Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:44].[Li+]>C(Cl)Cl.O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][Br:44])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(CO)cc2)nc1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(CBr)cc2)nc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 1-[6-(4-hydroxymethyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.80 g, 1.9 mmol) in 9.4 mL of methylene chloride was added triethylamine (0.46 mL, 0.33 g, 3.3 mL). After cooling to −40° C., the mixture was treated with methanesulfonyl chloride (0.20 mL, 0.30 g, 2.61 mmol). After stirring for 1 hour, an additional 0.10 mL of methanesulfonyl chloride and 0.4 mL of triethylamine were added, and stirring was continued for 1 hour. A solution of anhydrous lithium bromide (1.6 g, 19 mmol, flame dried under vacuum before use) in tetrahydrofuran (20 mL) was added via cannula, and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was filtered through a pad of silica gel eluting with 1:1 ethyl acetate-hexanes, affording 0.65 g of 1-[6-(4-bromomethyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup. 1H NMR (CDCl3, 500 MHz): 8.07 (d, 1H, J=3.0 Hz), 7.76 (dd, 1H, J=2.5, 8.5 Hz), 7.44 (d, 2H, J=8.5 Hz), 7.12 (d, 2H, J=8.0 Hz), 6.95 (d, 1H, J=9.0 Hz), 4.53 (s, 2H), 4.22 (q, 4H, J=7.0 Hz), 2.75 (m, 2H), 1.20 (t, 6H, J=7.0 Hz) ppm.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Cl)[C:12]=2[N+:18]([O-:20])=[O:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]1([S:7]([CH2:10][C:11]2[C:12]([N+:18]([O-:20])=[O:19])=[C:13]([N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1c(Cl)cccc1CS(=O)(=O)c1ccccc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cccc(CS(=O)(=O)c3ccccc3)c2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
10 g of 1-benzenesulfonylmethyl-3-chloro-2-nitro-benzene were slurried in 25 mL N-methylpiperazine under nitrogen and stirred. The mixture was heated to 80° C. (oil bath temperature) for a period of 14 hours. The reaction was quenched at 80° C. with 125 mL water, and the thick slurry was filtered, washed with 100 mL water and 100 mL hexanes., and vacuum dried at 45° C. under nitrogen purge for 4 hours, to yield 11.7 g of 1-(3-benzenesulfonylmethyl-2-nitro-phenyl)-4-methyl-piperazine mp 180-182° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:14]
Reactant: C1CCNC1
Reactant: CCOC(=O)CCCBr
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCN1CCCC1
Temperature: 25 °C

Procedure:
To a solution of pyrrolidine (8.42 mL, 102 mmol, 4.0 eq) in toluene (30 mL), ethyl 4-bromobutyrate (3.8 mL, 26 mmol, 1.0 eq) was added and the reaction mixture was refluxed for 10 hours. The mixture was allowed to cool down to room temperature, the white solid present was filtered off and washed with Et2O. The filtrate was concentrated under reduced pressure to give the title product which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])[CH3:20].ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:20][CH:19]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)=[CH:24][CH:23]=1)[CH3:21]
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)c1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Yield: 81 %

Procedure:
The title compound was prepared as described in Example 161, using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.400 g, 1.30 mmol), in ethylene glycol dimethyl ether (10 mL), 4-isopropyl phenyl boronic acid (0.321 g, 1.96 mmol), [1,1′-bis(diphenylphosphino)-ferrocene] complex with dichloromethane (1:1) (0.150 g, 0.130 mmol), and potassium phosphate (1.38 g, 6.5 mmol): (0.364 g, 81% yield): ES-MS (m/z) 346 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[OH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:15][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)[CH3:21]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.7 %

