Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][C:28]=1[O:35][CH3:36].C(N(CC)CC)C>C(O)CC>[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[CH:29][C:28]=1[O:35][CH3:36]
Reactant: COc1cc(CN)ccc1O
Reactant: Clc1ncnc2c1ncn2C1CCCO1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CCCO
Product: COc1cc(CNc2ncnc3c2ncn3C2CCCO2)ccc1O
Yield: 80 %

Procedure:
A mixture of 10 mmol (2240 mg) of 6-chloro-9-(tetrahydrofuran-2-yl)-purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1838 mg) of 4-hydroxy-3-methoxybenzylamine and 5 mL of triethylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 80%, white solid. TLC (EtOAc:hexane) (1:1) (v:v): single spot; HPLC: purity>98%. 1H NMR (400 MHZ, DMSO): 0.90d (3H, J=6.6 Hz); 1.32m (1H); 1.57m (1H); 1.84m (1H); 1.95m (1H); 2.12m (2H); 2.29m (1H); 3.26m (1H); 3.51 bs (2H); 3.73m (1H); 3.89m (1H); 4.40t (1H, J=5.1 Hz); 6.12d (1H, J=5.2 Hz); 7.74bs (1H); 8.18s (1H); 8.28s (1H. MS (ES): [M+H]+=342 (100).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:12][CH2:13][CH2:14][SH:15].C(Cl)(Cl)Cl>C(O)C.O>[S:15]1[CH2:14][CH2:13][NH:12][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: NCCS
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N#Cc1ccc(C2NCCS2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
To a solution of 4-cyanobenzaldehyde (0.86 g, 6.6 mmol) in ethanol (15 ml) was added a solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (5 ml) and the solution stirred at RT for 18 h. The bulk of the ethanol was removed by rotary evaporator and the residue was treated with water (15 ml) and extracted with diethyl ether (3×20 ml) to remove excess aldehyde. The aqueous layer was basified with solid sodium carbonate (0.3 g) resulting in the formation of an oil. The mixture was extracted with ether (2×25 ml), washed with brine (1×50 ml), dried (MgSO4) and evaporated to give a clear oil that solidified on standing (0.62 g). Column chromatography (silica gel, 100% chloroform) afforded pure 4-(1,3-thiazolidin-2-yl)benzonitrile (6) (0.56 g, 67%) as clear oil that solidified on standing, mp 57-58°. 1H nmr (CDCl3, 300 MHz) 3.05-3.15, m, H4,4; 3.2-3.35, m, H5; 3.4-3.5, m, H5; 5.64, s, H2; 7.63, app. s, H2′,3′,5′,6′. ESI (+ve) MS m/z 191 (M+H, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]1([CH3:24])[CH:17]=[CH:16][C:15]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:24][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=2)=[O:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Yield: 84.3 %

Procedure:
A solution of 8.0 g of 4-aminobenzotrifluoride in 10 ml of methylene chloride was added to a solution of 9.85 g of p-toluenesulfonyl isocyanate in 75 ml of methylene chloride with stirring. The mixture became quite warm and a heavy white precipitate formed. An additional 100 ml of methylene chloride were added. The reaction mixture was stirred an additional 15 minutes, and the precipitate was recovered by filtration affording 15.0 g of the title product as a white solid. A small amount of the material was crystallized from diethyl ether to provide 4-methyl-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide with a melting point of 194-197° C.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[CH3:31][S-:32].[Na+]>CO>[OH:25][C:24]1[C:4]2[O:3][C:2]([S:32][CH3:31])=[C:6]([C:7](=[O:20])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)[C:5]=2[CH:21]=[CH:22][C:23]=1[O:29][CH3:30]
Reactant: C[S-]
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)c2c(SC)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 0.33 h

Procedure:
To a suspension of 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (22 mg, 0.046 mmol) in methanol (1 ml) in a screw cap vial was added sodium thiomethoxide (16 mg, 0.23 mmol) and the resulting orange solution was shaken for 20 minutes during which time the reaction became homogeneous. The crude reaction mixture was concentrated onto silica and chromatographed (silica gel, eluent=2:1 hexanes:ethyl acetate) to give the product as a resin (10 mg, 54%) that could be crystallised by standing in hexanes in the freezer overnight; 1H NMR (CDCl3) δ 7.08 (s, 2H), 6.92 (d, J=8.3 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 5.73 (br s, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.84 (s, 6H), 2.66 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[S:23][C:24]([CH3:27])=[CH:25][N:26]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([C:34]([OH:36])=[O:35])[CH:29]=2)[N:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:47]=2N=N1>CO>[CH3:47][O:35][C:34]([C:30]1[CH:29]=[C:28]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]3[S:23][C:24]([CH3:27])=[CH:25][N:26]=3)(=[O:21])=[O:20])[N:6]=2)[CH:33]=[CH:32][N:31]=1)=[O:36]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ncc(C)s2)nc(-c2ccnc(C(=O)O)c2)nc1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Product: COC(=O)c1cc(-c2nc(NS(=O)(=O)c3ncc(C)s3)c(Oc3ccccc3OC)c(OC)n2)ccn1

