Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([CH:15]=[CH2:16])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Br)cc(N)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1cc(N)c(OC)c(C(=O)OC)n1
Yield: 33 %

Procedure:
Methyl 4-amino-6-bromo-3-methoxypicolinate (1 g, 3.83 mmol), tributyl(vinyl)stannane (1.822 g, 5.75 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.403 g, 0.575 mmol) in DCE (12.77 ml) were stirred at 70° C. overnight. The mixture was adsorbed onto celite and purified by flash column chromatography (ISCO, SiO2 40 g, hexane/EtOAc 100:0 to 0:100 gradient) to afford methyl 4-amino-3-methoxy-6-vinylpicolinate (263 mg, 1.263 mmol, 33% yield) as a yellow oil. EIMS m/z 208; 1H NMR (400 MHz, CDCl3) δ 6.86 (s, 1H), 6.71 (dd, J=17.6, 10.9 Hz, 1H), 5.98 (dd, J=17.6, 1.0 Hz, 1H), 5.42 (dd, J=10.9, 1.0 Hz, 1H), 4.45 (s, 2H), 3.97 (s, 3H), 3.87 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.94, 152.06, 148.02, 143.34, 141.60, 136.73, 118.02, 108.63, 61.49, 52.84.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]4)=[CH:17][C:15]3=2)[CH:10]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl.CCCCCC>[CH3:5][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]4)=[CH:17][C:15]3=2)[CH:10]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cc2ccc3cc4ccccc4cc3c2[nH]1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1cc2ccc3cc4ccccc4cc3c2n1C
Yield: 96.2 %

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 1H-naphth[2,3-g]indole-2-carboxylate (H.G. Pars Pharmaceutical Laboratories, Inc.) gave a 96.2% yield of ethyl 1-methyl-1H-naphth[2,3-g]indole-2-carboxylate, mp 165°-165.5°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH:6][C:7]1[CH2:12][CH:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([S:21](=[O:24])(=[O:23])[NH2:22])[C:14]=2[CH3:25])[CH2:10][C:9](=[O:26])[C:8]=1[C:27](=O)[CH2:28][CH3:29]>>[CH2:2]([O:4][N:5]=[C:27]([C:8]1[C:9](=[O:26])[CH2:10][CH:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([S:21](=[O:23])(=[O:24])[NH2:22])[C:14]=2[CH3:25])[CH2:12][C:7]=1[OH:6])[CH2:28][CH3:29])[CH3:3]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(S(N)(=O)=O)c2C)CC1=O
Agent: Cl
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(S(N)(=O)=O)c2C)CC1=O

