Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>ClCCl>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([NH:2][C:26]([CH2:27][CH2:28][CH3:29])=[O:30])[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[NH:6]2
Reactant: CCCC(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N[C@H]1C[C@H](C(=O)OC)Nc2cc(Cl)cc(Cl)c21
Yield: 84.4 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (example 9a) (0.200 g, 0.642 mmol) in anhydrous dichloromethane (15 ml) under an atmosphere of nitrogen was added dry triethylamine (0.197 ml, 1.41 mmol) and the mixture was stirred until dissolution was complete. To this solution was then added butyryl chloride (0.073 ml, 0.706 mmol) and the reaction was stirred at room temperature for 4 h. The mixture was then evaporated to dryness in vacuo and the residue was partitioned between ethyl acetate (50 ml) and 0.5M aqueous citric acid (30 ml). The organic layer was separated, washed successively with saturated sodium bicarbonate solution (1×30 ml) and brine (1×30 ml), then dried (MgSO4) and evaporated to give a solid which was triturated with diethyl ether. The solid was collected by filtration to give the pure title compound as colourless crystals (0.187 g), m.p. 205°-206° C. δ (CDCl3, 360 MHz) 0.96 (3H, t, J=7.4 Hz, COCH2CH2CH3). 1.64-1.72 (3H, m, CHACHBHCCHD and COCH2CH2CH3), 2.17 (2H, t, J=7.4 Hz, COCH2CH2CH3), 2.68 (1H, dm, J=14.0 Hz, CHACHBHCCHD), 3.81 (3H, s, CO2CH3), 3.94 (1H, dd, J= 12.6 and 2.9 Hz, CHACHBHCCHD), 4.85 (1H, br.s, ArNH), 5.26 (1H, m, CHACHBHCCHDNHCO), 5.37 (1H, br.d, J=18 7 Hz, CHDNHCO), 6.56 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.73 (1H, d, J=2.0 Hz, 6-H or 8-H). m/e (CI+) 345 (100%, (M+I)+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+]>CCO.O>[CH3:12][O:11][C:8]1[CH:7]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(OC)cc1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)O)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 95.4 %

Procedure:
5-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester (5.6 g) was placed in suspension in EtOH (80 mL) and a solution of NaOH (2.9 g) in water (40 mL) was added. The mixture was stirred under reflux for 2 hours and EtOH was evaporated under reduced pressure. The aqueous layer was then acidified with concentrated HCl and the resulting solid which formed was filtered, washed with water and dried to give the title compound (5.1 g) as white crystals. m.p.: 232-234° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:26]=4[CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c(C)c1
Yield: 56.7 %

Procedure:
As described in Example 9, 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.303 g (1.8 mmol) of 2,4-dimethylbenzoyl chloride in 10 ml of dichloromethane. The product is recrystallized from hexane-dichloromethane to give 0.38 g of crystals, m.p. 197°-199° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:8][C:7]=12.[CH2:37]([OH:40])[CH2:38][OH:39].CC(C)([O-])C.[K+]>CN(C=O)C>[OH:39][CH2:38][CH2:37][O:40][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:8][C:7]=12
Reactant: OCCO
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(OCCO)nccc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution of tert-butyl 1-(4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate (50 mg, 0.099 mmol) in DMF (1 mL) were added ethane-1,2-diol (30.8 mg, 0.497 mmol) and potassium tert-butoxide (33.5 mg, 0.298 mmol) under nitrogen. The reaction mixture was stirred at RT overnight, followed by heating at 50° C. for 4 h. The product was extracted with ethyl acetate, washed with water, dried, and purified by chromatography to give the title compound (20 mg, 38%). LCMS (Method J): RT=1.493 min, [M+H]+=529.
Reaction SMILES: CCCCCCCCC[CH2:10]/[CH:11]=[CH:12]/[CH:13]1[C:18](=[O:19])[O:17][C:15](=[O:16])[CH2:14]1.[OH-].[K+].[CH3:22][C:23]#[CH:24]>>[CH:24]([C:13]1([CH:12]=[CH:11][CH3:10])[C:18](=[O:19])[O:17][C:15](=[O:16])[C:14]1([CH:14]=[CH:13][CH3:18])[CH:10]=[CH:11][CH3:12])=[CH:23][CH3:22]
Reactant: CCCCCCCCCC/C=C/C1CC(=O)OC1=O
Reactant: C#CC
Agent: [K+]
Agent: [OH-]
Product: CC=CC1(C=CC)C(=O)OC(=O)C1(C=CC)C=CC

