Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCCCCCCCCCCCCCC(N[C@H:21]([C@H:91](O)/[CH:92]=[CH:93]/[CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH3:106])[CH2:22][O:23][C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@@]3(C(O)=O)O[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)[C@H]2O)[C@H](O)[C@H]1O)=O.[OH2:108]>>[C:22]([OH:23])(=[O:108])[CH2:21][CH2:91][CH2:92][C:93]#[C:94][C:95]#[C:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:22][CH2:21][CH2:91][CH3:92]
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC
Reactant: O
Product: CCCCCCCCCCCCCCC#CC#CCCCC(=O)O

Procedure:
Ganglioside GM1, cholera toxin from Vibrio Cholerae, human serum albumin, and wheat germ agglutinin were purchased from Sigma. 5,7-docosadiynoic acid was synthesized. Deionized water was obtained by passing distilled water through a Millipore μF ultrapurification train. Solvents used were reagent grade. The ganglioside GM1 was mixed at 5 mol % with the diacetylene “matrix lipid” monomers. Liposomes were prepared using the probe sonication method and polymerized by UV irradiation (254 nm). The conjugated ene-yne backbone of polydiacetylene liposomes results in the appearance of a deep blue/purple solution The visible absorption spectrum of the freshly prepared purple liposomes is shown in FIG. 25.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN(C=O)C.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:19])=[O:10])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCC(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of trans-4-methyl-1-cyclohexane carboxylic acid (8.2 g, 56.5 mmol) in CH2Cl2 (350 mL) at 0° C. was added DMF (44 μl, 0.6 mmol) and oxalyl chloride (11.5 g, 90.0 mmol) dropwise. The reaction mixture was stirred at rt for 18 h. The reaction mixture was concentrated. The product was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[NH:14][C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C>[CH3:17][C:10]1[CH:9]=[C:8]2[C:13]([NH:14][C:15](=[O:16])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7]2)=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]
Reactant: CCOC(=O)c1nc2cc(C)ccc2[nH]c1=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2cc(C)c([N+](=O)[O-])cc2[nH]c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of ethyl-3,4-dihydro-7-methyl-3-oxoquinoxaline-2-carboxylate (1.65 g, 7.10 mmol) in acetic acid (15 ml) was added dropwise fuming nitric acid (1.36 ml, 14.2 mmol), and the mixture was stirred for 1 hour at 60° C. The reaction mixture was poured into ice water and, after stirring for 25 minutes, the precipitate was collected by filtration. These were air-dried and then dissolved into ethyl acetate. Moreover, the filtrate was extracted with ethyl acetate, which was combined with foregoing organic layer. After dried over anhydrous sodium sulfate, solvent was distilled off. The residue obtained was purified by means of silica gel column chromatography [n-hexane:ethyl acetate=1:1] to obtain 887 mg of the title compound as pale yellow powder. Yield 45%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=1.[OH-].[NH4+].[CH:22](O)=[O:23]>>[CH2:18]([O:17][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][CH:22]=[O:23])[N:8]=2)=[CH:10][CH:11]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1ccc(-c2cccc(CN)n2)cc1
Reactant: O=CO
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)c1ccc(-c2cccc(CNC=O)n2)cc1

