Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[OH-].[Na+].Cl>O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a clean flask, 34.73 g (R)-methyl 3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyrate, 100 ml toluene, 160 ml water and 4.8 g sodium hydroxide were added. The mixture was warmed to 60° C. and kept at this temperature for 3 hours. 4.73 g hydrochloric acid was added dropwisely. After completion, the resulting mixture was kept at 20-30° C. for 2 hours and filtrated to obtain 30.66 g (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)n-butyric acid (yield: 92%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](O)=[O:21])=[N:18][CH:19]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:20](=[O:21])[C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][N:18]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H), 5-chloropicolinic acid (160 mg, 1.04 mmol) and BOP-Cl (332 mg, 1.30 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (2 N, 3 mL) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-chloropicolinamide (240 mg, 73% yield) as a solid.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[NH:37]1[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]1>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:37]3[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: O[C@@H]1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC[C@@H](O)C3)ccc2n1CC1CCC(F)(F)CC1

Procedure:
Following the same procedure in Example 1, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (50 mg, 0.12 mmol), N,N-diisopropylethylamine (0.1 mL, 0.48 mmol) and (R)-(−)-3-pyrrolidinol hydrochloride (23 mg, 0.19 mmol) in (1 mL) methylene chloride. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 42 mg (61% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.43-1.52 (m, 2 H), 1.56 (s, 9 H), 1.60-1.69 (m, 3 H), 1.90-2.01 (m, 3 H), 2.09-2.21 (m, 1 H), 3.05-3.11 (m, 1 H), 3.20-3.25 (m, 2 H), 3.26-3.34 (m, 3 H), 4.13-4.18 (m, 1 H), 4.44 (d, J=7.62 Hz, 2 H), 7.81 (dd, J=8.79, 1.76 Hz, 1 H), 7.89-7.93 (m, 1 H), 8.04 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=455.2; Anal. Calc. for C22H31F2N3O3S+1.3 TFA+0.50H2O+0.2 CH3CN: C, 48.75; H, 5.46; N, 7.16. Found: C, 48.78; H, 5.48; N, 7.11.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH3:30])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O>O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][C@H:24]([O:29][CH3:30])[C@H:25]([O:27][CH3:28])[CH2:26]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CO[C@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1OC
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC
Reaction time: 8 h
Yield: 89.4 %

Procedure:
708 mg of N-iodosuccinimide was added little by little to a mixture of 783 mg of 2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)pyridine and 7.0 ml of N,N-dimethylformamide under ice-cooling, followed by stirring overnight as it was. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with sodium thiosulfate, water and brine, and the solvent was removed. Then, the residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (5:1) and then with hexane/ethyl acetate (3:1), to give 995 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])=[CH:4][CH:3]=1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Si:27]([O:26][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][O:16][C:15]1=[O:25])=[O:13])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: O=C(CCCC(O)c1ccc(F)cc1)N1C(=O)OCC1c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
27 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one, 13.6 g of tert-butyldimethylsilyl chloride and 10.2 g of imidazole were dissolved in 36 ml of dimethylformamide and stirred at 60° C. for 90 min. After the reaction ended, the mixture was dissolved in ethyl acetate and extracted two times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. This produced 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one (1) of molecular weight 471.65 (C26H34FNO4Si); MS (ESI): 340.28 (MH+-HOSi(CH3)2C(CH3)3).
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:11](O)(C)([CH3:13])[CH3:12].N1C2C(=CC=CC=2)C=C1>O.CCCCCCC>[CH:12](=[N:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:11][CH3:13]
Reactant: Nn1ccc2ccccc21
Reactant: CC(C)(C)O
Agent: c1ccc2[nH]ccc2c1
Solvent: CCCCCCC
Solvent: O
Product: CCC=Nn1ccc2ccccc21