Procedure:
The experiments in Example 3 were repeated with tetrapropenylsuccininc anhydride (DDSA) instead of oleic acid. DDSA was supplied by Milliken Chemicals and had a neutralization number of 406 mg KOH/g. Milliken uses C12 branched-chain olefin derived from propylene tetramer to make DDSA.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:34]1C=C(N(C2C3C(=CC=CC=3)N=C(CCl)N=2)C)C=CC=1OC.C1(=O)NC(=O)C2=CC=CC=C12.[K]>CN(C=O)C>[NH2:22][CH2:21][C:13]1[N:12]=[C:11]([N:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[CH3:34])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: COc1ccc(Nc2nc(CN3C(=O)c4ccccc4C3=O)nc3ccccc23)cc1Cl
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1Cl
Agent: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1Cl

Procedure:
2-[4-(3-Chloro-4-methoxy-phenylamino)-quinazolin-2-ylmethyl]-isoindole-1,3-dione: The title compound was prepared from (3-chloro-4-methoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-methyl-amine (428 mg, 1.1 mmol) and potassium phthalimide (453 mg, 2.4 mmol) in DMF (3.7 mL) by a procedure similar to Example 203d. 1H NMR (DMSO-d6) δ 7.98-7.90 (m, 4H), 7.62-7.60 (m, 2H), 7.48 (d, 1H), 7.2-7.13 (m, 3H), 6.96-6.93 (d, 1H), 4.96 (s, 2H), 3.87 (s, 3H), 3.28 (s, 3H); LC-MS (ESI+; 459 ([M+H]+)).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12]([CH:13]=[CH:14][C:15](OC)=[O:16])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12](/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C=Cc1ccc(OCc2nc(-c3ccccc3)c(C)o2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1oc(COc2ccc(/C=C/CO)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 23, methyl 4-(5-methyl-4-phenyl-2-oxazolylmethoxy)cinnamate was subjected to reduction with diisobutylaluminum hydride to give (E)-3-[4-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2-propen-1-ol. Recrystallization from chloroform-isopropyl ether gave colorless prisms, m.p.154°-155° C.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=[O:14])=[CH:12][C:7]=2[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][CH2:4][C:3]1=[O:22].O1CCCC1.O.O.O.C([O-])(=O)C.[Na+].N>C(Cl)Cl.CO>[OH:14][NH:13][C:11]1[CH:10]=[CH:9][C:8]2[N:2]([CH3:1])[C:3](=[O:22])[CH2:4][N:5]=[C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:12]=1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(NO)ccc21

Procedure:
A mixture of 15 g. (0.05 mol) of 1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one, 250 ml. of tetrahydrofuran, 250 ml. of methanol, 56 g. of stannous chloride dihydrate and 68 g. of sodium acetate trihydrate was stirred under nitrogen for 3 hours. 1 l. of methylene chloride and 15 ml. of concentrated ammonia was added. The inorganic material was separated by filtration over celite. The filtrate was washed with 1N sodium hydroxide solution, was dried over sodium sulfate and evaporated. Crystallization of the residue from methylene chloride and recrystallization from ethanol/methylene chloride yielded light yellow product with m.p. 211°-213°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16](=[O:25])[C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: COc1ccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)cc1