Procedure:
A solution of 6-aminomethyl-2-(p-ethoxycarbonylphenyl)pyridine (10.76 g) in 10 ml of formic acid is heated at 90° for 15 hours. The reaction is cooled to 0°, basified with excess saturated ammonium hydroxide solution and extracted with chloroform (4×30 ml). The organic extracts are dried and evaporated to yield 2-(p-ethoxycarbonylphenyl)-6-formylaminomethylpyridine which is recrystallized from toluene, m.p. 119.5°-120.5°.
Reaction SMILES: N1(O[C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:48]1[CH:52]=[CH:51][N:50]=[CH:49]1>COCCOC>[N:48]1([C:11]2[N:41]=[CH:40][N:39]=[C:38]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21])[CH2:17]2)[CH:52]=[CH:51][N:50]=[CH:49]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(-n4ccnc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 85 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
In a clean, dry reaction vial equipped with a stirring bar were placed O6-(benzotriazol-1-yl)-2′,3′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and imidazole (13.6 mg, 0.200 mmol). Dry DME (1.0 mL) was added and the reaction mixture was flushed with N2 and the mixture was allowed to stir at 85° C. for 4 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The mixture was washed with water, dried over Na2SO4, and evaporated to dryness. Chromatographic purification (SiO2, elution with 50% EtOAc in hexanes) afforded 32.0 mg (60% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.07. 1H NMR (500 MHz, CDCl3): δ 9.19 (s, 1H, Ar—H), 8.77 (s, 1H, Ar—H), 8.48 (s, 1H, Ar—H), 8.40 (s, 1H, Ar—H), 7.25 (s, 1H, Ar—H), 6.56 (t, 1H, H-1′, J=6.3), 4.64 (app q, 1H, H-3′, Japp˜4.2), 4.06 (m, 1H, H-4′), 3.90 (dd, 1H, J=11.2, 3.9), 3.80 (dd, 1H, H-5′, J=11.2, 2.9), 2.65 (app quint, 1H, H-2′, Japp˜6.3), 2.51 (m, 1H, H-2′), 0.92, 0.915 (2 s, 18H, tert-Bu), 0.11, 0.10 (2 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 153.0, 152.1, 145.6, 143.0, 137.7, 130.6, 122.9, 117.3, 88.1, 84.7, 71.7, 62.6, 41.5, 25.9, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1>CO>[CH3:1][O:2][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
A suspension of sodium methoxide (40.5 g, 0.750 mol) in 200 mL of methanol was slowly added to a solution of 2-chloro-3-nitro-pyridine (79.3 g, 0.500 mol) in 800 mL of methanol at 0° C. The reaction mixture was stirred for 4 hours and then poured into 1000 g of ice. The resulting precipitate was filtered, washed with water, and dried to give 2-methoxy-3-nitro-pyridine (70. g, 0.45 mmol, 90%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>C1C=CC=CC=1>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([Cl:23])=[O:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-nitrobenzoic acid (1.5 g) and phosphorus pentachloride (1.1 g) in benzene (10 ml) was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure to give crystals of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride. A solution of the above chloride in dichloromethane (5 ml) was added to a mixture of methoxylamine hydrochloride (0.85 g) and sodium bicarbonate (2.2 g) in water (10 ml) and dichloromethane (5 ml) at to 5° C. After stirring for 1 hour at the same temperature, the mixture was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was crystallized from isopropyl ether to give pale brown crystals of N-methoxy-3-(2,4-difluorophenoxy)-4-nitrobenzamide (1.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:20][CH2:21][CH3:22])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]([CH2:18]O)[CH2:5]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:21]([O:20][C:4]1([O:3][CH2:1][CH3:2])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[C@@H:6]([CH2:18][N:46]2[C:42](=[O:52])[C:43]3=[CH:51][CH:50]=[CH:49][CH:48]=[C:44]3[C:45]2=[O:47])[CH2:5]1)[CH3:22]
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CO)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72485.8 %

Procedure:
A solution of 4,4-Diethoxy-1-((S)1-phenyl-ethyl)-(R)-2-hydroxymethyl-piperidine (65.35 g, 0.213 mmol), triphenylphosphine (61.3 g, 0.234 mol) and phthalimide (34.4 g, 0.234 mol) in tetrahydrofuran (700 ml) cooled to 0° C. was added diethyl azodicarboxylate over the course of 1.5 hour. The reaction mixture was stirred at 0° C. for another 2 hours before the solvent was removed in vacuo. The residue was dissolved in hot heptane-toluene (3:2) (650 ml) before it was cooled on an ice bath. The precipitate consisting of triphenyl phosphine oxide was filtered off and washed with heptane. The filtrate was concentrated in vacuo and the residue subjected to column chromatography using a mixture of toluene-ethyl acetate-heptane (3:1:3) as eluent. The solvent was evaporated in vacuo whereupon a viscous oil was obtained. Upon addition of light petrol ether the product crystallized to give 67.4 g (73%) of the title compound as a solid.
Reaction SMILES: [CH3:1][CH2:2][O:3]C1C=CC2N(C)[C@H]3N(C)CC[C@@]3(C)C=2C=1.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=2)[CH:22]([CH3:30])[C:21]1=[O:31]>>[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([O:29][C:2](=[O:3])[CH3:1])=[CH:26][CH:27]=2)[CH:22]([CH3:30])[C:21]1=[O:31]
Reactant: CCOc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Reactant: CC1C(=O)N(C)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(C)C(=O)N2C

Procedure:
A process for the preparation of eserethole of formula ##STR7## which comprises the steps of: a) acylating the compound II 1,3-dimethyl-5-hydroxy-oxindole to obtain 1,3-dimethyl-5-acyloxy-oxindole (III);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].IC.CN(C)[C:38](=O)[CH3:39]>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:38][CH3:39])[C:12]2[CH:13]=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cc(C(C)(C)C)c3c(c2)C(C)(C)CO3)cc1
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOC(=O)c1ccc(N(CC)c2cc(C(C)(C)C)c3c(c2)C(C)(C)CO3)cc1
Yield: 56 %

