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 43.4 %

Procedure:
1-Fluoro-2-nitro-benzene (0.53 mL, 5.0 mmol), 2-Amino-benzoic acid (750 mg, 5.5 mmol) and Na2CO3 (420 mg, 4.0 mmol) are added together in reaction flask and the mixture is heated at 130° C. for 60 hrs. After it is cooled down to room temperature, 50 mL of water is added and HOAc is used to adjust the pH to slightly acidic. Then the mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, washed with water (3×50 mL), dried (Na2SO4) and concentrated to give crude product. Purifiction by flash column chromatography affords 560 mg (43%) of 2-(2-Nitro-phenylamino)-benzoic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH:13][CH3:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1ccc2cc[nH]c2c1
Reaction time: 3 h
Yield: 98.7 %

Procedure:
Indole-6-carboxaldehyde (90 mg, 0.62 mmol) was dissolved in anhydrous methanol (3 mL). Methylamine (0.95 mL of 2M solution in methanol, 1.86 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (3 mL). Sodium borohydride (24 mg, 0.62 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated. Sodium hydroxide (2 mL, 1N) was added and the indole was extracted with ethyl acetate (3×10 mL), dried over MgSO4 and concentrated to afford the title compound as a yellow oil (98 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 9.02 (s, 1H), 7.57(d, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.12 (d, J=3.1 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 3.81 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>Cl>[C:10]1([CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCOCCc1ccccc1
Agent: Cl
Product: c1ccc(CCOCCCCCNCc2ccccc2)cc1

Procedure:
[2-[(5-Bromopentyl)oxy]ethyl]benzene (10.0 g) was added over 1 h to benzylamine (30 ml) at ca. 120° under nitrogen. After 2 h at 120° the reaction mixture was added to 2N hydrochloric acid (200 ml), the mixture was extracted with ethyl acetate (2×250 ml) and the combined organic extracts were washed with 2N sodium carbonate, water and brine, dried and concentrated in vacuo to give the title compound as a pale yellow oil (8.6 g), t.l.c. (ethyl acetate-triethylamine 99:1) Rf 0.78
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]=1>C(O)C>[ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1=NCCCCC1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Solvent: CCO
Product: c1ccc([C@H]2CCC[C@H]2N=C2CCCCCN2)cc1
Reaction time: 144 h

Procedure:
A mixture of 4.0 g of cis-2-phenylcyclopentylamine hydrochloride, M.P. 205°-206° C and 5.0 ml of O-methylcaprolactim is allowed to stand at room temperature for 6 days with occasional stirring. A few drops of ethanol are added to maintain a stirrable slurry, after which the mixture is cooled. The resulting solid is washed with ether and recrystallized from acetone/methanol to give the desired product, M.P. 181.5°-183.5° C (dec.).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[O:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCN(c2nc3ccc(C(=O)O)cc3s2)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(c2nc3ccc(C(=O)N4CCOCC4)cc3s2)CC1
Temperature: 45 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxylic acid (800 mg, 2.1 mmol) in THF (14 mL) was added HOBt (342 mg, 2.5 mmol), EDAC (807 mg, 4.2 mmol), triethylamine (1.7 g, 17 mmol) and morpholine (735 mg, 8.4 mmol) at room temperature. The reaction mixture was stirred at 40-50° C. for 12 h under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel with a gradient of CH2Cl2/MeOH (100:1→50:1) as eluent to give the crude product, which was further purified by preparative HPLC to give 224 mg (28%) of [2-(4-isopropyl-piperazin-1-yl)benzothiazol-6-yl]morpholin-4-ylmethanone as a trifluoroacetate salt.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19]Br)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>C(N(CC)CC)C.C(Cl)Cl.[OH-].[Na+]>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][N:5]2[CH2:6][CH2:7][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(CCBr)cc1OC
Reactant: OCC1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCN2CCC(CO)C2)cc1OC

Procedure:
3 g (0.03 mol) of 3-hydroxymethyl-pyrrolidine and 7.5 g of 2-(3,4-dimethoxy-phenyl)-ethylbromide are heated in 20 ml of triethylamine for 7 hours at 100° C. The excess triethylamine is then distilled off in vacuo and the residue obtained is dissolved in methylene chloride and 6 molar sodium hydroxide solution. The organic phase is separated off, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue obtained is then purified over 400 g of alumium oxide (neutral, activity II) with methylene chloride and with increasing amounts of ethanol (up to 1%). Yield: 5.4 g (67.8% of theory), Rf value: 0.41 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:6]([CH:8]=1)[NH2:7].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:6]([NH:7][S:29]([C:21]2[O:20][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH:22]=2)(=[O:30])=[O:31])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1SCc1ccccc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 69 %

Procedure:
Following General Procedure B, the title compound (485 mg, 69%) was prepared from 5-chloro-2-((2-nitrobenzyl)thio)aniline (435 mg, 1.48 mmol) and benzofuran-2-sulfonyl chloride (320 mg, 1.48 mmol) in pyridine (5 ml).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8](=[O:9])[N:10]2[CH:14]([C:15]([NH:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.29 mL, 2.6 mmol). The reaction was stirred for 2 hours at 0° C. Aniline (93 mg, 1.0 mmol) was added to the reaction, which was allowed to warm to room temperature and stirred for 3 hours. The solvent was then removed under reduced pressure, and water (5 mL) and DCM (15 mL) were added to the residue. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organics were dried over sodium sulfate and concentrated. The resulting residue was purified by Combiflash silica gel chromatography (0-60% EtOAc in hex) to give 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(phenylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoate (386 mg, 0.90 mmol, 90% yield) as a yellow oil. MS: 428 ([M+H]).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:27])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC1CCCC1
Product: Cc1cc2ccc(C#CC3CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(cyclopentylethynyl)-3-methylnaphthalen-2-yl)acetic acid (74) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using ethynylcyclopentane.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][C:10](O)=[O:11])[CH2:3]1.P(Cl)(Cl)[Cl:15]>CCOCC>[CH3:1][C:2]1([CH3:13])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][C:10]([Cl:15])=[O:11])[CH2:3]1
Reactant: ClP(Cl)Cl
Reactant: CC1CC(CC(=O)O)CC(C)(C)C1
Solvent: CCOCC
Product: CC1CC(CC(=O)Cl)CC(C)(C)C1
Yield: 264.4 %