Procedure:
Reaction of ethoxyamine hydrochloride with 3-hydroxy-5-(2,4,6-trimethyl-3-sulfamoylphenyl)-2-propionylcyclohex-2-en-one following essentially the same procedure as that described in Example 1 part (iv) gave 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethyl-3-sulfamoylphenyl)cyclohex-2-en-1-one (12). The compound was characterized by its proton magnetic resonance spectrum which is given in Table 5, Example 37.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:34]>C(Cl)Cl>[F:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:33](=[O:34])[N:21]([C@H:10]2[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH3:22])=[CH:37][CH:38]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3.35 g (10 mmol) (3S,4R)-1-benzyl-4-(3,4-dichlorophenyl)-N-methylpyrrolidin-3-amine (example 159, h), 1.61 g (12.5 mmol) DIPEA and 1.92 g (11 mmol) 4-fluorophenyl chloroformate in 50 mL DCM at 0-5° C. was stirred at 0° C. for 1 h and evaporated to dryness. The residue was subjected to column chromatography on silica eluting with a gradient formed from heptane and t-butyl-methylether to yield after evaporation of the product containing fractions 3.07 g (65%) of the title compound as colourless viscous oil. MS m/e: 473.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:31]([Cl:34])=[CH:32][N:33]=1)[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][C:14]3[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:18]=3[C:10]=2[CH:9]=1)=[O:6].[NH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CCO>[Cl:34][C:31]1[C:4]([C:5]([NH:7][C:8]2[CH:30]=[CH:29][C:11]3[CH2:12][CH2:13][C:14]4[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)[C:18]=4[C:10]=3[CH:9]=2)=[O:6])=[CH:3][C:2]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:33][CH:32]=1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Reactant: C1CNCCN1
Solvent: CCO
Product: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(N4CCNCC4)ncc3Cl)cc1-2
Reaction time: 24 h
Yield: 53 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (1 g, 0.0020 mol) and piperazine (3.44 g, 0.040 mol) in 5 mL of EtOH. The reaction was run at 100° C. for 24 h. The off-white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH to afford 0.579 g of title compound (yield: 53%). 1H NMR (300 MHz, d6-DMSO): 2.67 (t, 4H, J=4.9 Hz), 2.85-2.90 (m, 4H), 3.36 (t, 4H, J=4.9 Hz), 6.80 (s, 1H), 7.18-7.19 (m, 1H), 7.25 (s, 1H), 7.27-7.35 (m, 3H), 7.37-7.39 (dd, 1H, J=8 Hz, 2 Hz), 7.51-7.55 (m, 3H), 8.09 (s, 1H), 10.28 (s, 1H). M=1=547
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].Cl[CH2:32][CH2:33][CH2:34][CH:35]1[O:39][CH2:38][CH2:37][O:36]1.[OH-].[Na+]>CN(C=O)C.C(O)C>[O:36]1[CH2:37][CH2:38][O:39][CH:35]1[CH2:34][CH2:33][CH2:32][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:28])=[O:2])[CH2:14][CH2:15]2)=[CH:20]1
Reactant: ClCCCC1OCCO1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCCC3OCCO3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.75 g (7 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester (prepared as in Example 1, part D) in 10 mL of anhydrous DMF was added to a suspension of 0.36 g (9.1 mmol) of a NaH (60% dispersion in mineral oil) in 5 mL of anhydrous DMF under an inert atmosphere. After stirring for 30 minutes at room temperature, a solution of 1.1 mL (8.4 mmol) of 2-(3-chloro-propyl)-[1,3]dioxolane in 3 mL of DMF was added. The crude mixture was stirred at room temperature for 16 hours and the solvent was removed under reduced pressure. The residue obtained was dissolved with 150 mL of ethanol and 6 mL of a 2N NaOH aqueous solution were added. After 12 h at room temperature, the solvent was removed under reduced pressure. The crude mixture was dissolved with 50 mL of water and neutralised with a 2N HCl aqueous solution. The crude mixture was purified by flash chromatography over silica gel affording 0.83 g (29% of yield) of the expected product.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12>CC(C)=O.Cl.O>[C:4]1(=[O:16])[N:5]([CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:1](=[O:21])[C:2]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:3]12
Reactant: COC(=O)CCC/C=C\CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CCC/C=C\CN1C(=O)c2ccccc2C1=O
Yield: 80.9 %