Procedure:
Following general procedure G and using 4-[(7-t-butyl-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 18, 0.15 g, 0.41 mmol), potassium carbonate (1.65 g, 12 mmol) and iodomethane (0.94 g, 6 mmol) in 5 mL of anhydrous N,N-dimethylacetamide, the title compound (0.090 g, 56%) was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.85 (d, 2H, J=8.9 Hz), 6.87 (d, 1H, J=2.2 Hz), 6.77 (d, 1H, J=2.2 Hz), 6.57 (d, 2H, J=9.1 Hz), 4.29 (q, 2H, J=7.1 Hz), 4.28 (s, 2H), 3.74 (q, 2H, J=7.0 Hz), 1.36 (t, 3H, J=7.1 Hz), 1.36 (s, 9H), 1.33(s, 6H), 1.26 (t, 3H, J=7.1 Hz)).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=O)[NH:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=[S:33])[NH:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C(=O)NC[Si](C)(C)C)c2ccccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)OCc1ccc(C(=S)NC[Si](C)(C)C)c2ccccc12
Yield: 58.5 %

Procedure:
(4{[(trimethylsilyl)methyl]carbamoyl}naphthalen-1-yl)methyl acetate (2.0 g) and Lawesson reagent (2.4 g) were suspended with toluene (30 ml). The mixture was heated to reflux for 2 hours. The reaction mixture was returned to room temperature, washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain (4{[(trimethylsilyl)methyl]carbamothioyl}naphthalen-1-yl)methyl acetate (1.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].I[CH:17]([CH3:19])[CH3:18]>>[CH:17]([O:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:19])[CH3:18]
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1C
Reactant: CC(C)I
Product: COC(=O)c1cc(OC(C)C)cc([N+](=O)[O-])c1C

Procedure:
reacting methyl 5-hydroxy-2-methyl-3-nitrobenzoate with 2-iodopropane in the presence of a base to form methyl 5-isopropoxy-2-methyl-3-nitrobenzoate;
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20]Cl>CCCCC>[C:1]([N:5]=[N:6][C:7]([Cl:20])([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CC(C)C)=NNC(C)(C)C
Reactant: ClCl
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CC(C)CC(C)(Cl)N=NC(C)(C)C
Temperature: -15 °C

Procedure:
Into a 5 liter, 4-neck round bottom flask equipped with a low temperature thermometer, a chlorine inlet tube, a mechanical stirrer, and a gas exit tube protected from the atmosphere with a CaCl2 tube, was added 510 grams (3.0 moles) of methyl isobutyl ketone t-butylhydrazone, 303.6 grams (3.0 moles) of triethylamine and 2400 ml of pentane. The contents were cooled to -15°C with a dry ice-isopropanol bath. Then with rapid stirring 213 grams (3.0 moles) of chlorine were passed into the reaction mixture as fast as it was possible to control the temperature at 5°C or below. After all of the chlorine had been added the reaction temperature was adjusted to -5°C to 0°C and the reaction mixture filtered to remove the triethylamine hydrochloride. The triethylamine hydrochloride filter cake was washed with fresh pentane and the filtrate added to the original pentane solution.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:20].[C:21]1([N:27]([CH2:34][C:35](O)=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:35](=[O:36])[CH2:34][N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:3]1=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CN(c1ccccc1)c1ccccc1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CN(c1ccccc1)c1ccccc1)NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 3-amino-1-benzhydryl-pyrrolidin-2-one (42) (0.2 g, 0.75 mmol) in dry CH2Cl2 (20 ml)was added diphenylamino ethanoic acid (0.19 g, 0.82 mmol) under nitrogen. To the reaction was added EDC (0.18 g, 0.9 mmol) and DMAP (cat) and the reaction mixture was stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate:water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane:ethyl acetate (2:1) to give the desired product in 69% yield.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11](N)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[I:10].CI.[CH3:17][N:18]([CH:20]=O)C>>[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:18]([CH3:20])[CH3:17])(=[O:12])=[O:13])[CH:7]=[CH:8][C:9]=1[I:10]
Reactant: CN(C)C=O
Reactant: NS(=O)(=O)c1ccc(I)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)S(=O)(=O)c1ccc(I)c(Cl)c1
Reaction time: 0.33 h

