Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Temperature: 100 °C
Yield: 32.3 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (1.0 gm., 1.9 mmoles) in 20 ml DMF. To this solution add 2,6-difluorophenylboronic acid (0.6 gm., 3.8 mmoles), potassium phosphate (2.42 gm., 11.4 mmoles) and tetrakis(triphenylphosphine)palladium (0) (0.44 gm., 0.38 mmoles) and heat to 100° C. for 18 hours. Cool and filter the mixture and purify on an SCX column, eluting the impurities with methanol, then eluting the product with 2N ammonia/methanol. Purify further on a silica gel column eluting with a gradient of 50-100% methylene chloride/hexane containing 1% isopropyl amine to give 300 mg (32%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]2[C:10]([I:11])=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1c(Br)cnc2[nH]cc(I)c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)c(Br)cnc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
5-Bromo-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (7.68 g, 21.5 mmol) was dissolved in 100 mL dry DMF and cooled to 0° C. Sodium hydride (60% suspension in mineral oil, 1.03 g, 25.8 mmol) was added cautiously over 5 min. The mixture was cooled to −42° C. and 2-trimethylsilanyl-ethoxymethylchloride (5 mL, 28 mmol) was added slowly over 10 min. The mixture was stirred at −42° C. for 2 h and quenched with 200 mL saturated ammonium chloride solution and 200 mL water. The aqueous mixture was extracted with dichloromethane and the organic phase was washed with water, dried and concentrated to afford 5-Bromo-4-chloro-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (10.1 g, 20.7 mmol, 96% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.07 (s, 1H), 5.57 (s, 2H), 3.49 (t, J=8 Hz, 2H), 0.79 (t, J=8 Hz, 2H), −0.11 (s, 9H). MS: m/z 486.7/488.7 (M+H+).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>ClC(Cl)C.CN(C)C=O>[ClH:16].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([Cl:1])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCc1ccncc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCc1ccncc1

Procedure:
4-(Pyrid-4-yl)butyric acid hydrochloride (ca. 35 g) in dichloroethane (250 ml) and dimethylformamide (0.5 ml) was treated with thionyl chloride (100 ml). The vigorous exothermic reaction was allowed to subside and then the mixture was heated under reflux for 10 minutes, followed by evaporation to dryness in vacuo to give crude 4-(pyrid-4-yl)butyroyl chloride hydrochloride.
Reaction SMILES: [N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([OH:19])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:30](O)[CH3:31]>>[N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([O:19][CH2:30][CH3:31])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc2c(c1)CCc1cccnc1S2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc2c(c1)CCc1cccnc1S2
Temperature: 0 °C
Yield: 85 %

Procedure:
A mixture of 30 mg of (5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-8-yl)-acetic acid, 3 ml of ethanol and 100 mg of sulfuric acid was refluxed for 1 hour. After the completion of the reaction, the solvent was distilled off to obtain a residue, to which was added ice water, and the mixture was basified with a 5% sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain an oil, which was chromatographed over silica gel and eluted with benzene/chloroform (2/1), thereby yielding 28 mg (yield: 85%) of ethyl (5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-8-yl)-acetate as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:12](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(Br)c(O)cc1Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(Cl)c(C#N)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
To a solution of 5-bromo-2-chloro-4-hydroxybenzonitrile (7.0 g, 30.11 mmol) in DMF (70 mL) was added cesium carbonate (19.62 g, 60.22 mmol, GLR Scientific) and MeI (3.74 mL, 60.22 mmol, Spectrochem). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice cold water (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude compound which was purified by column chromatography (silica gel 100-200 mesh and 0-4% EtOAc in hexane) to obtain 5-bromo-2-chloro-4-methoxybenzonitrile (5.5 g, 74.1%) as white solid. m/z (ESI) N/A (no ionization observed).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: CCOC(=O)N1CCNC[C@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C[C@H]1C
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 28 μl DIPEA, 64 mg HATU and 29 mg (R)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 186 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[O:18]=[C:19]1[C@@H:22]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:21][N:20]1S([O-])(=O)=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.OC1C=CC=C2C=1[NH+]=CC=C2>C(#N)C>[C:28]1([CH2:27][O:26][C:24]([NH:23][C@H:22]2[CH2:21][NH:20][C:19]2=[O:18])=[O:25])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(N[C@H]1CN(S(=O)(=O)[O-])C1=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Oc1cccc2ccc[nH+]c12
Solvent: CC#N
Product: O=C(N[C@H]1CNC1=O)OCc1ccccc1

