Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCCCC1.C1(C(C)C)C=CC=CC=1.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([Li])CCC.[CH:29]12[O:35][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34]2>>[CH3:16][N:17]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1CCC2OC2C1
Reactant: CNc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)c1ccccc1
Solvent: C1CCCCC1
Product: CN(c1ccccc1)[C@@H]1CCCC[C@H]1O
Reaction time: 24 h
Yield: 75 %

Procedure:
To a 500 mL round bottom flask was added 100 mL of 1.2 M potassium t-amylate in cyclohexane (0.12 moles) and 41.7 mL of cumene (0.3 moles) under a constant flow of nitrogen gas. Then 10.8 mL of N-methylaniline (0.1 moles) was added to the reaction mixture while the reaction was continuously stirred. n-Butyllithium (46 mL of a 2.2 M solution, 0.1 moles) was added and the resulting amide was left stirring for two days. Cyclohexene oxide (10.1 mL, 0.1 moles) was added. After 24 hours, the reaction was quenched by carefully adding water under the flow of nitrogen. Washing of the product with 100 mL of distilled water yielded two layers of which the organic layer was extracted. Repeated rotovapor distillations removed most of the cumene. Any leftover cumene after rotovapor distillation was removed by vacuum horizontal distillation. This device employs a vacuum (<1 mm Hg) and liquid nitrogen to trap cumene, which distilled at about 85° C., but 16 g of racemic MPAC (0.075 moles, 75% yield) distilled at 120° C. The product, MPAC, was analyzed by NMR spectroscopy and the spectrum confirmed the presence of the compound when it was compared to that of literature (Swamy and Raghavendra, 2002).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH2:12]2)=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[N:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[CH:11]1([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:12][CH2:13]1
Reactant: COC(=O)c1ccc(C2CC2)c(Nc2ccc(Cl)cc2Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C2CC2)c(Nc2ccc(Cl)cc2Cl)n1
Yield: 10.1 %

Procedure:
A solution of 5-cyclopropyl-6-(2,4-dichloro-phenylamino)-pyridine-2-carboxylic acid methyl ester (62 mg, 184 μmol) and lithium hydroxide hydrate (9.3 mg, 221 μmol) in THF (100 μl) and water (50 μl) was stirred at ambient temperature for 20 h. The reaction mixture was poured onto 1 M HCl/ice water (1×20 mL) and extracted with i-PrOAc (2×25 mL). The combined organic layers were dried over sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (6 mg, 10%) as colorless liquid, which was sufficiently pure to be used in the next reaction step, MS (EI): m/e=323.3 [M+H]+.
Reaction SMILES: BrC1[CH:3]=[C:4]2[C:9](=CC=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.C[Sn](C)(C)C.[Cl-].[Li+]>CN(C=O)C.O.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>[NH:20]1[CH:21]=[C:17]([C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:3][CH:4]=[C:5]([CH3:6])[CH:3]=3)[CH:8]=2)([OH:16])[CH:13]([CH3:15])[CH3:14])[N:18]=[CH:19]1
Reactant: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Sn](C)(C)C
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 318.5 %

Procedure:
1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (2.0 g), tetramethyltin (0.94 ml), dichlorobis(triphenylphosphine)palladium (70 mg) and lithium chloride (432 mg) were dissolved in DMF (20 ml). The solution was stirred at 80° C. for 17 h. After cooling, the solution was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, and dried. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (eluent, hexane:THF=6:1→4:1), and crystallized from isopropyl ether to give the titled compound (1.52 g) as colorless needles.
Reaction SMILES: O.O.Cl[Sn]Cl.C(OC([N:13]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:20][C:19]=2[CH3:36])[CH2:14]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(O)(C)C>[CH3:36][C:19]1[CH:20]=[C:21]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH:22]=[CH:23][C:18]=1[CH:15]1[CH2:16][CH2:17][NH:13][CH2:14]1
Reactant: Cc1cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(S(=O)(=O)c2ccc(N)cc2)ccc1C1CCNC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
SnCl2.2H2O (1.74 g, 7.726 mmol) was added to a solution of 3-[2-methyl-4-(4-nitro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.69 g, 1.545 mmol) (prepared following the procedure described in Example 3) in isopropanol (20 mL) and the mixture was stirred at 75° C. for 2 hours. The reaction mixture was then cooled to 0° C. and a saturated solution of NaHCO3 was added. The gelatinous material obtained was filtered and the solvent was evaporated under reduced pressure. The crude material was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.407 g (83% yield) of 4-(3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl)-phenylamine as a white foam: MS (M+H)=317.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>C(O)C>[NH2:8][C@@H:12]([CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCOc2ccc(Cl)cc2)COC1(C)C
Agent: Cl
Solvent: CCO
Product: N[C@H](CO)CCOc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 57.6 %