Procedure:
To a solution of methyl 6-chloro-5-nitronicotinate (3 g, 13.85 mmol) in THF (60 mL) and DMF (30.0 mL) was added ethyl 2-hydroxyacetate (1.573 mL, 16.62 mmol) and potassium carbonate (5.74 g, 41.6 mmol). The reaction was stirred at room temperature for 24 hours. TLC analysis of the reaction mixture indicated partial consumption of starting material. Ethyl 2-hydroxyacetate (1 mL, 10.57 mmol) and potassium carbonate (2 g, 14.5 mmol) were added and the reaction was stirred at room temperature for 72 hours. TLC analysis of the reaction mixture indicated nearly complete consumption of starting material. The reaction mixture was partially concentrated under reduced pressure for removal of THF. The resulting red solution was diluted with H2O (200 mL) and 1N HCl was added to adjust the pH to 7. The aqueous layer was extracted with EtOAc (3×200 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 10-70% EtOAc to provide methyl 6-(2-ethoxy-2-oxoethoxy)-5-nitronicotinate (2.43 g, 8.55 mmol, 61.7% yield) as a white solid.
Reaction SMILES: N(OC(C)(C)C)=O.[Br-:8].C(OC([N:16]1[CH2:22][CH2:21][C:20]2[S:23][C:24](N)=[N:25][C:19]=2[CH2:18][CH2:17]1)=O)(C)(C)C>C(#N)C>[Br:8][C:24]1[S:23][C:20]2[CH2:21][CH2:22][NH:16][CH2:17][CH2:18][C:19]=2[N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2CC1
Reactant: [Br-]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Brc1nc2c(s1)CCNCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
238 μl tert.-butyl nitrite was added to 447 mg cupper (II) bromide in 50 mL acetonitrile. The reaction was stirred 10 min. at RT and then 270 mg 2-amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]-azepine-6-carboxylic acid tert-butyl ester was added. The reaction was stirred 30 min. at 60° C. The reaction was purified by HPLC. The residue was dissolved in 10 mL dichlormethane and 10 mL trifluor acetic acid and stirred at RT for 1 h. The mixture was evaporated to give 112 mg of the desired product. Rt: 0.92 min (method I), (M+H)+: 233/235
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([OH:25])[CH:17]=2)=[C:8]([CH:26]([CH3:28])[CH3:27])[C:7]=1[CH3:29])(=[O:4])[CH2:2][CH3:3].[H][H]>[Pd].CO>[C:1]([O:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([OH:25])[CH:17]=2)=[C:8]([CH:26]([CH3:28])[CH3:27])[C:7]=1[CH3:29])(=[O:4])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCC(=O)Oc1cc(C(C)C)c(Oc2ccc([N+](=O)[O-])c(O)c2)c(C(C)C)c1C
Agent: [Pd]
Solvent: CO
Product: CCC(=O)Oc1cc(C(C)C)c(Oc2ccc(N)c(O)c2)c(C(C)C)c1C
Yield: 100.9 %

Procedure:
Methyl(3,5-diisopropyl-4-[3-hydroxy-4-nitrophenoxy]phenyl) propionate (0.30 g), methanol (10 mL), palladium on carbon (10%) and 1–2 atmospheres of hydrogen gas was stirred at room temperature for 4 hours. After filtration, 0.28 g of methyl(3,5-diisopropyl-4-[4-amino-3-hydroxyphenoxy]phenyl) propionate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C)[CH2:10][CH:9]2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]([O:36][CH2:37][C:38]([Cl:41])([Cl:40])[Cl:39])=[O:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:34]([O:36][CH2:37][C:38]([Cl:41])([Cl:40])[Cl:39])=[O:35])[CH2:10][CH:9]2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: CN1CCC(c2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1
Reaction time: 12 h
Yield: 57 %

Procedure:
A solution of 0.526 g (1.43 mmol) of (3RS,4RS)-4-(4-chloro-phenyl)-1-methyl-3-(naphthalen-2-ylmethoxy)-piperidine in 12 ml of toluene was treated with 100 mg of potassium carbonate and heated to 100°. Subsequently, 0.423 g (0.288 ml, 2 mmol) of 2,2,2-trichloroethyl chloroformate was added thereto and the mixture was stirred at 100° for 12 hours. The reaction solution was evaporated, taken up in 50 ml of ethyl acetate and washed with 20 ml of water and 20 ml of saturated sodium hydrogen carbonate solution. Drying over magnesium sulphate, filtration (sic) and evaporation yielded a colourless oil which was chromatographed on silica gel using a 3:2 mixture of hexane and ethyl acetate as the eluent. There was obtained 0.426 9 (57% of theory) of 2,2,2-trichloroethyl 4-(4-chloro-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; Rf: 0.31 (silica gel, hexane/ethyl acetate: 3/2).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]([O:16][S:17](=[O:38])(=[O:37])[NH:18][C:19](=[O:36])[CH2:20][C:21]2[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=2[CH:33]([CH3:35])[CH3:34])=[C:9]([CH:39]([CH3:41])[CH3:40])[CH:8]=1)(C)(C)C>C(#N)C>[OH:6][C:7]1[CH:8]=[C:9]([CH:39]([CH3:41])[CH3:40])[C:10]([O:16][S:17](=[O:38])(=[O:37])[NH:18][C:19](=[O:36])[CH2:20][C:21]2[C:22]([CH:33]([CH3:34])[CH3:35])=[CH:23][C:24]([CH:30]([CH3:31])[CH3:32])=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(O[Si](C)(C)C(C)(C)C)cc2C(C)C)c(C(C)C)c1
Solvent: CC#N
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(O)cc2C(C)C)c(C(C)C)c1
Reaction time: 16 h
Yield: 90.8 %