Procedure:
In analogy to example 22, from 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-thiazole-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid, product of example 61, by coupling with MeOH and benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) as regent there was obtained 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-thiazole-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid methyl ester as an off-white solid. ISP mass spectrum, m/e 544.2 (M+1 calculated for C23H21N5O7S2: 544).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]2([C:31]([F:34])([F:33])[F:32])[CH2:17][CH2:16][N:15]([C:18]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:21]([C:22](O)=[O:23])=[CH:20][N:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C:13]2([C:31]([F:32])([F:33])[F:34])[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[CH:20][C:21]([CH2:22][OH:23])=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)c1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reaction time: 5 h
Yield: 90.6 %

Procedure:
6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-4-(trifluoromethyl)nicotinic acid (1.11 g) was dissolved in methylene chloride (30 ml), and to the solution was added oxalyl chloride (0.54 ml, 6.16 mmol) and one drop of dimethylformamide at room temperature. After stirring for 5 hours, the solvent and excess oxalyl chloride were distilled off under reduced pressure. The residue was dissolved in dioxane, added with water, and then added with sodium borohydride (0.23 g) at 0° C. The mixture was stirred for 2 hours at room temperature and added with diluted hydrochloric acid. The mixture was extracted with ethyl acetate, dried over magnesium sulfate and filtered. After concentration under reduced pressure, the target compound (0.98 g) was obtained by purification with silica gel column chromatography.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.Cl.N([O-])=O.[Na+].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[CH-:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1.[Fe+2:29]>O.C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:11]=[CH:10][C:8]([C-:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:7][CH:6]=1.[CH-:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1.[Fe+2:29]
Reactant: C[Si](C)(C)C#Cc1ccc(N)cc1
Agent: [Fe+2]
Agent: Cl
Agent: O=N[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc(-[c-]2cccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.4 %

Procedure:
4-[2-(Trimethylsilyl)ethynyl]aniline (Takahashi et al. (1980) Synthesis, 8: 627-630) (1.0 g, 5.3 mmol) was suspended in a mixture of conc. HCl (2.4 mL) and H2O (10 mL) and cooled to 0° C. under stirring. A solution of NaNO2 (0.40 g, 5.8 mmol) in H2O (2 mL) was added while the temperature was carefully maintained between 0-5° C. After the addition was complete, the mixture was stirred for 30 min at 0° C. The resulting diazonium salt solution was then added slowly to a solution of ferrocene (0.49 g, 2.7 mmol) in toluene (100 mL) at 0° C., resulting in gas evolution. After the addition was complete, the mixture was stirred for 1 h at 0° C., warmed to rt and stirring was continued for an additional 16 h. The layers were separated and the aqueous layer was extracted with toluene (3×50 mL). The combined organic layers were washed with satd aq NaHCO3 (3×50 mL), brine (3×50 mL), dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography (silica, CH2Cl2/hexanes, 1:1) to remove unreacted ferrocene. Elution with CH2Cl2 afforded 0.42 g (44%) of compound 3. 1H NMR δ 0.27 (s, 9H), 4.02 (s, 5H), 4.35 (A2B2, J=1.5 Hz, 2H), 4.65 (A2B2, J=1.5 Hz, 2H), 7.40 (s, 4H); 13C NMR δ 0.04, 66.5, 69.3, 69.7, 84.1, 94.0, 105.5, 120.2, 125.6, 132.0, 140.1; FAB-MS obsd 358.0851, calcd exact mass 358.0840 (C21H22FeSi).
Reaction SMILES: Cl[CH:2]([C:10](=[O:13])[CH2:11][CH3:12])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([SH:22])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.O>[Cl:14][C:15]1[CH:16]=[C:17]([S:22][CH:2]([C:10](=[O:13])[CH2:11][CH3:12])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: CCOC(=O)C(=O)C(Cl)C(=O)CC
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)C(Sc1cc(Cl)cc(Cl)c1)C(=O)CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.4 %