Procedure:
To a solution of (3S)-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, tetrabutylammonium salt in acetonitrile was added 8-hydroxyquinolinium p-toluenesulfonate. The mixture was refluxed, yielding the title compound as verified by thin layer chromatography (Merck silica gel 60F, ethyl acetate).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21].[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)=[CH:30][NH:29][N:28]=1>>[F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:28]3[N:29]=[CH:30][C:31]([C:32]4[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=4)=[C:27]3[N:26]=2)=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(OCC(F)(F)F)c(C(F)(F)F)c1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(OCC(F)(F)F)c(C(F)(F)F)c4)nc23)cc(C)n1
Yield: 61.8 %

Procedure:
Reaction of 1-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (165 mg, 62%). MS (ISP) 535.5 [(M+H)+]; mp 229° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:41](=[O:42])[N:12]2[C:13]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:14]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>CCCCCCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:41](=[O:42])[N:12]2[C:13]([C:25]([OH:27])=[O:26])=[C:14]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(=O)c3ccccc3)CS[C@H]12
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(C(=O)c3ccccc3)CS[C@H]12
Temperature: 5 °C

Procedure:
To a cooled (5° C.), stirred slurry of 0.227 g. of benzhydryl 7-(2-thienylacetamido)-3-benzoyl-3-cephem-4-carboxylate in 2 ml. of anisole was added 1 ml. of cold trifluoroacetic acid. After the reaction mixture was allowed to stir with cooling for 20 minutes, 20 ml. of n-heptane was added, and the resulting solution was evaporated in vacuo to a low volume to remove excess trifluoroacetic acid. An additional 20 ml. of n-heptane was added to the residue and the resulting solution was stirred with cooling for approximately 5 minutes. The white precipitate which formed was filtered from the solution and dissolved in acetone. The acetone solution was filtered and the filtrate evaporated in vacuo to a low volume. The residue was dissolved in cold ethyl acetate and transferred to a separatory funnel. The ethyl acetate solution was extracted twice with cold aqueous sodium bicarbonate solution. The aqueous extracts were combined, layered with cold ethyl acetate and acidified with cold 1N.HCl. The ethyl acetate layer was separated, washed twice with brine, and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided 0.157 g. (96 percent) of the title acid which crystallized from methylene chloride/hexane. The product exhibited activity against gram-positive and gram-negative organisms at 0.1 mg/ml in a standard disc assay.
Reaction SMILES: C(=O)(O)O.[NH:5]([C:7](=[NH:9])[NH2:8])[NH2:6].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:14](Cl)=[O:15].[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:14]([NH:6][NH:5][C:7](=[NH:8])[NH2:9])=[O:15]
Reactant: N=C(N)NN
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: N=C(N)NNC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of hydrazinecarboximidamide carbonic acid salt (15.6 g, 114.61 mmol) in pyridine (100 ml) was added 3,4-dichlorobenzoyl chloride (20 g, 95.48 mmol), and the resulting mixture was stirred overnight at room temperature, then concentrated under vacuum to give a residue, which was dissolved in water (30 ml) and adjusted to pH 12 with sodium hydroxide (aq., sat). The product precipitated and was collected by filtration and dried in an oven under reduced pressure to afford 2-(3,4-dichlorobenzoyl)hydrazinecarboximidamide as a light yellow solid (9.5 g, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH3:11].O.C(O)C.N>[Fe].C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH3:11])[NH2:8]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: N
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(N)cc1Br
Temperature: 70 °C
Yield: 69.7 %