Procedure:
To the 1H-indol-1-amine solution prepared in accordance with the procedures set forth in Example 6 in a 150-gal steel reactor, under nitrogen purge, slight exhaust, agitation ca. 150 rpm, at 10–25° C. (preferably 10–18° C.) and with slow jacket cooling, charge approximately 21.6 kg acetic acid to pH 3.9–4.0 (0.1 mL of the reaction mixture in 5 mL water) at a rate of ca. 1 kg/min. Charge incrementally more HOAc if needed to attain the pH level. Rinse pump with ca. 2 L NMP. Charge 10.8 L water (a slight temperature rise of about 3–6° C. is expected), essentially in one portion (ca. 1 min addition time). Charge 14.4 kg (13.9 kg corrected for 97% purity) propionaldehyde at ca. 0.8 kg/min (0.5–1.0 kg/min) while maintaining 10–24° C., preferably 10–20° C. A mild exotherm is expected. Depending on the rate of addition and cooling, expect about a 5° C. temperature rise. Rinse pump with ca. 3 L NMP. Agitate at 10–24° C., preferably 17–20° C., until the reaction is judged complete as evidenced by the HPLC assay, conditions of which are detailed further below (>99% conversion in 2–3 h). Monitor the progress of the reaction by withdrawing samples of the reaction mixture for HPLC assays. When the reaction is judged complete, prepare for a vacuum distillation directly from the reactor to a suitable receiver. Expect a forerun (ca. 45–50 L) of volatiles including tert-butanol and water initially at 50–70° C. and ca. 30–40 mm pressure. As the distillation rate slows, gradually increase the pot temperature to 95–100° C. and reduce the pressure to 5–25 mm and begin collecting NMP. Collect a total of about 320 kg distillates (to give a pot weight of 9.5 parts w/w with respect to the initial indole charge), then release the vacuum with nitrogen and cool to 10–25° C. If necessary, or for convenience of scheduling, the distillation can be interrupted at any time, by releasing the vacuum with nitrogen, cooling to <30° C., storing under nitrogen, and then restarting as required. Work up the reaction by charging 133 L heptane followed by, with chilled water cooling to keep exotherm temperature below 30° C., 234 L water through a reactor charging nozzle (maximum process volume of ca. 450 L is attained). Agitate for >10 min, then separate the phases. Extract the bottom aqueous phase with 54 L heptane. Combine the organic extracts, and wash with aqueous potassium bicarbonate solution (prepared from 0.6 kg potassium bicarbonate dissolved in 58 L (58–95 L) water) followed by a 58 L water wash. Concentrate the organic phase to obtain crude N-propylidene-1H-indol-1-amine as an oil. Purify by short path distillation, first pass to remove volatiles at ca. 120° C. evaporator and ca. 200–800 mbar pressure, and then a second pass at 110° C. evaporator and 0.2–0.4 mbar pressure to collect purified product.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6].[CH2:23]([N:25]([CH2:36][CH3:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:24].CN(C)C=O>C(OCC)(=O)C>[CH2:36]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][NH:4][C:5]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][C:9]3[CH:19]=[CH:20][CH:21]=[N:22][C:8]2=3)=[O:6])[CH2:34][CH2:35]1)[CH3:37]
Reactant: O=C1Nc2cccnc2N(C(=O)NCCBr)c2ccccc21
Reactant: CCN(CC)CCCCC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCCCC1CCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 60 %