Procedure:
A solution of 15 mL concentrated HF in 150 mL acetonitrile was added dropwise to a solution of [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 4-(tert-butyl-dimethyl-silanyloxy)-2,6-diisopropyl-phenyl ester (9.71 g, 15.4 mmol) in 400 mL acetonitrile at room temperature under a nitrogen atmosphere. Stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between water and dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an oily solid. Trituration with hexanes gave 7.24 g of [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 4-hydroxy-2,6-diisopropyl-phenyl ester as a white solid; mp 182-183° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.Cl.[CH2:38]1[C:43]2([CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][N:39]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C(N(C(C)C)CC)(C)C>C(O)CCCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:46]4[CH2:45][CH2:44][C:43]5([CH2:38][N:39]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:40][CH2:41][CH2:42]5)[CH2:48][CH2:47]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(Cl)nn45)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCNCC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCC7(CCCN(C(=O)OC(C)(C)C)C7)CC6)nn45)ccnc32)cc1
Temperature: 140 °C
Yield: 0.1 %

Procedure:
A mixture of 0.15 g (0.29 mmol) of 6-chloro-2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, prepared according to the method described in step 3.2 of Example 3, 0.337 g (1.15 mmol) of tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate hydrochloride (1:1) (CAS 1023301-88-3) and 0.224 g (1.7 mmol) of diisopropylethylamine in 2 ml of pentanol is heated under reflux for 40 hours at 140° C. The solvent is then evaporated under reduced pressure and the residue is purified by chromatography on a silica gel column by eluting with a gradient of dichloromethane, methanol and aqueous ammonia (of 100/0/0 to 90/10/1) in order to give 0.190 mg of tert-butyl 9-{2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazin-6-yl}-2,9-diazaspiro[5.5]undecane-2-carboxylate after crystallization in methanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[CH:20]4)=[O:15])=[C:12]([CH3:26])[NH:11][C:10](=[O:27])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[NH2:16][C:17]1[CH:25]=[C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]3[C:13]([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][N:21]=[CH:20]5)=[O:15])=[C:12]([CH3:26])[NH:11][C:10](=[O:27])[NH:9]3)[CH:3]=2)[CH:23]=[CH:19][CH:18]=1
Reactant: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2cccc(Br)c2)NC(=O)N1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2cccc(-c3cccc(N)c3)c2)NC(=O)N1
Temperature: 185 °C
Reaction time: 0.1 h

Procedure:
The product of Example 76 (0.100 g, 0.230 mmol, 1.00 equiv), Pd(dppf)Cl2.CH2Cl2, and 3-aminoboronic acid (107 mg, 0.690 mmol, 3.00 equiv) were dissolved in dioxane (2 mL) and 1M aq. Na2CO3 (0.690 mL, 0.690 mmol, 3.00 equiv) was added. The reaction mixture was heated to 185° C. In a SmithSynthesizer for 6 minutes. The crude reaction mixture was filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (30×100 Xterra prep, 25-80% CH3CN/5 mM NH4HCO3 over 18 minutes) to afford the title compound as a white solid. MS (ES+) m/e 439 [M+H]
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=1>O.Cl>[F:12][C:10]1[CH:9]=[CH:8][C:7]2[N:13]([C:14]3[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[N:1]=[N:5][C:6]=2[CH:11]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2ccc(F)cc2N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(Oc1ccc(-n2nnc3cc(F)ccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2.1 of sodium nitrite in 25 ml of water was added drop-by-drop to a stirred solution of 6.7 g of 7B in 150 ml of 12% hydrochloric acid at 2° C. The resulting mixture was stirred at room temperature for 12 hours, then was filtered. Recrystallization of the filter cake from ether/hexane gave 7, as a solid, m.p.: 164°-166° C.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([CH2:25][C:26]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]3[C:27]=2[CH:28]=[CH:29][N:30]3S(C2C=CC=CC=2)(=O)=O)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[NH4+].[Cl-]>CO>[C:1]1([S:7]([NH:10][CH:11]([CH2:25][C:26]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]3[C:27]=2[CH:28]=[CH:29][NH:30]3)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2ccn(S(=O)(=O)c3ccccc3)c12
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2cc[nH]c12

