Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].Cl.[CH3:10][O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C.Cl>ClCCl>[CH3:10][O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][NH:16][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4]
Reactant: COC(=O)CCCN
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCNS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
Trifluoromethanesulfonyl chloride (0.23 mL, 2.16 mmol) was added dropwise to a solution of 4-amino-butyric acid methyl ester hydrochloride (0.30 g, 1.96 mmol) and triethylamine (0.68 mL, 4.90 mmol) in dichloromethane and stirred at room temperature for 18 hours. 1N HCl was added and the product was extracted with dichloromethane, dried with magnesium sulfate and evaporated to give the title compound (0.42 g, 85%). 1H-NMR (CDCl3): δ 4.89 (s, 1H), 3.12 (t, 2H, J=7.2 Hz), 2.94 (s, 3H), 2.41 (t, 2H, J=7.2 Hz), 1.84 (m, 2H, J=7.2 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12]([O:14]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:3]1.Cl.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38][C:39](=[NH:44])[O:40]C(C)C)=[CH:30]1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38]2[C:39](=[O:40])[NH:44][C:12](=[O:14])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:30]1
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Reactant: Cn1cc(C(=O)C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 1 h
Yield: 44.7 %

Procedure:
A solution of 369 mg (1 mmol) of pentafluorophenyl 1-methylindole-3-glyoxylate in 20 ml of dichloromethane was added to a stirred solution of 266 mg (1 mmol) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride and 404 mg (4 mmol) of triethylamine in 25 ml of dichloromethane. The solution obtained was heated to reflux under nitrogen for 18 hours, cooled and treated with 950 mg (5 mmol) of p-toluenesulfonic acid. After 1 hour, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (8:1) for the elution to give 159mg (45%) of 3,4-bis-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione in the form of an orange colored solid of melting point >310° C.
Reaction SMILES: CN(C)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=O)[CH2:10]2)=CC=1.C1(C(=O)C)CCCCC=1.C([O-])(=O)C.[NH4+:31]>>[NH2:31][C:11]1[CH2:10][CH:9]2[CH:14]([CH2:3][CH2:8][CH2:7][CH2:6]2)[C:13](=[O:15])[CH:12]=1
Reactant: [NH4+]
Reactant: CN(C)c1ccc(C2CC(=O)CC(=O)C2)cc1
Agent: CC(=O)C1=CCCCC1
Agent: CC(=O)[O-]
Product: NC1=CC(=O)C2CCCCC2C1

Procedure:
In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) hexahydro-naphthalene-1,3-dione (prepared from 1-cyclohex-1-enyl-ethanone according to (Chuang; Tien. Chem. Ber. 1936; 69; 25-29) was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:20]=[CH:19][NH:18][C:13]=3[C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CS(O)(=O)=O>O1CCOCC1.CO>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:20]=[CH:19][NH:18][C:13]=3[C:14]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:22]([Cl:21])[CH:23]=3)=[N:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(NCC1CCOCC1)c1cnc(Cl)c2[nH]ccc12
Reactant: Nc1cccc(Cl)c1
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCC1CCOCC1)c1cnc(Nc2cccc(Cl)c2)c2[nH]ccc12
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (20 mg), 3-chloroaniline (15 ul), and methanesulfonic acid (9 ul) in 1,4-dioxane (0.5 ml) was heated under microwave conditions at 180° C. for 30 minutes. The solid mass obtained was dissolved in methanol, transferred to a round bottom flask and evaporated. The residue was partitioned between ethyl acetate and 5% sodium hydrogen carbonate solution whereby the title compound remained as a solid at the interface. The solid was filtered off, and washed with 5% sodium hydrogen carbonate solution, water and diethyl ether, then sucked dry and dried at 60° C. under vacuum to afford the title compound (17 mg).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[Br:19]N1C(=O)CCC1=O.O>ClCCl.C(#N)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][C:8]=2[C:9]=1[Br:19])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1Br
Reaction time: 3 h
Yield: 70.6 %