Procedure:
A solution of methyl (Z)-7-phthalimidohept-5-enoate (1.56 g) in acetone (30 ml), concentrated hydrochloric acid (15 ml) and water (15 ml) was refluxed for 2.5 hours. Water (180 ml) was added and the solution was cooled. The precipitate was collected by filtration to give the title compound (1.2 g). m.p. 86°-88° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CC(C)C(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, isobutyryl chloride (0.24 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 solid was purified from ether (10 mL) and hexane (10 mL) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-methylpropanamide (0.48 g, 73%) as a white solid: mp 218-220° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.39 (t, J=5.8 Hz, 1H), 7.87-7.78 (m, 2H), 7.66-7.63 (m, 1H), 5.19-5.12 (dd, J=6.9 and 12.5 Hz, 1H), 4.71 (d, J=5.8 Hz, 2H), 2.97-2.83 (m, 1H), 2.63-2.43 (m, 3H), 2.08-2.04 (m, 1H), 1.07 (d, J=6.9 Hz, 6H); 13C NMR (DMSO-d6) δ 176.52, 172.75, 169.82, 167.49, 166.95, 139.54, 134.77, 132.85, 131.50, 127.02, 121.77, 48.83, 37.48, 33.98, 30.92, 21.96, 19.53; Anal. Calcd. For C18H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C, 60.48; H, 5.33; N, 11.64.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:12]1([OH:16])[CH2:15][CH2:14][CH2:13]1.[OH-].[K+].Cl>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:16][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: OC1CCC1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
5-Bromo-6-chloronicotinic acid (CAN 29241-62-1; 3 g, 12.7 mmol) was dissolved in DMSO (30 mL); cyclobutanol (1.19 g, 1.29 ml, 16.5 mmol) and potassium hydroxide (powder) (2.14 g, 38.1 mmol) were added and the reaction mixture was stirred at room temperature for 5 h. More cyclobutanol (0.5 mL) and KOH (1 g) was added and the reaction mixture was stirred at room temperature for another 2 days. Water (30 mL) was added and the mixture was acidified (cooling) with 5 mL 37% HCl in water (pH=2). The suspension was filtered and washed with water. The cake was dried in vacuo to obtain the title compound (3.1 g, 88.7%) as white solid; MS (ESI) 270.2 (M−H)−.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][S:11]([NH2:14])(=[O:13])=[O:12].[Cl:15][C:16]1[C:17]([S:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)=[CH:18][C:19]([F:25])=[C:20]([CH:24]=1)[C:21](O)=[O:22].CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:15][C:16]1[C:17]([S:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)=[CH:18][C:19]([F:25])=[C:20]([CH:24]=1)[C:21]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])=[O:22]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
N,N-Diisopropylethylamine (0.248 mL, 1.422 mmol) and methansulfonamide (135 mg, 1.42 mmol) were added to a mixture of 5-chloro-4-(3,4-dichlorophenylthio)-2-fluorobenzoic acid (Preparation 159, 250 mg, 0.71 mmol), 4-dimethylaminopyridine (130 mg, 1.07 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (204 mg, 1.07 mmol) in DCM (4.4 mL) and the reaction stirred at room temperature for 18 hours. The reaction was concentrated to dryness and the residue taken up in EtOAc (30 mL), washed with 1N aq. HCl (2×5 mL), brine (4×5 mL), dried over MgSO4, filtered and evaporated to give a yellow solid. The solid was purified using silica gel column chromatography eluting with 19:1 DCM:heptanes to afford the title compound as a white solid (221 mg, 73%).
Reaction SMILES: [ClH:1].O[CH:3]([CH3:17])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[ClH:20].[ClH:1].[Cl:20][CH:3]([CH3:17])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CC(O)CN1CCN(c2ccccc2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)CN1CCN(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
1-(2-Hydroxypropyl)-4-phenylpiperazine hydrochloride (155 g.) was suspended in 1200 ml. dry chloroform and 87.5 ml. thionyl chloride added dropwise. The mixture was refluxed 21/2 hrs, and cooled overnight at room temperature. The solid was filtered, washed with chloroform, them with ether, and dried to give 175 g., m. 216-18° .
Reaction SMILES: [Na].Cl.[CH2:3]([CH:5]([CH2:10][CH3:11])[CH2:6][C:7]([NH2:9])=[NH:8])[CH3:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=1>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:8][C:7](=[NH:9])[CH2:6][CH:5]([CH2:10][CH3:11])[CH2:3][CH3:4])=[S:21])=[CH:15][CH:14]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CCC(CC)CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCC(CC)CC(=N)NC(=S)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 42 but using 3.8 g. sodium in 350 ml. dry acetone, 27.2 g. 3-ethylvaleramidine hydrochloride, and 27 g. 4-chlorophenyl isothiocyanate in 175 ml. dry acetone there was obtained 1-(4-chlorophenyl)-3-(3-ethylpentanimidoyl)-2-thiourea; m.p. 116°-118°C. (from acetonitrile); hydrochloride (42.7 g.).
Reaction SMILES: [Cl-].[C:2]1([NH+:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=O.C(O)C>O>[C:2]1([N:8]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:18]3[C:19]4[C:24]([CH2:16][C:17]2=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[NH+](c1ccccc1)c1ccccc1
Reactant: O=C1Cc2ccccc2C1
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: c1ccc(-n2c3c(c4ccccc42)-c2ccccc2C3)cc1
Yield: 42.7 %