Procedure:
Sodium hydride (0.33 g) was added to a solution of the product from step (i) (1.2 g) in DMF (25 ml) and stirred for 20 min. Methyl iodide (0.5 ml) was added dropwise and then stirred for a further 1 h. The reaction mixture was quenched with water, extracted with EtOAc, dried (MgSO4) and evaporated. The residue was treated with ether to give to give the subtitle compound as a white solid. Yield 0.45 g.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][C@H:31](O)[CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][C@H:31]([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: O[C@H]1CCN(c2nnc3ccc(F)cn23)C1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[Si](O[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (250 mg, 0.81 mmol) was added to a solution of Intermediate 26a (150 mg, 0.67 mmol) and Et3N (101 mg, 1.00 mmol) in DMF (2 mL) and the mixture stirred at RT for 1 h. The reaction mixture was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (220 mg, 86%). LCMS (Method 4): Rt 4.15 min, m/z 379 [MH+].
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19](S(C)=O)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=2)[NH2:36])[CH2:29][CH2:28]1>>[O:1]=[S:2]1(=[O:25])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:36][C:35]4[CH:37]=[CH:38][CH:39]=[C:33]([N:30]5[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]5)[CH:34]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(N4CCCS4(=O)=O)c3)n2n1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cccc(N6CCCS6(=O)=O)c5)n4n3)c2)CC1
Yield: 20.8 %

Procedure:
Analogous to Example 1491c, 7-[3-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-2-(methylsulfinyl)pyrrolo[2,1-f][1,2,4]triazine (90.0 mg, 0.239 mmol) and 3-(4-Methylpiperazin-1-yl)aniline (91.4 mg, 0.478 mmol) were reacted to afford 7-[3-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-N-[3-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine (25 mg, 18%). LCMS (HPLC): 0.84 min, m/z=504 (M+H); 1H-NMR (DMSO-d6): 9.29 (s, 1H), 8.99 (s, 1H), 7.86 (d, 1H, J=7.8 Hz), 7.75 (s, 1H), 7.49 (m, 1H), 7.32 (m, 2H), 7.18 (d, 1H, J=8.0 Hz), 7.11 (m, 2H), 6.96 (d, 1H, J=4.7 Hz), 6.56 (d, 1H, J=7.8 Hz), 3.73 (t, 2H, J=6.4 Hz), 3.52 (t, 2H, J=7.4 Hz), 2.99 (m, 4H), 2.37 (m, 6H), 2.20 (s, 3H).
Reaction SMILES: CO.[NH3:3].[Br:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11](OCC)=[O:12])=[CH:7][CH:6]=1>>[Br:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([NH2:3])=[O:12])=[CH:7][CH:6]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1
Reactant: N
Solvent: CO
Product: NC(=O)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
7M-Ammonia methanol solution (10 ml, 70 mmol) was added to ethyl 2-(4-bromophenoxy)acetate (1.0 g, 3.86 mmol), and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was concentrated under reduced pressure to give 2-(4-bromophenoxy)acetamide (870 mg, yield 98%) as a white solid.
Reaction SMILES: [Cl:1]N(Cl)S(C1C=CC(C)=CC=1)(=O)=O.Cl.[CH2:15]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)(=O)C>[Cl:1][C:25]1[CH:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)[CH:28]=[CH:29][C:24]=1[O:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cc1ccc(S(=O)(=O)N(Cl)Cl)cc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1Cl
Reaction time: 8 h
Yield: 128.2 %

Procedure:
N,N-dichloro-p-toluenesulfonamide (hereinafter abbreviated to "dichloramine T") (7.5 g, 0.032 mol) was dissolved in acetic acid (100 ml), followed by adding to the solution, hydrochloric acid (0.4 ml), dropwise adding to the acetic acid solution of dichloramine T, a solution of 4'-octyloxy-4-biphenycarboxylic acid (20 g, 0.063 mol) dissolved in acetic acid (100 ml), refluxing the mixture, allowing it to stand overnight, distilling off acetic acid and filtering off deposited crystals to obtain 3'-chloro-4'-octyloxy-4-biphenylcarboxylic acid (14.8 g) (C-Sc 146° C., Sc 'N' 224° C. and N'-I 232° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:11]=1[C:26](OCC)=[O:27]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][C:26]([C:11]2[C:10](=[O:9])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)=[O:27])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Reactant: Cc1cccc(N)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)c2cn(-c3ccccc3)c3ccccc3c2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.49 g of 2-amino-6-methylpyridine and 10 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 500 ml of toluene was refluxed for 24 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. The solution was filtered and evaporated. The residue was purified by means of high pressure liquid chromatography (silica gel: dichloromethane as the eluent) to afford 9.8 g of 1,2-dihydro-4-hydroxy-N-(6-methyl-2-pyridyl)-1-phenyl-3-quinolnecarboxamide which was dissolved in chloroform, treated with 35 g of activated manganese dioxide and stirred for three hours at room temperature.