Procedure:
5.34 g (0.02 mol) of N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide (II) is dissolved in 60 mL of dichloromethane and 5.34 g (0.03 mol, 1.5 eq) of N-bromosuccinimide in 60 mL of acetonitrile is added dropwise at −8±2° C. in 30 min. The reaction mixture is stirred for 3 hours at this temperature and then is poured into 150 mL of water. The product is extracted with 2×60 mL of dichloromethane. The organic layer is evaporated and the residue is purified by column chromatography (spheric silica; eluent: toluene:methanol=7:3) to give 4.89 g (71%) of the title compound (IIIb) as an orange solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]([F:21])([F:20])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:9]([F:8])([F:20])[F:21])=[CH:12][CH:13]=2)[C:18]1=[S:19])[CH3:2]
Reactant: FC(F)(F)Oc1ccc(N=C=S)cc1
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=S
Yield: 30.4 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 10.9 g of 4-trifluoromethoxyphenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Title compound (4.6 g) was obtained as a creamy solid, m.p. 116°-119° C. Anal. Calcd. for. C12H11F3N2O2S: C, 47.37; H, 3.64; N, 9.21. Found: C, 47.20; H, 3.50; N, 9.13. Mass spectrum (EI, M.+) m/z 304.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[NH:5][N:4]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[C:40](I)[CH:39]=3)=[CH:32][C:31]=2[C:46]([F:49])([F:48])[F:47])[CH2:25][CH2:24]1)[CH3:22]>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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]>[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:8]4[CH:7]=[C:6]5[C:11]([C:3]([NH:2][CH3:1])=[N:4][NH:5]5)=[CH:10][CH:9]=4)[CH:39]=3)=[CH:32][C:31]=2[C:46]([F:49])([F:47])[F:48])[CH2:25][CH2:24]1)[CH3:22]
Reactant: CNc1n[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: CCN1CCN(Cc2ccc(NC(=O)c3cccc(I)c3)cc2C(F)(F)F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCN1CCN(Cc2ccc(NC(=O)c3cccc(-c4ccc5c(NC)n[nH]c5c4)c3)cc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 18.3 %

Procedure:
To a solution of N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (14 mg, 0.05 mmol) in dioxane (1.25 mL) and 1N sodium carbonate solution (0.25 mL) were added N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodobenzamide (26 mg, 0.05 mmol) and Pd(dppf)Cl2 (4 mg, 5 μmol). After the reaction was stirred at 100° C. for 4 hours and cooled to room temperature, the mixture was filtered through Celite and washed by ethyl acetate. The combined organic solution was washed by brine, dried with sodium sulfate and concentrated in vacuo. The crude residue was purified by HPLC to afford the title product (4.9 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][Si:11]([CH3:27])([CH3:26])[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15]2.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH3:10][Si:11]([CH3:26])([CH3:27])[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15]2
Reactant: CCOC(=O)c1cc2cc([Si](C)(C)C)ccc2[nH]1
Reactant: Fc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc([Si](C)(C)C)ccc2n1Cc1cccc(F)c1
Yield: 88.4 %

Procedure:
0.32 g (1.68 mmol) of 3-fluorobenzyl bromide and 100 mg (0.31 mmol) of tetrabutyl-ammonium bromide are added, slowly at ambient temperature, to a suspension of 0.4 g (1.53 mmol) of ethyl 5-trimethylsilyl-1H-indole-2-carboxylate, obtained according to the protocol described in stage 3.4, and of 0.64 g (4.59 mmol) of potassium carbonate in 15 ml of dry acetonitrile, maintained under an inert atmosphere. The reaction mixture is stirred at reflux for 2 h. After this period of time, the cooled suspension is filtered through a frit and rinsed with acetonitrile. The reaction crude obtained after evaporation of the filtrate under reduced pressure is purified by flash chromatography on a silica gel column, elution being carried out with a gradient of 5 to 15% of ether in heptane. 0.5 g of the expected ethyl 5-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate is thus isolated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:25]3[C:20](=[C:21]([O:26]CC4C=CC=CC=4)[CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:18]2)[CH:5]=[C:6]([F:16])[C:7]=1[O:8]CC1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:26])[C:20]=3[CH:19]=[N:18]2)[CH:5]=[C:6]([F:16])[C:7]=1[OH:8]
Reactant: Fc1cc(-n2ncc3c(OCc4ccccc4)cccc32)cc(F)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1c(F)cc(-n2ncc3c(O)cccc32)cc1F
Yield: 82.8 %