Procedure:
In a 0.25 l bulb were placed 10 g (45 mmol) of N,N-diphenylhydrazinium chloride, 6.0 g (45 mmol) of 2-indanone and 50 ml of ethanol. The thus obtained mixture was heated at reflux for 4 hours and it was poured into water; the residual mixture was extracted with CH2Cl2 (150 ml) and the solvent was evaporated. The wanted compound was isolated by passing the obtained mixture through a column of silicagel, eluting with benzene/hexane=1:2. The resulting solution was evaporated and treated with 10 ml of hexane, obtaining the precipitation of crystals. Said crystals were separated, washed with hexane (10 ml) and finally dried, thus yielding 5.4 g of N-phenyl-5,6-dihydroindeno[2,1-b]indole (yield=45%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:27])[CH2:23][C:24](Cl)=[O:25])[CH3:20]>C1C=CC=CC=1>[CH2:1]([N:8]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:24](=[O:25])[CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Cl)cc1NCc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)N(Cc1ccccc1)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
52 g of N-benzyl-N-(2-nitro-5-chlorophenyl) amine and 35.5 g of (chloroformyl)acetic acid ethyl ester in 500 ml benzene are refluxed for 15 hours. The reaction is cooled, washed with dilute aqueous sodium bicarbonate, dried and the solvent evaporated to give the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][N:13](CC3C=CC=CC=3)[CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>Cl.CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[OH:16])=[CH:32][CH:33]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccccc1C(=O)CN(CCOc1ccc(-n2ccnc2)cc1)Cc1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1C(O)CNCCOc1ccc(-n2ccnc2)cc1

Procedure:
Dissolve 3.8 9 2-[[2-[4-(1H-imidazol-1-yl)phenoxy]ethyl](phenylmethyl)amino]-1-(2-methoxyphenyl)ethanone in 50 mL 5 M HCl in methanol and remove the solvents in vacuo. Dissolve the residue in 50 mL H2O with 0.85 9 10% palladium hydroxide on charcoal. Hydrogenate the solution under 52 psi hydrogen for 20 h. After this time, filter the catalyst and remove the solvents to givethe crude product. Recrystallize the solid from ethanol to give the title compound.
Reaction SMILES: C([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])(OC(C)(C)C)=O.F[C:19]1[CH:20]=[C:21]([CH3:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]>[OH-].[Na+].C(O)C.Cl.C(O)(=O)C>[NH2:8][C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:19]1[CH:20]=[C:21]([CH3:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])c(NCCCC[C@H](N)C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.7 %

Procedure:
A mixture of 2.37 g (10 mmol) of Nα -BOC-L-lysine and 1.65 g (11.0 mmol) of 3-fluoro-4-nitrotoluene in 10 mL of 1N NaOH and 10 mL of ethanol were heated at reflux for 48 hours, then cooled to room temperature. A precipitate was filtered off and discarded. Removal of the solvent/n vacuo gave an oil which was dissolved in 50 % ethanol/3M NH3 and taken to dryness. The residue was dissolved in 12 mL of 4N HCl in 33% acetic acid and stirred for four hours, then concentrated to dryness and purified by flash chromatography (eluting with 12:1:1 acetonitrile/water/HOAc). The resulting oil was recrystallized from water/methanol to afford 470 mg (42% yield) of the title product as bright orange prisms.: mp 234°-235° (dec.); MS M/Z (DCl/NH3): 282 [M+H]+ ; 1H NMR (300 MHz, D2O) δ: 1.1-1.45 (m, 6H), 2.78 (t, J=6.6 Hz, 2H), 2.99 (t, J=6.0 Hz, 1H), 5.88 (d, J=7.8 Hz, 1H), 6.07 (s, 1H), 7.32 (d, J=7.8 Hz, 1H). 13C NMR (75.5 MHz, D2O) δ: 185.73, 151.31,148.37, 131.02, 119.60, 116.09, 58.83, 45.20, 37.87, 31.19, 25.86; Analysis calc'd for C13H19N3O4 : C, 55.51;H, 6.81;N, 14.94; found: C, 55.25;H, 6.94; N, 14.75.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]23[CH:11]([CH2:12][CH2:13][CH:4]2[CH2:3]1)[C:10]1[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:9]=1[CH2:8][CH2:7]3.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:1][N:2]1[CH2:6][C:5]23[CH:11]([CH2:12][CH2:13][CH:4]2[CH2:3]1)[C:10]1[CH:14]=[CH:15][C:16]([C:31]2[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=2)=[CH:17][C:9]=1[CH2:8][CH2:7]3
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN1CC2CCC3c4ccc(OS(=O)(=O)C(F)(F)F)cc4CCC23C1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CC2CCC3c4ccc(-c5ccc(C#N)cc5)cc4CCC23C1
Temperature: 90 °C
Reaction time: 20 h
Yield: 30.9 %