Procedure:
A mixture of 2-benzenesulfonylamino-3-(1-benzenesulfonyl-7-methoxy-1H-indol-4-yl)-N-(4-phenyl-butyl)-propionamide (1.0 g, 1.6 mmol) and 2.5 M KOH (2.0 mL, 5.0 mmol) is refluxed in MeOH (9 mL) for 22 h. The resulting solution is poured into a saturated NH4Cl solution and extracted twice with EtOAc. The organics are dried (MgSO4) and concentrated to provide 2-benzenesulfonylamino-3-(7-methoxy-1H-indol-4-yl)-N-(4-phenyl-butyl)-propionamide as an oil which is used as is without further purification.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CCOC(C)=O>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[N:3]=[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:10]=[CH:9][C:5]=2[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Nc2nc(N3CCCCC3)ccc2C(N)=O)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of 6-chloro-2-(4-(methylsulfonyl)phenylamino)nicotinamide (19.4 mg, 0.060 mmol) and piperidine (2 mL) in a sealed tube was stirred in a 90° C. oil bath for 5 h. The mixture was diluted with EtOAc (25 mL), washed with saturated NH4Cl(2×5 mL), brine (5 mL), dried (MgSO4), and concentrated. After addition of CH2Cl2 (2 mL), white solid precipitated from the solution upon sitting. The solid was collected by filtration (14.1 mg, 60%). LCMS: (M+H)+=375.1. 1H NMR (400 MHz, acetone-d6) δ ppm 12.20 (1H, s), 7.90-8.09 (3H, m), 7.78-7.89 (2H, m), 6.33 (1H, d, J=8.78 Hz), 3.58-3.89 (4H, m), 3.07 (3H, s), 1.52-1.85 (6H, m).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCOc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCCOc1ccccc1
Yield: 91 %

Procedure:
The title compound was prepared by the procedure of Preparation 2 in 91% yield from 4-phenoxy-1-butanoic acid and lithium aluminum hydride.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:36]=[CH:35][C:11]([CH2:12][NH:13][C:14]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27]CC5C=CC=CC=5)[CH:22]=4)=[CH:19][NH:18][N:17]=3)=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)=[CH:19][NH:18][N:17]=3)=[O:15])=[CH:35][CH:36]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(CNC(=O)c3n[nH]cc3-c3cccc(OCc4ccccc4)c3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(CNC(=O)c3n[nH]cc3-c3cccc(O)c3)cc2)CC1
Yield: 40.9 %

Procedure:
A solution of 4-(3-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid 4-(4-methyl-piperazin-1-yl)-benzylamide (25 mg; 0.05 mmol) in methanol (5 ml), was treated with 10% palladium on carbon (10 mg) then hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration through Celite and the filtrate evaporated. Purification by preparative LC/MS gave 8 mg of the required product as a cream solid. (LC/MS: Rt 1.67 [M+H]+392).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>CN(C=O)C>[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:36]
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1cccc(C)c1

Procedure:
1-(3-Methylbenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 3-methylbenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=O)[N:6]([C:13]1[C:14]([CH3:33])=[C:15]([CH3:32])[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:17]=3[C:30]=1[CH3:31])[C:5]2=O>C(OCC)(=O)C>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[Cl:1])[CH2:5][N:6]([C:13]1[C:14]([CH3:33])=[C:15]([CH3:32])[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:17]=3[C:30]=1[CH3:31])[CH2:7]2
Reactant: Cc1c(C)c(N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)c(C)c2c1OC(C)(C)C2c1ccc(F)cc1
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2Cc3cc(Cl)c(Cl)cc3C2)c(C)c2c1OC(C)(C)C2c1ccc(F)cc1
Yield: 25 %

Procedure:
By using 5,6-dichloro-2-[3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione, the title compound was synthesized according to Example 2a. Yield: 25%. Melting point: 233-238° C. (Ethyl acetate)