Procedure:
114 g of 3,3,5-trimethyl-cyclohexylacetic acid in 350 ml of dry ether in a round flask which is fitted with a thermometer, stirrer, reflux condenser and dropping funnel are treated rapidly with 32.8 g of phosphorus trichloride and the mixture is subsequently held at reflux temperature for a further 4 hours. The phosphorous acid is decanted off and the ether is evaporated in vacuo. There are obtained 128 g (yield: quantitive) of crude 3,3,5-trimethyl-cyclohexylacetyl chloride.
Reaction SMILES: C([NH:8][C:9](=[O:42])[C@@H:10]([N:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)[C:18]1=[O:41])[CH2:11][CH2:12][C:13](OC)=[O:14])C1C=CC=CC=1.[C:43]1([CH3:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:49]([N:8]1[C:13](=[O:14])[CH2:12][CH2:11][C@H:10]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:30][CH:29]=3)[C:18]2=[O:41])[C:9]1=[O:42])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)CC[C@@H](C(=O)NCc1ccccc1)N1Cc2c(OCc3ccc(CN4CCOCC4)cc3)cccc2C1=O
Product: O=C1CC[C@H](N2Cc3c(OCc4ccc(CN5CCOCC5)cc4)cccc3C2=O)C(=O)N1Cc1ccccc1

Procedure:
A mixture of (S)-methyl 5-(benzylamino)-4-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (2.5 mmol) and p-TsOH monohydrate (1.25 mmol) in toluene, under argon, is refluxed for 8 hours. The solvent is evaporated. The crude is taken up in ether (50 mL) and washed with saturated aqueous NaHCO3 (2×20 mL). The organic layer is dried and purified by silica gel chromatography to afford (S)-1-benzyl-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7]CC)=[O:6])[NH2:3].CN(C)/[CH:12]=[CH:13]/[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C([O-])([O-])=O.[K+].[K+].Cl>CCO.CC(=O)OCC>[C:16]1([C:14]2[N:2]([CH2:4][C:5]([OH:7])=[O:6])[N:3]=[CH:12][CH:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)/C=C/C(=O)c1ccccc1
Reactant: CCOC(=O)CNN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)Cn1nccc1-c1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 63.6 %

Procedure:
To a solution of ethyl hydrazinoacetate hydrochloride (866 mg) in EtOH (20 mL) was added (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (981 mg) and K2CO3 (774 mg). The reaction mixture was stirred at 80° C. for 20 h, cooled down and the pH was brought to 2-3 by adding 1M HCl. EA was added and the phases were separated. The org. layer was washed with brine, dried (Na2SO4) and evaporated in vacuo to afford 720 mg of white solid. LC-MS (B): tR=0.63 min; [M+H]+: 203.43.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]3=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[CH:20]1[C:32]2[N:31]([C:33]3[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([N:39]4[C:51]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[C:45]5[C:40]4=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:38]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]1[C:32]2[N:31]([C:33]3[CH:34]=[C:35]([C:2]4[CH:11]=[N:10][C:9]5[C:4](=[C:5]6[CH:19]=[CH:18][CH:17]=[CH:16][C:6]6=[C:7]6[CH:15]=[CH:14][CH:13]=[CH:12][C:8]6=5)[N:3]=4)[CH:36]=[C:37]([N:39]4[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=5[C:46]5[C:51]4=[CH:50][CH:49]=[CH:48][CH:47]=5)[CH:38]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Reactant: Clc1cnc2c3ccccc3c3ccccc3c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc2c(c1)c1ccccc1c1nc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)cnc21
Yield: 94 %

Procedure:
Into a 100-mL three-neck flask were put 1.2 g (4.8 mmol) of 2-chlorodibenzo[f,h]quinoxaline, 2.1 g (4.7 mmol) of 3,5-bis(9H-carbazol-9-yl)phenylboronic acid, and the air in the flask was replaced with nitrogen. To this mixture were added 18 mL of toluene, 6.0 mL of ethanol, and 6.0 mL of an aqueous solution of potassium carbonate (2.0 mol/L). This mixture was stirred to be degassed while the pressure was reduced. To this mixture was added 0.11 g (0.096 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 80° C. for six hours under a nitrogen stream, so that a solid was precipitated. The precipitated solid was collected by suction filtration. To the obtained solid was added about 100 mL of water, washed by ultrasonic wave irradiation, and subjected to suction filtration to obtain a solid. To the obtained solid was added about 100 mL of ethanol, washed by ultrasonic wave irradiation, and subjected to suction filtration to obtain a solid. The obtained solid was dissolved in about 1.5 L of hot toluene, and this solution was suction-filtered through Celite and Florisil. A solid obtained by concentration of the filtrate was washed with toluene, so that 2.8 g of a yellow solid, which was the object of the synthesis, was obtained in a yield of 94%. The synthesis scheme of Step 3 is shown in (a-3).