Procedure:
A solution of ethyl 3-chloro-2,4-dioxohexanoate (EP117082 A2) (7.10 g, 34.4 mmol) in acetone (175 ml) was treated with 3,5-dichlorothiophenol (6.16 g, 34.4 mmol), potassium carbonate (5.22 g, 37.8 mmol) and sodium iodide (5.16 g, 34.4 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (70 ml) and concentrated under reduced pressure. The residue was diluted with 2M aqueous hydrochloric acid (70 ml) and extracted with dichloromethane (3×150 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (3:1, by volume) gradually changing to cyclohexane:ethyl acetate (1:1, by volume) to afford the title compound (12.3 g) as a red oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:24](=[O:25])[CH2:23][O:22][CH3:21])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N(C)C)c3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (54 mg, 177 μmol) and 2-methoxyacetyl chloride (25 mg, 230 μmol) in DCM-pyridine (0.5 mL each) was stirred at rt. More 2-methoxyacetyl chloride (25 mg, 230 μmol) was added after overnight, resulting in a solution. The reaction was complete after 1 h. The mixture was concentrated, and diluted with NaHCO3 (saturated, 5 mL). After agitating for 30 min, the mixture was filtered, and washed with H2O (3×3 mL) to give a green solid (55 mg, 82%). LCMS: calc'd for C17H17ClN4O2S:376.0. found: 377.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.86 (s, 6H) 3.32 (s, 3H) 4.23 (s, 2H) 7.76-7.88 (m, 3H) 8.36 (s, 1H) 8.43 (s, 1H) 12.39 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)[NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(c2ccncc2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NC(c2ccncc2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-B), the title compound was prepared as a solid having a melting point of 100° C. C25H22N4O3F2 (MW=464); mass spectroscopy: 464.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)=O.[H-].[Al+3].[H-].[H-].[H-].[OH-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>C(O)(C)C.O.C(OCC)(=O)C.CCOCC>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31].[CH3:1][NH:3][CH2:4][CH:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: O=CNCC1c2ccccc2C=Cc2ccccc21
Agent: O=C(O)/C=C\C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CNCC1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 26 h

Procedure:
5-Formamidomethyl-5H-dibenzo[a,d]cycloheptene (3.80 g., 0.015 mole), dissolved in 400 ml. of absolute ether is added gradually to a solution oflithium aluminum hydride (0.87 g., 0.023 mole) in 45 ml. of absolute ether at a rate such that gentle refluxing is maintained. The reaction mixture, containing a precipitate, is heated to refluxing with stirring for 26 hours. After cooling to room temperature, 10 ml. of ethyl acetate is addedto decompose the excess hydride. Water, 1 ml., 15% sodium hydroxide, 1 ml. and water, 3 ml. then are added to the vigorously stirred reaction mixture. After standing several days, the reaction mixture is filtered andthe solid washed several times by suspension in ether. The combined filtrates and ether washings are evaporated on a film evaporator under reduced pressure, the pale yellow oily residue is dissolved in dilute hydrochloric acid, the solution extracted with ether to remove non-basic material, then rendered alkaline and the product extracted with ether. After washing with water and drying over anhydrous sodium sulfate, the ether is evaporated on a film evaporator under reduced pressure. The yellow oily residue weighs 3.05 g. A 2.95 g. portion is dissolved in isopropyl alcohol and a solution of 1.60 g. (0.0138 mole) of maleic acid in 5 ml. of isopropyl alcohol is added. The hydrogen maleate salt of the product separates out in white crystals. It melts at 163°-164° C. (clears, 165° C.) after further recrystallization from isopropyl alcohol and drying in vacuo over phosphorus pentoxide.
Reaction SMILES: CC(C)(CNC(C[C@@H]1CC[C@]2(O[C:15]3([CH:21]4CC5CC(C4)CC3C5)[O:14][O:13]2)CC1)=O)N.[CH2:29]=[CH:30][C:31]([CH2:34][CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])([CH3:33])[OH:32]>>[O:32]1[CH2:21][CH2:15][O:14][O:13]1.[CH2:29]=[CH:30][C:31]([CH2:34][CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])([CH3:33])[OH:32]
Reactant: CC(C)(N)CNC(=O)C[C@H]1CC[C@@]2(CC1)OOC1(O2)C2CC3CC(C2)CC1C3
Agent: C=CC(C)(O)CCC=C(C)C
Product: C1COOO1