Procedure:
Prepared analogously to Example 109 from 11-[[[2-bromo-ethyl]amino]carbonyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[4-(diethylamino)butyl]-piperidine, but using dimethylformamide instead of acetonitrile, in a yield of 60% of theory. Colourless crystals, m.p. 167° C. (ethyl acetate).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[CH3:42][O:41][C:39](=[O:40])[NH:30][C:27]1[CH:28]=[N:29][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][N:10]=3)[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-ylamine (80 mg, 0.202 mmol), CH2Cl2 (0.5 mL), triethylamine (37 μL, 0.227 mmol), and methyl chloroformate (17 μL, 0.222 mmol) are combined and stirred at room temperature. Reaction complete in less than 15 minutes. Concentrate reaction mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (39 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][C:15]([C:26]#[N:27])=[N:14]1.ClCCl.[F:31][CH:32]([F:35])[S:33]Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[C:16]([S:33][CH:32]([F:35])[F:31])[C:15]([C:26]#[N:27])=[N:14]1
Reactant: FC(F)SCl
Reactant: N#Cc1cc(NCc2ccccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2ccccn2)c1SC(F)F
Temperature: 25 °C
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, 500 mg (1.21 mmol) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyridin-2-ylmethylamino)pyrazole-3-carbonitrile was suspended into 5.0 mL of dried dichloromethane, and 2.0 mL of dried dichloromethane containing 180 mg (1.52 mmol, 1.25 eq.) of difluoromethylsulfenyl chloride was added dropwise thereto under stirring at room temperature, followed by reaction for 2 hours. Ethyl acetate (100 mL) was added thereto, and the organic layer was washed successively with 20 mL of a saturated aqueous sodium hydrogen carbonate solution and 20 mL of water, followed by drying over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the solvent was removed by distillation under reduced pressure and the crude product was recrystallized from a mixed solvent of hexane/ethyl acetate (3/1) to thereby obtain 535 mg of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-difluoromethylthio-5-(pyridin-2-ylmethylamino)pyrazole-3-carbonitrile (yield: 90%, purity: 96%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][CH:14]([C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:22][CH:23]=1)[C:15]([O:17][CH3:18])=[O:16])([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:23]1[S:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:20][C:19]=1[CH:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(OC(C)(C)C)c1csc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1nc(-c2ccccc2)sc1Br
Temperature: 70 °C
Yield: 78 %

Procedure:
Under a nitrogen atmosphere, N-bromosuccinimide (108 mg, 0.6 mmol) was added to a solution of methyl 2-(tert-butoxy)-2-(2-phenyl-1,3-thiazol-4-yl)acetate (6b) (30 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was warmed at 70° C. for 3 hours and ethyl acetate (20 mL) was then added. The organic layer was washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired product (6c) as a yellow oil (30 mg, 0.078 mmol, 78%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15](Cl)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C([NH:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][N:44](C(=O)C(F)(F)F)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)=O>C(#N)C>[C:7]1([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:39][CH:40]=2)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(N2CCN(C(=O)C(F)(F)F)CC2)cc1)C(F)(F)F
Reactant: O=C(Cl)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)Nc1ccc(N2CCNCC2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
To an ice cooled and stirred solution of 4-(4-aminophenyl)piperazine (4.29 g, 24.2 mmol) in dichloromethane (100 mL) containing Et3N (7.42 mL, 52.5 mmol) was added trifluoroacetic anhydride (7.52 mL, 53.2 mmol) in dichloromethane (25 mL) over a 5 minute period. The mixture was allowed to warm to room temperature and stirred two days, then stirred with ice water. The pink solid that separated was isolated by filtration, washed with dichloromethane, aqueous sodium bicarbonate, and water, and dried to obtain 1-(4-(trifluoroacetamido)phenyl)-4-trifluoroacetylpiperazine (4.09 g, 46% , mp 193°-194° C.). To a mixture of this material (0.37 g, 1 mmol ) and anhydrous potassium carbonate (1.1 g, 8.0 mmol) in acetonitrile (50 mL) was added 3,3,3-triphenylpropionyl chloride (0.54 g) and the mixture stirred at 80° C. for two days. With tlc monitoring, four additional lots of the acid chloride (4×0.54 g) and potassium carbonate (4×1.1 g) were added at 3 hr intervals, with continued reflux until complete disappearance of the starting piperazine by tlc. The solvent was removed in vacuo, the residue triturated with methanol, the solids removed by filtration and the filtrate evaporated to dryness in vacuo. The residue was stirred with 20% KOH in methanol (15 mL) for 3 hr and then evaporated to dryness in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer extracted with 2N HCl. The acid extract was basified with 2N NaOH to pH 9.5 and extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate and evaporated to dryness to give the title compound as a tan solid (0.40 g, 87%), mp 193°-195° C. 1H NMR (CDCl3) δ 7.33 (m,15H), 6.89 (d, J=8.9, 2H) 6.73 (d, J=8.9, 2H), 6.26 (s, 1H), 3.70 (s, 2H), 3.00 (d, J=10.0, 8H). IR 3056, 1665, 1598, 1515, 1447, 1239, 700 cm-1. MS 462 (MH+). Anal. calcd. for: C31H31N3O·0.5 H2O: C, 79.12; H, 6.85; N, 8.93. Found: C, 78.84; H, 6.66; N, 8.64.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][S:10][C:9]2=[CH:13][N+:14]([O-:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C([OH:21])C.Cl>O>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][S:10][C:13](=[N:14][OH:16])[C:9]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=[N+]([O-])C=C1SCCN1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1C(=NO)SCCN1Cc1ccccc1