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and p-anisoyl chloride (66 mg; 0.50 mmol; 2.0 eq.) as a white powder (58.2 mg, 69%). HPLC, Rt: 3.19 min. (purity 97.0%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]4[CH:23]=[N:22][N:21]([CH3:24])[C:20](=[O:25])[C:19]=4Cl)[CH2:11][CH2:10]3)=N[O:8][C:4]=2[CH:3]=1.C[OH:30].[OH-].[Na+]>[Pd].O>[F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[N:22][N:21]([CH3:24])[C:20](=[O:25])[CH:19]=3)[CH2:11][CH2:10]2)=[O:30])=[C:4]([OH:8])[CH:3]=1
Reactant: Cn1ncc(NCCN2CCC(c3noc4cc(F)ccc34)CC2)c(Cl)c1=O
Reactant: CO
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1ncc(NCCN2CCC(C(=O)c3ccc(F)cc3O)CC2)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
Into a pressure-tight hydrogenating apparatus 5.0 g (0.0123 mole) of 5-{2-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-piperidine-1-yl]-ethylamino}-4-chloro-2-methyl-2H-pyridazine-3-one, 450 ml of a solvent mixture (a 9:1 mixture of methanol and distilled water), 0.56 g (0.014 mole) of sodium hydroxide and 10 g of a palladium/charcoal catalyst (composition: 8% of palladium, 28% of carbon, 64% of water) are weighed in. The reaction mixture is stirred at room temperature under a hydrogen pressure of 10 atm. for 16 hours. The unreacted hydrogen is removed from the apparatus, the reaction mixture is heated to reflux temperature and stirred at this temperature for 5 minutes. The mixture is filtered hot and the palladium charcoal catalyst is washed three times with 33 ml of a 1:1 mixture of methanol and dichloro methane each. The united mother lyes are evaporated to 15 ml and stirred under cooling with icecold water for half an hour. The precipitated crystals are filtered off. The crude product is recrystallized from 2-propanol. Thus 3.12 g of the desired compound are obtained. Yield 67.8%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[OH:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.O.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>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:27]2[CH:28]=[C:23]([CH2:22][OH:21])[CH:24]=[CH:25][CH:26]=2)[CH:3]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: OCc1cccc(B(O)O)c1
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: O
Solvent: CC#N
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(CO)c2)n1
Reaction time: 0.42 h
Yield: 54.4 %