Procedure:
2-Bromo-4-nitrotoluene (10.0 g, 46.3 mmol) was added to a mixture of water (60 mL), ethanol (130 mL) and acetic acid (40 mL) under nitrogen. The mixture was heated to 70° C. and iron powder (10.3 g, 185 mmol) was added portionwise. After the mixture was heated at refluxed for 2 hours, it was cooled and aqueous ammonia (34%, 180 mL) was added slowly. The mixture is filtered through celite and the aqueous phase was extracted with ethyl acetate. It was dried over MgSO4, filtered, and solvent was removed to give the product as a brown oil (6.0 g, 71%). LCMS (ESI): M+H=185.8.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1

Procedure:
When direct esterification was carried out using p-toluenesulfonic acid as a catalyst, the yield of the final product was very low. Even when toluene was used as an azeotropic dehydrating solvent, the yield was as low as 26%. In addition, under the reaction conditions employed, a greater portion of the charged benzyl alcohol self-condensed to form dibenzyl ether. The results are summarizd in Table 4.
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:3]=1.[H-].[Na+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=2[F:30])[N:23]=[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:21]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:30][C:28]1[CH:27]=[C:26]([F:31])[CH:25]=[C:24]2[C:29]=1[C:20]([NH:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:3]=1)=[C:21]([CH3:38])[C:22]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[N:23]2
Reactant: N#Cc1cc(I)c(N)cc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)c(C#N)cc1I
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 4-amino-5-iodo-2-morpholinobenzonitrile (140 mg, 0.42 mmol) in dry DMF (3.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (34.7 mg, 0.87 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 minutes, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (185 mg, 0.64 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 2.5 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:methanol (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the black residue was treated with methanol and placed on the rotovap. (without vac.) in a 45° C. water bath. After 30 minutes, the solid was filtered and rinsed twice with methanol to afford an off white solid as 4-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-iodo-2-morpholinobenzonitrile. Mass Spectrum (pos.) m/e: 583.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([OH:27])[CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].[ClH:41].C(O)C>N1C=CC=CC=1.CC(C)=O.O.C(OCC)(=O)C>[ClH:41].[C:28]([O:27][CH:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH:15]=1)[CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])(=[O:30])[CH3:29]
Reactant: CN(C)CCOCC(O)c1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OC(COCCN(C)C)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 12 ml of pyridine was suspended 3.0 g of 1-(6-benzyloxy-2-naphthyl)-2-[2-(N,N-dimethylamino)-ethoxy]ethanol. To the suspension was added 1.6 ml of acetic anhydride. The resulting mixture was stirred at room temperature for 24 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 60 ml of ethyl acetate and 60 ml of water. The mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated. The aqueous layer was extracted with 30 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 30 ml of acetone. To the solution was added 1.5 ml of a 5N dry hydrogen chloride-ethanol solution. The resulting mixture was stirred at room temperature for 1 hour. The resulting crystals were collected by filtration and dried to obtain 2.6 g of 1-acetoxy-1-(6-benzyloxy-2-naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethane hydrochloride (compound No. 286).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([F:10])[C:3]=1[NH2:4].[Br:11]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Br:11])[C:6]([CH3:9])=[C:5]([F:10])[C:3]=1[NH2:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(N)c1F
Solvent: CN(C)C=O
Product: Cc1c(Br)cc(Cl)c(N)c1F
Reaction time: 8 h