Procedure:
2.36 g (0.01 mol) of 3-phenylmethyl-2-nitromethylenethiazolidine are boiled under reflux in the mixture of 50 ml of 1N sodium hydroxide solution and 25 ml of ethanol until the dissolution of the starting substance (when, based on the TLC examination, no starting substance is detected in a sample taken from the reaction mixture). Then, the mixture is cooled, acidified by adding hydrochloric acid diluted to 1:1 with water (to a pH value of 1), the precipitated product is filtered off, washed with water and dried to give the title compound in a yield of 2,15 g (91%), m.p.: 225°-227° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>>[C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([Cl:23])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCc1cccc(C(=O)c2ccccc2)c1
Product: O=C(Cl)CCc1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 10 g of 3-(m-benzoyl-phenyl)-propionic acid and 50 ml of oxalyl chloride was stirred for 4 hours at room temperature and the excess oxalyl chloride was removed under reduced pressure. The resulting oil was taken up twice in 50 ml of benzene and evaporated to dryness under reduced pressure to obtain 10.7 g of 3-(m-benzoyl-phenyl)-propionyl chloride identical to Example I.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[CH:7]=[C:6]2[NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH:25]=O.N>>[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:25][N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[CH:4]=3)[O:9][C:8](=[O:13])[CH:7]=2)[CH2:16][CH2:17]1
Reactant: Cc1ccc(C=O)cc1C
Reactant: CCc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Agent: N
Product: CCc1ccc2oc(=O)cc(NC3CCN(Cc4ccc(C)c(C)c4)CC3)c2c1

Procedure:
Prepared from 6-Ethyl-4-(piperidin-4-ylamino)-chromen-2-one and 3,4-dimethylbenzaldehyde in a manner analogous to that described above. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.21 (m, 3H) 1.77 (m, 2H) 2.16 (m, 2H) 2.27 (m, 6H) 2.66 (m, 2H) 3.07 (m, 2H) 3.45 (m, 2H) 3.73 (m, 1H) 4.23 (m, 2H) 5.36 (m, 1H) 7.25 (m, 5H) 7.44 (m, 1H) 7.95 (m, 1H); MS (DCI/NH3) m/z 391 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:18].C1COCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: N
Reactant: O=C(O)c1c(Cl)cccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)c1c(Cl)cccc1I

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 2-chloro-6-iodobenzoic acid (2.7 g, 9.6 mmol), oxalyl chloride (1.4 g, 11.5 mmol), ammonia gas, THF (20 mL) and DCM (10 mL) to afford 2.3 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.11 (t, J=7.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 8.00 (s, 1H); MS (m/z): 281.98 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:14])[CH3:2].[Se](=O)=[O:16]>>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:16])[C:9]2=[O:14])[CH3:2]
Reactant: CCOc1cccc2c1CCCC2=O
Reactant: O=[Se]=O
Product: CCOc1cccc2c1C=CC(=O)C2=O

Procedure:
Treatment of 5-ethoxy-1-tetralone with selenium dioxide as described in Reference Example 1A yielded 5-ethoxy-[1,2]naphthoquinone which was coupled with 2,3-diamino-benzoic acid, diacetate salt, as described to yield the title compound.
Reaction SMILES: [CH2:1](Br)[CH3:2].[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH2:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)[CH3:2]
Reactant: CCBr
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNc1ccc(C)c(O)c1

Procedure:
88.6 gm of ethyl bromide were added to a solution of 50 gm of 5-amino-2-methylphenol in 250 ml of ethanol; and the mixture was refluxed for four hours. After the solution had cooled, it was diluted with 1.2 liters of water and was made weakly alkaline with sodium carbonate. After repeated extraction with ether, the ether extracts were dried and concentrated. The residue was recrystallized from ethanol, and had a melting point of 128° C. to 129° C.