Procedure:
To (S)-4-[2-(4-chloro-phenoxy)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (530 mg) was added under an argon atmosphere 5.5 M HCl solution in ethanol (2 ml). The mixture was stirred for 16 h. The mixture was concentrated. The residue was dissolved in dichloromethane and an excess of ammonia in methanol and some silica gel was added. The solvents were evaporated and the crude product was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: dichloromethane/methanol=90:10) to give (S)-2-amino-4-(4-chloro-phenoxy)-butan-1-ol (185 mg, 58%) as a white solid. MS (ISP): 216.3 ([M+H]+)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]2[N:21]=[C:20]([O:22][CH3:23])[C:19]([N:24]=O)=[C:16]2[S:17][CH:18]=1>[C].[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]2[N:21]=[C:20]([O:22][CH3:23])[C:19]([NH2:24])=[C:16]2[S:17][CH:18]=1
Reactant: COCc1cc(OC)c(-c2csc3c(N=O)c(OC)nn23)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCc1cc(OC)c(-c2csc3c(N)c(OC)nn23)c(OC)c1
Reaction time: 1 h
Yield: 63.5 %

Procedure:
Ethyl acetate (109 mL) and 10% palladium-carbon powder (50% wet: 2.34 g, 2.2 mmol) were added in that order to 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxy-7-nitrosopyrazolo[5,1-b][1,3]thiazole (2.34 g, 6.44 mmol), and the mixture was stirred for 1 hour under a hydrogen atmosphere. The mixture was filtered with Celite and the solvent in the obtained filtrate was distilled off under reduced pressure. The residue was purified by (NH)silica gel column chromatography (ethyl acetate) to obtain the title compound (1.43 g, 4.09 mmol).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1)[CH3:25]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH2:24][CH3:25])[CH:27]=3)[C:33]2=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: CCc1cccc(N=C=O)c1
Product: CCc1cccc(-n2c(=O)c3cnc4c(OC)cccc4c3n(C3CCCC3)c2=O)c1
Yield: 66.9 %

Procedure:
1-Cyclopentyl-3-(3-ethyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (89 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.32 mmol) and 1-ethyl-3-isocyanato-benzene (0.48 mmol) following general procedure C. LCMS: m/z 416 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11](=[O:14])[C:12]=1[CH3:13])=[CH:9][C:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)=[C:7]([CH3:27])[CH:6]=2)[CH3:2].[H-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O>[C:31](=[O:32])([O:33][CH3:34])[O:14][C:11]1[C:10]2[C:5](=[CH:6][C:7]([CH3:27])=[C:8]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)[CH:9]=2)[N:4]=[C:3]([CH2:1][CH3:2])[C:12]=1[CH3:13]
Reactant: COC(=O)Cl
Reactant: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(OC(=O)OC)c1C
Temperature: 15 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Dimethylformamide (980 ml) and 98 g of 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one were charged into a 2000-ml glass flask equipped with a stirring device, a thermometer, a reflux condenser, and a calcium chloride tube under a nitrogen atmosphere, and the temperature of the contents of the flask was cooled to 15° C. A 55% sodium hydride (18.2 g) was added thereto, and a reaction was allowed to proceed at 15 to 20° C. for one hr. Methyl chloroformate (32.1 g) was added dropwise into the reaction solution, and a reaction was allowed to proceed at room temperature for one hr. The reaction mixture was poured into 5 L of ice-water contained in the a 10-L plastic container, and the mixture was stirred at room temperature for two hr. The precipitated solid was collected by filtration through a suction filter and was washed with water and n-hexane. The solid was dried under the reduced pressure to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4-yl methyl carbonate (103.3 g, yield: 91.4%). The results of 1H-NMR analysis showed that the compound thus obtained was No. 120 described in a brochure of International Publication No. 2006/013896.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH:9]([S:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH2:10][C:11]([OH:13])=[O:12])[CH2:7][S:8][C@H:3]12.CN(C)C=O.C(N(CC)CC)C.[C:37]([O:41][C:42]([CH:44]([C:48]1[S:49][CH:50]=[CH:51][CH:52]=1)[C:45](N)=[O:46])=[O:43])([CH3:40])([CH3:39])[CH3:38]>C(N)=O.CCOCC>[C:37]([O:41][C:42]([CH:44]([C:48]1[S:49][CH:50]=[CH:51][CH:52]=1)[C:45]([NH:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH:9]([S:14][C:15]3[NH:16][N:17]=[N:18][N:19]=3)[CH2:10][C:11]([OH:13])=[O:12])[CH2:7][S:8][C@H:3]12)=[O:46])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)C(C(N)=O)c1cccs1
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: NC=O
Product: CC(C)(C)OC(=O)C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12)c1cccs1
Reaction time: 3 h