Procedure:
In a hard walled glass tube, a solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (250 mg, 0.75 mmol), 3-(hydroxymethyl)phenylboronic acid (137 mg, 0.9 mmol) and Na2CO3 (79.7 mg, 0.75 mmol) in acetonitrile/water (6 mL, 2:1) is degassed over nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (43.5 mg, 0.04 mmol) is added and the tube is sealed and set in a microwave for 25 minutes at 130° C. The reaction is dilute with 25 mL of water and extracted twice with ethyl acetate. The combined organic extracts are washed with brine, dried over sodium sulfate, filtered and concentrate in reduced pressure. The residue is purified by chromatography (SiO2 packed column), eluted with EtOAc/DCM to afford (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-methanol [165 mg, Example 78 (a)]. LCMS: RT=2.24 minutes, MS: 405 (M+H); 1H NMR (300 MHz, CDCl3): □8.05 (1H, s), 7.95 (1H, b)), 7.48 (3H, b), 7.42 (1H, s), 7.2 (1H, s), 6.45 (1H, s), 4.95 (1H, b), 4.78 (2H, b), 4.05 (3H, s), 3.72 (2H, b), 3.1 (2H, t, J=3.5 Hz); and to afford (3′-chloro-4′-{2-[6-(3-hydroxymethyl-phenyl)-2-methoxy-pyrimidin-4-ylamino]-ethyl}-biphenyl-3-yl)-methanol [110 mg, Example 78(b)]. LCMS: RT=2.12 minutes, MS: 477 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH3:22])O)#[N:2].[N:23]1C=CC=CC=1.O=S(Cl)Cl>C(Cl)Cl.O>[NH2:23][C:6]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][C:7]1=[O:12]
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Reactant: c1ccncc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOc1ccccc1C1(N)C(=O)Nc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
8.0 g (27.2 mMol) of intermediate 1b and 43 ml (54.4 mMol) of pyridine were dissolved in 70 ml of methylene chloride. Then, at 0° C., 3 ml (40.8 mMol) of SOCl2 were slowly added dropwise. The reaction mixture was then stirred for a further 30 minutes. The reaction solution was subsequently poured into ice-water, and the organic phase was separated off, washed with water, dried and concentrated in vacuo. This residue was added at 0° C. to a solution of 300 ml of 0.5M NH3 solution in dioxane and 150 ml of methylene chloride. The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated in vacuo, and the residue obtained in this way was suspended in water. The precipitate was separated off and recrystallized from a little methanol. 4.7 g of the product were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:4][CH:3]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>CN(C)C=O>[O:31]=[C:29]1[NH:28][C:27](=[O:32])[CH:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:21]([O:20][CH2:19][C:17]3[N:16]([CH3:35])[C:15]4[CH:36]=[C:11]([O:10][CH2:9][CH2:8][C:5]5[CH:6]=[CH:7][C:2]([NH:1][C:46]([NH:45][C:42]6[CH:41]=[CH:40][C:39]([C:38]([F:37])([F:48])[F:49])=[CH:44][CH:43]=6)=[O:47])=[CH:3][CH:4]=5)[CH:12]=[CH:13][C:14]=4[N:18]=3)=[CH:22][CH:23]=2)[S:30]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(N)cc3)cc21
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a mixture of 5-[4-[6-[2-(4-aminophenyl)ethoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g) and N,N-dimethylformamide (10 ml) was added α,α,α-trifluoro-p-tolyl isocyanate (0.17 g) and the mixture was stirred at room temperature for 2 hours and allowed to stand overnight. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. To the residue was added a mixture of ethyl acetate and diethyl ether (1:1). The precipitate was isolated by filtration and washed with diethyl ether to afford the title compound (0.4 g, mp 145-147° C.).
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>Cl.O.C1COCC1>[Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7]([NH2:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNc2cccc(Cl)c2CC1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2c(Cl)cccc2N(N)CC1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of 7-chloro-4-methyl-1,2,3,4,5,6-hexahydro-benzo[e][1,4]diazocine (4.0 g, 0.021 mole approximately) in hydrochloric acid (2 N, 100 mL) cooled to 0° C. was added sodium nitrite (2.5 g, 0.036 mole) in water (20 mL). The mixture was stirred for 1 hour and treated with sodium bicarbonate and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated sodium chloride (200 mL), dried and concentrated to a light brown oil. The oil was redissolved in THF (50 mL) and added to a suspension of lithium aluminum hydride (2.5 g, 0.063 mole) in THF (100 mL) and the mixture refluxed for 3 hours. The excess hydride was destroyed at 0° C. by the cautious addition of water. The mixture was diluted with THF (200 mL) and filtered. Evaporation of the filtrate in vacuo provided 3.5 g of the title compound as a light yellow oil. This oil was used for indole formation without further purification. MS (ES) m/z 226.5 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12].O>ClCCl>[F:9][C:10]([F:17])([F:16])[C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCCCCCO
Solvent: O
Solvent: ClCCl
Product: O=C(NCCCCCCO)C(F)(F)F
Reaction time: 8 h