Procedure:
A solution of 1-{3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indazole (D35) (257 mg, 0.58 mmol) in ethanol (10 mL) and ethyl acetate (10 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated and then the crude product purified by silica gel chromatography eluting with 5-100% ethyl acetate in hexane to yield the title compound (E19) (126 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=2)=[CH:23][C:24]#[N:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>C1COCC1>[C:1]1([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:22]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=3)=[CH:23][C:24]#[N:25])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])=[O:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: CCOc1cc(C(=CC#N)c2ccc(OC)c(N)c2)ccc1OC
Solvent: C1CCOC1
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(NC(=O)NS(=O)(=O)c3ccccc3)c2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
Benzenesulfonyl isocyanate (0.4 mL, 2.6 mmol) was added to a stirred solution of (E/Z) 3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.70 g, 2.2 mmol) in anhydrous THF (25 mL). The reaction mixture was stirred at room temperature for 2 h. Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 1-benzenesulfonyl-3-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-urea as a solid (0.66 g, 61% yield): mp, 168-170° C.; 1H NMR (CDCl3) δ 1.38-1.46 (m, 6H, 2CH3), 3.87-4.14 (m, 16H, 4OCH3+2CH2), 5.55-5.58 (2s, 2H, 2CH), 6.78-7.98 (m, 22H, Ar), 8.03-9.06 (m, 4H, 4NH); 13C NMR (CDCl3) δ 14.67, 55.92, 55.97, 56.06, 56.24, 64.53, 92.07, 92.54, 109.82, 109.88, 110.99, 111.07, 112.65, 114.13, 118.58, 118.78, 119.77, 121.04, 122.25, 123.07, 125.52, 125.98, 126.56, 126.80, 127.02, 127.11, 129.35, 129.45, 129.50, 129.87, 131.16, 132.15, 133.96, 134.05, 139.46, 147.88, 148.19, 149.75, 150.25, 150.85, 151.59, 162.14, 162.83; Anal. Calcd for C26H25N3O6S+0.12H2O: C, 61.27; H, 4.99; N, 8.24; S, 6.29. Found: C, 60.90; H, 5.04; N, 8.05; S, 6.28.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]Br>C(Cl)(Cl)Cl>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH2:17][Br:19])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(NC(=O)c2ccccc2)cc1

Procedure:
A warm solution of 4'-benzamidoacetophenone (1.031 g) in chloroform (100 ml) was treated with bromine (0.22 ml). After dilution with more chloroform (50 ml), the resulting solution was washed with 2N-sodium hydroxide solution (2×25 ml) and water (50 ml), dried (MgSO4) and evaporated to a white solid (1.315 g). This was crystallised from ethanol to give the title acetophenone (922 mg); m.p. 171°-174°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)=[C:20]([C:40]([F:43])([F:42])[F:41])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:45]>C(O)C>[ClH:45].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:32][CH:33]=2)=[C:20]([C:40]([F:41])([F:42])[F:43])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(-c4ccccc4)cc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc(-c3ccccc3)cc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 77-4 (870 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (530 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[CH:4][CH:3]=1.[Cl-].ClC=[N+:19](C)C.[OH-].[NH4+]>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([NH2:19])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1csc(-c2ccc(O)cc2)n1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1csc(-c2ccc(O)cc2)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
2-(4-Hydroxyphenyl)-1,3-thiazole-4-carboxylic acid (0.835 g, 3.77 mmol) was dissolved in 20 ml of dry tetrahydrofuran and cooled to 0° C. (Chloromethylene)dimethylammonium chloride (0.58 g, 4.53 mmol) was added in one portion. The mixture was stirred at 0° C. for 5 h. 28% Ammonium hydroxide aqueous solution (5 ml) was added, and the reaction mixture was stirred for 15 h at the room temperature. The organic solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated sodium carbonate solution. The organic layer was separated and the aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to give the title compound as beige solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH:37]2[CH2:42][CH2:41][N:40]([CH2:28][C:16]3[C:15]4[C:20](=[CH:21][CH:22]=[C:13]([C:8]5[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=5[CH3:12])[C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:30])[CH:14]=4)[C:19](=[O:23])[N:18]([CH2:24][CH:25]4[CH2:27][CH2:26]4)[CH:17]=3)[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCC(N4CCCCC4)CC3)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and 1,4′-bipiperidine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9](=[O:18])[N:8]1[CH3:19].[OH-].[Na+].CN([CH:25]=[O:26])C>O>[CH3:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH:25]=[O:26])[C:9](=[O:18])[N:8]1[CH3:19]
Reactant: CN(C)C=O
Reactant: Cn1c(-c2ccccc2)cc(=O)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(-c2ccccc2)c(C=O)c(=O)n1C
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
N,N-Dimethylformamide (3.4 mL, 43.6 mmol) was added to a flask under nitrogen atmosphere. After cooling to 0° C., phosphorus oxychloride (1.4 mL, 15.2 mmol) was added. The resulting reaction mixture was stirred at room temperature for 50 minutes. The resulting reaction mixture was transferred to a reaction flask containing a solution of 1,2-dimethyl-5-phenyl-1H-pyrazol-3(2H)-one (820 mg, 4.36 mmol) in DMF (4.9 mL). The reaction flask was immersed in a preheated oil bath (120° C.) and, after stirring for 12 minutes, cooled to room temperature. 5 N NaOH (15 mL) was added to the cooled reaction mixture. After diluting with icy water, the mixture was extracted with chloroform. The organic layer was dried with sodium sulfate and then filtered. The filtrate was concentrated. After diluting DMF remaining in the resulting residue again with chloroform and then washing with water, the aqueous layer was extracted again with chloroform. The organic layer was collected, dried with sodium sulfate, and then filtered. The filtrate was concentrated. The concentrated residue was subjected to the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][N:16](CC3C=CC(OC)=CC=3OC)[C:15](=[O:30])[C:14]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][NH:16][C:15](=[O:30])[C:14]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CN2Cc3c(-c4nc(C5CC5)no4)ncn3-c3ccc(C)cc3C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(=O)NCc1c(-c3nc(C4CC4)no3)ncn1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxy-benzyl)-8-methyl-4,5-dihydro-2,5,10b-triaza-benzo[e]azulene-6-one (17.5 g, 37.1 mmol) was suspended in CH2Cl2 (100 mL), cooled in ice, and diluted slowly with trifluoroacetic acid (85.2 mL). The resulting solution was treated at 5° C. with trifluoromethanesulfonic acid (4.9 mL, 55.7 mmol). The red solution was stirred at room temperature for 4 h. The mixture was then evaporated and dissolved in CH2Cl2 (100 mL), washed with sodium hydrogen carbonate (10%, 2×50 mL) and the organic layer was dried (Na2SO4) and evaporated. Digestion in EtOAc (100 mL) followed by the slow addition of hexane (100 mL). The solid obtained was washed twice with EtOAc: Hexane (1:1, 2×20 mL). Yield: 9.3 g (78%) m/z 321 (M).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:39]=[CH:38][C:27]([C:28]([O:30]CC4C=CC=CC=4)=[O:29])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7].[H][H]>CO.[Pd]>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:38][CH:39]=3)[CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc(C(=O)OCc4ccccc4)cc3)CC2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc(C(=O)O)cc3)CC2)C1
Yield: 97.4 %