Procedure:
7-Amino-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (1.0 g., 2.68 mmol.) was suspended in 10 ml. of dry dimethylformamide and 1.12 ml. of triethylamine was added followed by 85 drops of formamide. A solution of 0.91 g. (2.68 mmol.) of the activated ester of α-t-butoxycarbonylthienylacetamide, prepared as described above, in 2 ml. of dimethylformamide was added and the reaction mixture was stirred at 25° for three hours. An additional 0.45 g. of activated ester was then added and the mixture stirred another five hours. Ether (ca. 300 ml.) was added and the solution was decanted. The remaining oily material was washed with ether, dissolved in water and the aqueous solution was extracted with ethyl acetate. The pH of the ethyl acetate solution was adjusted to 1.5 by addition of dilute hydrochloric acid. Extraction with ethyl acetate and evaporation of the solvent gave 7-(α-t-butoxycarbonylthienylacetamido)-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
Reaction SMILES: B.[Na].[CH2:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]1=[O:20])[CH3:4].CC(C)=O>C(O)C>[CH2:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]1[OH:20])[CH3:4]
Reactant: CCC1Cc2c(cccc2-c2ccccc2)C1=O
Agent: B
Agent: [Na]
Solvent: CC(C)=O
Solvent: CCO
Product: CCC1Cc2c(-c3ccccc3)cccc2C1O
Yield: 99.3 %

Procedure:
To a 200-ml three-necked round flask (equipped with a stirrer tip, a Dimroth condenser, a dropping funnel and a thermometer) were introduced 0.85 g (22.6 mmol) of sodium boron hydride and 28 ml of ethanol, and then in a nitrogen atmosphere at room temperature, a solution of 10.6 g (45.1 mmol) of 2-ethyl-4-phenyl-1-indanone in 20 ml of ethanol was dropwise added. After the dropwise addition was completed, the temperature was elevated to 50° C. to perform reaction for further 3.5 hours. After the reaction, the mixture was cooled, and acetone was dropwise added to decompose the unreacted sodium boron hydride. Then, the reaction mixture was concentrated under reduced pressure and extracted with 50 ml of water and 50 ml of ether. The organic phase was separated, and the aqueous phase was extracted twice with 50 ml of ether. The combined organic phases were washed with 100 ml of a saturated saline solution and dried over anhydrous Na2SO4. Then, the solvent was distilled off under reduced pressure to obtain 10.67 g of the aimed product (a mixture of two isomers) as a viscous, light yellow liquid (yield: 99%). The properties of the product thus obtained are described below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:17][N:18]([CH3:23])[S:19](Cl)(=[O:21])=[O:20].C(O)C(N)(CO)CO>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:8][S:19](=[O:21])(=[O:20])[N:18]([CH3:23])[CH3:17])[CH:5]=[N:6][CH:7]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Oc1cncc(Br)c1
Agent: NC(CO)(CO)CO
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)S(=O)(=O)Oc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A flask is charged with 5-bromo-pyridin-3-ol (0.200 g, 1.126 mmol), potassium phosphate (0.631 g, 2.884 mmol) and acetone (5 mL) and cooled to 0° C. Dimethylsulfamoyl chloride (0.261 g, 1.802 mmol) is then added dropwise and the cooling bath is removed. After 2 h, the mixture is diluted with acetone, filtered and the filtrate is concentrated in vacuo. The residue is dissolved in THF (30 mL) and polymer-supported trisamine (3.85 mmol/g, 0.7 g, 2.7 mmol) is added. After 1 h, the mixture is filtered. Concentration in vacuo gives a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 9:1 to 4:1) to give dimethyl-sulfamic acid 5-bromo-pyridin-3-yl ester as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.05 (s, 3H), 7.86 (m, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.62 (d, J=1.9 Hz, 1H).
Reaction SMILES: N1(O[C:11]([N:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C@H:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:15]=[C:14]2[C:32]2[CH:37]=[C:36]([S:38](=[O:42])(=[O:41])[NH:39][CH3:40])[C:35]([Cl:43])=[CH:34][C:33]=2[O:44][CH2:45][CH3:46])=[O:12])C2C=CC=CC=2N=N1.[N:47]1([C:53](=[O:61])[CH2:54][N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:16]2[C@@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:13]([C:11]([N:58]3[CH2:59][CH2:60][N:55]([CH2:54][C:53]([N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)=[O:61])[CH2:56][CH2:57]3)=[O:12])[C:14]([C:32]3[C:33]([O:44][CH2:45][CH3:46])=[CH:34][C:35]([Cl:43])=[C:36]([S:38]([NH:39][CH3:40])(=[O:41])=[O:42])[CH:37]=3)=[N:15]2)=[CH:30][CH:29]=1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)On1nnc2ccccc21
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Temperature: 40 °C
Yield: 100.4 %