Procedure:
6-aminohexanol (11.7 g; 100 mmol) is dissolved in dry dichloromethane (100 mL) and drop wise added ethyl trifluoroacetate (15 g; 105 mmol) in dry dichloromethane (50 mL) (˜30 min), and the mixture is stirred overnight. Water (10 ml) is added, and the mixture is stirred for 30 min. The solution is washed with water (2×100 mL), dried (Na2SO4), and concentrated. The residue is redissolved in acetonitrile (100 μL) and concentrated. The residue is placed on vacuum overnight, and a white crystalline solid is obtained. Yield 19 g.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]2[O:14][CH2:15][O:16][C:11]2=[C:10]([O:17][CH3:18])[CH:9]=1)(=O)=O.[I-:19].[Na+]>CC(C)=O>[CH3:18][O:17][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][I:19])[CH:13]=[C:12]2[O:14][CH2:15][O:16][C:11]=12
Reactant: [I-]
Reactant: COc1cc(CCOS(C)(=O)=O)cc2c1OCO2
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(CCI)cc2c1OCO2
Yield: 95.2 %

Procedure:
5.45 g (19.9 mmol) of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl methanesulfonate (4) and 3.58 g (23.9 mmol) of sodium iodide were added to 100 ml of acetone and refluxed under heating for 2 hours. To this reaction mixture was added again 0.89 g (5.9 mmol) of sodium iodide, and the reaction mixture was refluxed under heating for 3 hours and 20 minutes. After the refluxed mixture was cooled, the deposited salt was filtered out and washed with acetone. The filtrate and the acetone used for washing were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate: ethyl acetate n-hexane=1/2) to obtain 5.80 g of 2-(3-methoxy-4,5-methylenedioxyphenyl) ethyl iodide (7) as a crystal with a yield of 95%, which was recrystallized from n-hexane/ethyl acetate. Melting point: 78°-80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.Cl.[NH2:23][C@H:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15]([NH:23][C@@H:24]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)N[C@@H](Cc3ccccc3)C(=O)OC(C)(C)C)c2nc1OC
Reaction time: 24 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 200 mg (0.64 mmol) and L-phenylalanine, tert-butyl ester hydrochloride 173 mg (0.67 mmol). Reaction was continued for 24 hours, and the crude product was eluted through a flash column (4:1 hexanes:ethyl acetate), 180 mg (57%), mp 86-88° C.; 1H NMR (CDCl3): δ 8.32 (s, 1H), 7.22 (m, 5H), 6.39 (d, 1H, J=6.6 Hz), 4.88 (q, 1H, J=6.1, J=6.8 Hz), 4.07 (s, 3H), 4.00 (s, 3H), 3.23 (d, 2H, J=5.9 Hz), 2.56 (s, 3H), 1.37 (s, 9H); MS (APCI): m/z 497 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([O:11][CH3:12])=[CH:5][C:6]=1[O:9][CH3:10])=[O:20]
Reactant: COc1ccc(OC)c(OC)c1
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(OC)c(C(=O)CCCCCBr)cc1OC
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
6 ml (40 mmol) of 1,2,4-trimethoxybenzene are introduced into 80 ml of dry CH2Cl2 and the mixture is cooled to −10° C. with stirring. 6-Bromohexanoyl chloride (6.2 ml, 40 mmol) dissolved in 20 ml of CH2Cl2 is then added dropwise. AlCl3 (5.6 g, 42 mmol) is progressively introduced in small portions into the reaction mixture. The reaction is maintained with stirring for 8 h with a return to ambient temperature. The reaction mixture is then poured onto ice (200 ml) and acidified to pH 1 using HCl. The mixture is stirred until it returns to ambient temperature, 1 h. After evaporation of the CH2Cl2, the mixture is extracted with AcOEt, and the organic phases are separated, dried over MgSO4, filtered and evaporated. The residue is subjected to flash chromatography over SiO2 with a gradient of pure heptane to heptane-AcOEt 50-50. The pure fractions are evaporated to obtain 13.6 g (yield=99%) of crystals. TLC SiO2 (heptane-ACOEt 70-30) Rf=0.5; 1H NMR (CDCl3): 7.41 (s, 1H), 6.50 (s, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 3.43 (t, 2H, J=6.76 Hz), 2.98 (t, 2H, J=6.32 Hz), 1.91 (m, 2H), 1.71 (m, 2H), 1.51 (m, 2H).