Procedure:
Trifluoro-methanesulfonic acid 8-methyl-5,6,6a,7,8,9,10,11-octahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrol-2-yl ester (Example 1D) (23.0 mg, 0.061 mmol) and 4-cyanophenylboronic acid (18 mg, 0.122 mmol) were dissolved in toluene (2 mL) and ethanol (0.5 mL). 0.15 mL of 1M Na2CO3 solution was added. Nitrogen was bubbled through the reaction mixture for 10 min. Tetrakis(triphenylphosphine)palladium (7.1 mg, 0.006 mmol) was then added. The mixture was stirred at 90° C. for 20 h. The reaction mixture was quenched with water (2 mL), extracted with CH2Cl2 (5 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel twice using 10% methanol in dichloromethane and 0.5% ammonium hydroxide and 5% methanol in dichloromethane, providing 6.2 mg (30.8%) of the title compound 1E.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[CH3:17])=[O:5])[CH3:2].[NH2:19][CH:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:19][CH:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[CH3:17])=[O:5])[CH3:2]
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCOC(=O)c1cc2cc(Cl)cc(C)c2nc1Cl
Product: CCOC(=O)c1cc2cc(Cl)cc(C)c2nc1NC(Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloro-8-methyl-quinoline-3-carboxylic acid ethyl ester is reacted with DL-tryptophan to provide 2-[1-carboxy-2-(1H-indol-3-yl)-ethylamino]-6-chloro-8-methyl-quinoline-3-carboxylic acid ethyl ester. The ester (107 mg, 0.24 mmol) is dissolved in THF (2 mL), then 0.7M aqueous NaOH (1 mL) is added and the mixture is stirred at rt for 23 h. The mixture is concentrated under reduced pressure treated with water and filtered. The filtrate is acidified by addition of 3N HCl till pH 2-3, and stirred for 40 min. Precipitate is filtered off and washed with cold water to provide after drying the title compound (55 mg, 61%) as pale green powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C@@H:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[O:16][CH3:17].N1CCCCC1.[S:32]1[CH2:36][C:35](=[O:37])[NH:34][C:33]1=[O:38]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C@@H:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:36]2[S:32][C:33](=[O:38])[NH:34][C:35]2=[O:37])=[CH:20][CH:19]=1)[O:16][CH3:17]
Reactant: O=C1CSC(=O)N1
Reactant: CO[C@@H](CCc1nc(-c2ccccc2)oc1C)c1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CO[C@@H](CCc1nc(-c2ccccc2)oc1C)c1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 86.6 %

Procedure:
The title compound of Example 16 (580 mg, 1.7 mmol), piperidine (30 mg, 0.34 mmol) and 2,4thiazolidinedione (405 mg, 3.4 mmol) were combined in ethanol (20 mL) and the resulting solution was refluxed overnight. The solvent was removed in vacuo and the residue was purified on silica gel, eluting with hexane/ethyl acetate (3/1) plus 5% acetic acid, to afford the title compound as a solid (640 mg, 87%). mp 205-206° C. 1HNMR (300 MHz, DMSO-d6): δ2.0 (m, 2H), 2.3 (s, 3H), 2.4 (t, 2H), 3.1 (s, 3H), 4.2 (dd, 1H), 7.4 (m, 5H), 7.6 (d, 2H), 7.7 (s, 1H), 7.9 (m, 2H).