Procedure:
To a solution of (4S,5R)-2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester (9 mg, 0.0124 mmol) in 0.5 mL of dimethylformamide was added a solution of 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (5.3 mg, 0.026 mmol) and diisopropylethylamine (4.53 uL). The resulting mixture was heated to 40° C. for 1 h. The solution was concentrated in vacuo then extracted from 1 mL of water with 1 mL of methylene chloride. The organic extract was applied to a 4 gram silica gel cartridge. The product was eluted using a gradient of methanol in methylene chloride to give 5-{(4S,5R)-4,5-bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-4-ethoxy-N-methyl-benzenesulfonamide (9.69 mg, 97%). LC-MS: 777.3 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[CH:5][NH:6][C:7](=[O:9])[CH:8]=1.[Cl:12][C:13]1(F)[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]1(F)F.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([N:6]2[C:7](=[O:9])[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:4]=[CH:5]2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]=1[C:2]([F:11])([F:10])[F:1]
Reactant: O=c1cc(C(F)(F)F)nc[nH]1
Reactant: O=[N+]([O-])C1=CC(F)(F)C(F)(Cl)C([N+](=O)[O-])=C1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)ncn1-c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-trifluoromethylpyrimidin-6-one (0.48 g), 2,4-dichloro-3,5-dinitrotrifluorobenzene (0.9 g) and potassium carbonate (0.41 g) in dry dimethylformamide (10 ml) was vigorously stirred at ambient temperature for a period of 15 minutes. The reaction mixture was then poured into water, and extracted into ethyl acetate. After drying and evaporation of the solvent, under reduced pressure, the residue was subjected to chromatography on silica gel using 30% (by volume) ethylacetate in petroleum ether (boiling range 60°-80° C.) as eluent. The required fractions were combined, and the solvent removed under reduced pressure to give a yellow solid, which was then triturated with petroleum ether (boiling range 60°-80° C.). The solid was dissolved in boiling ethanol, filtered, and the solvent removed under reduced pressure. The residue was again triturated with petroleum ether (boiling range 60°-80° C.) and finally recrystallised from petroleum ether (boiling range 60°-80° C.) containing ethylacetate (9% by volume) to give 1-(3-chloro-2,6-dinitro-4-trifluoromethylphenyl)-4-trifluoromethylpyrimidin-6-one as a yellow solid:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(I)c4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 682.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29].CO>N1C=CC=CC=1>[CH2:28]([S:30]([O:26][C:11]1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=1[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:27])[NH:6]2)(=[O:32])=[O:31])[CH3:29]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCS(=O)(=O)Oc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
133 mg (0.367 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one are suspended in pyridine (5 ml), and 700 (0.73 mmol) of ethanesulfonyl chloride are added. The suspension is stirred at RT for 3 h (during which the precursor dissolves), and then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 63 mg (43% of theory) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:26](O)[CH3:27].C1(C)C=CC=CC=1.S(=O)(=O)(O)O>ClCCl.CCCCCC.O>[CH2:26]([O:2][C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]=2)=[CH:6][CH:5]=1)=[O:3])[CH3:27]
Reactant: O=C(O)c1ccc(-c2nn(CCc3ccccc3)c3ccccc23)o1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(-c2nn(CCc3ccccc3)c3ccccc23)o1
Reaction time: 3 h
Yield: 46 %

Procedure:
0.8 g (2.4 mmol) of 3-(5-carboxy-2-furyl)-1-(2-phenylethyl)indazole were admixed with 25 ml of ethanol, 150 ml of toluene and 2 ml of conc. sulfuric acid and heated on a water separator for 3 h. Silica gel chromatography using dichloromethane/hexane (2:1) of the residue that was obtained after concentration using a rotary evaporator gave 400 mg (46%) of the title compound.