Procedure:
In a round-bottom flask, a solution of benzyl 4-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidin-1-yl)benzoate (120 mg, 0.20 mmol) in methanol (400 μL) and Palladium (10%) on Carbon (50 mg) was purged with hydrogen gas for two minutes; the reaction was then subjected to 1 atmosphere of hydrogen gas for two hours. The flask was purged with argon, then the mixture was filtered and concentrated to afford 4-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidin-1-yl)benzoic acid (101 mg, 96%) as an off-white solid. 1H-NMR (CD3OD) δ: 1.60-1.98 (m, 4H), 1.90-2.40 (m, 4H), 2.85-3.05 (m, 3H), 3.38-4.10 (m, 8H), 4.40-5.58 (m, 1H), 7.01 (d, J=9.0 Hz, 2H), 7.70 (t, J=8.1 Hz, 2H), 7.84-7.90 (m, 1H), 7.89 (d, J=8.7 Hz, 2H), 8.15 (d, J=7.8 Hz, 1H), 8.22 (s, 1H). MS m/z: 519 (M+1).
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:23][C:24]2[CH:29]=[C:28](OC)[C:27](OC)=[C:26]([O:34][CH3:35])[CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16](C)[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C2C(=CC=C([Cl:54])C=2)N(CC)C1=O)(=O)C1C=CC=CC=1.COC1C=C(C=CC=1)CCl>>[C:1]([O:9][C:10]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:34][CH3:35])[CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:54])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Agent: COc1cccc(CCl)c1
Product: CCN1C(=O)C(Cc2cccc(OC)c2)(OC(=O)c2ccccc2)c2cc(Cl)ccc21

Procedure:
This compound was made in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 5-chloro-1-ethyl-2-oxoindolin-3-yl benzoate and 3-methoxy benzyl chloride (purchased from Fisher Scientific). 1H NMR δ 8.06 (d, 2H), 7.61 (t, 1H), 7.46 (t, 2H), 7.25 (dd, 1H), 7.09 (t, 1H), 7.02 (d, 1H), 6.76 (dd, 1H), 6.64 (m, 2H), 6.52 (s, 1H), 3.72 (m, 4H), 3.57 (m, 2H), 3.27 (d, 1H), 1.04 (t, 3H). Calculated mass for C25H22NClO4, 435.12. Observed 458.1 (M+Na).