Procedure:
A culture of E.coli was harvested with sterile saline using swabs. The number of Colony Forming Units (CFUs) per ml in the suspension was determined by Standard Plate Count Method. A working suspension of E. coli with approximately 1.0×107CFUs/ 0.1 ml was then prepared. Four aliquots of 1 ml of test ointment containing 1.0% trioxolane or diperoxide derivative of linalool were removed and place in separate sterile screw-capped tubes. Each sample was inoculated with 0.1 ml of the working suspension of E. coli to yield a final concentration of approximately 1×106 CFUs/1 ml of the product. The samples were stored at 20°-25° C. for a total of 28 days. Samples were selected at 7 day intervals to determine the number of viable CFUs present. A control with uninoculated ointment was also stored with samples selected at the same intervals. At 7 days, and all subsequent sample selections, there were less than 10 CFUs present. No CFUs were present in any control sample.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:28]4[CH2:29][CH2:30][N:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: CC(C)N1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Yield: 93.9 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.23 g, 0.80 mmol) and 1-isopropylpiperazine (0.102 g, 0.80 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(4-isopropylpiperazin-1-yl)ethanone as a white solid (0.298 g, 93.7% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.C(OC([N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:24]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=23)[CH:26]=[N:25]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of 4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (15.70 g, 47.97 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14.04 g, 52.77 mmol), tetrakis(triphenylphosphine)palladium(0) (2.772 g, 2.398 mmol) and sodium carbonate (15.25 g, 143.9 mmol) in 1,4-dioxane (150 mL) and water (75 mL) was stirred at 110° C. for 1 hour. After being cooled to room temperature, the mixture was diluted with EtOAc, and washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatograpgy on silica gel eluting with 10-30% EtOAc/hexanes. The purified intermediate was dissolved in THF (21 mL), water (90 mL) and hydrogen chloride (75 mL, 240 mmol). The resulting suspension was stirred at room temperature for 2 hours. The mixture was adjusted to pH=9-10 with 6 N NaOH. Hexanes (150 mL) were added. The solids formed was filtered and washed with water (3×) to provide 12.9 g (85%) of 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine as a white solid. LC/MS found: 315.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:27](O)=[O:28])[C:7]2[NH:11][C:10]([NH:12][C:13]([C:15]3[N:16]=[CH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:14])=[N:9][C:8]=2[C:25]=1[F:26])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.S(O)(O)(=O)=O.[NH2:68][C:69]1[NH:70][CH:71]=[CH:72][N:73]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:27](=[O:28])[NH:68][C:69]2[NH:70][CH:71]=[CH:72][N:73]=2)[C:7]2[NH:11][C:10]([NH:12][C:13]([C:15]3[N:16]=[CH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:14])=[N:9][C:8]=2[C:25]=1[F:26])[CH3:2]
Reactant: Nc1ncc[nH]1
Reactant: CCOc1cc(C(=O)O)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOc1cc(C(=O)Nc2ncc[nH]2)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1F
Yield: 46.4 %

Procedure:
60 mg (0.15 mmol) of 6-ethoxy-7-fluoro-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (from Example 485) and 100 mg (0.25 mmol) of HBTU were dissolved in 1.0 mL of DMF and 0.2 mL of DIEA and treated with 50 mg (0.5 mmol) of 2-aminoimidazole sulfate as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 32 mg (46%) of Isoquinoline-3-carboxylic acid [5-ethoxy-4-fluoro-7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 460 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20](O)[CH:21]=[CH:22][C:23]=1[F:24].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][O:16][C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([CH3:17])[CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCCCN(Cc2ccccc2)C1
Reactant: Cc1cc(O)ccc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: ClCCl
Product: Cc1cc(OCC2CCCCN(Cc3ccccc3)C2)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-4 (500 mg, 2.280 mmol), 3-methyl-4-fluorophenol (288 mg, 2.280 mmol), and tiphenylphosphine-resin bound (1.060 g @ 2.15 mmol/g) in DCM (20 ml) was treated with DIAD (0.443 ml, 2.280 mmol). The mixture was stirred overnight at RT, filtered, and the filtrate was concentrated. The crude material was purified by gradient elution on silica gel (0 to 50% EtOAc in Hex) to yield 1-5 as a pale yellow oil. Data for 1-5: LRMS m/z (M+H): 328.2.