Procedure:
2-Chloro-5-methyl-6-fluoroaniline (23 g, 0.14 mol) and N-bromosuccinimide (25 g, 0.14 mol) are dissolved with stirring in 200 mL of anhydrous DMF. The reaction mixture is stirred overnight and then most of the DMF is removed by rotary evaporator under high vacuum. The dark brown residue is partitioned between 1:1 Et2O/hexane (500 mL) and water (500 mL). The organic layer is washed with brine (5×250 mL), dried (MgSO4) and concentrated by rotary evaporator. The crude material is purified using flash chromatography (20% CH2Cl2/hexanes) and then further purified by bulb-to-bulb distillation (b.p. 155–165° C. at ˜20 mm of Hg) to give 2-chloro-4-bromo-5-methyl-6-fluoroaniline as a peach-colored solid which is re-crystallized from ice-cold hexanes (m.p. 67–71° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][O-:12].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:12][CH3:11])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: C[O-]
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc(SC)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4,6-Dichloro-2-(methylthio)pyrimidine (40 g, 205 mmol) was dissolved in methanol (1025 mL) and cooled to 0° C. Sodium methoxide (55.4 g, 1025 mmol) was added slowly and the mixture was stirred at room temperature for 18 h. 300 mL of 3 M HCl was added and the methanol was evaporated. Additional water (500 mL) was added and the mixture was filtered, washed with water and dried to give the title compound as a white solid. 1H NMR (CDCl3) δ 6.41 (s, 1H), 3.97 (s, 3H), 2.55 (s, 3H); LCMS 2.40 min, 191 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH2:18][N:19]2[C:28](=[O:29])[C:27]3[N:26]([CH2:30][C:31]#[C:32][CH3:33])[C:25]([N:34]4[CH2:39][CH2:38][CH2:37][CH:36]([NH:40]C(OC(C)(C)C)=O)[CH2:35]4)=[N:24][C:23]=3[N:22]([CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:20]2=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:8]1([CH2:18][N:19]2[C:28](=[O:29])[C:27]3[N:26]([CH2:30][C:31]#[C:32][CH3:33])[C:25]([N:34]4[CH2:39][CH2:38][CH2:37][CH:36]([NH2:40])[CH2:35]4)=[N:24][C:23]=3[N:22]([CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:20]2=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1cccc3ccccc13)c(=O)n2CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(N2CCCC(N)C2)nc2c1c(=O)n(Cc1cccc3ccccc13)c(=O)n2CC(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.7 ml of trifluoroacetic acid are added to a solution of 200 mg 1-(naphth-1-ylmethyl)-3-(methoxycarbonylmethyl)-7-(but-2-ynyl)-8-(3-tert-butoxycarbonylamino-piperidin-1-yl)-xanthine in 3 ml dichloromethane. The solution is stirred for 3 h at ambient temperature and then added to ice-cooled aqueous potassium carbonate solution. The aqueous phase is extracted with dichloromethane, the combined organic extracts are dried over sodium sulphate, and the solvent is removed. The residue is purified by chromatography on a silica gel column with methylene chloride/methanol (7:3) as eluant.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[S:10][C:9]=2[CH:21]=[N:22]O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(OCC)(=O)C.CCCCCC>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[S:10][C:9]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(O)cc2)sc(C=NO)c1-c1cccc(O)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(-c2ccc(O)cc2)sc(C#N)c1-c1cccc(O)c1
Temperature: 200 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
A mixture of 3-(3-hydroxyphenyl)-5-(4-hydroxyphenyl)-4-methylthiophene-2-carbaldehyde oxime (0.76 g, 2.3 mmol) and pyridinium hydrochloride (2.7 g, 23 mmol) was heated at 195-205° C. in a 200 mL round bottom flask fitted with a 250 mL bump trap. After 2 h, the reaction mixture was cooled to 23° C. and taken up in a minimum of ethyl acetate (100 mL). The organic phase was washed with water (2×50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product as a brown solid (0.61 g) which was pre-adsorbed on silica gel (2 g). Flash chromatography (10 g silica gradient 20%-30%-40% ethyl acetate-hexane) gave the title compound (0.37 g, 52%, m.p. 220-22° C.) as a pale orange solid after recrystallization from hot ethyl acetate-hexane.