Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8](=O)[CH2:9][C:10]([N:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[NH2:22])[CH3:13])=[O:11])C>C(O)C>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][C:15]2[NH:22][C:8](=[O:7])[CH2:9][C:10](=[O:11])[N:12]([CH3:13])[C:14]=2[CH:19]=1
Reactant: CCOC(=O)CC(=O)N(C)c1cc(OC)ccc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)N(C)C(=O)CC(=O)N2
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
Sodium ethoxide (204 mg) was added to an ethanol solution (15 ml) of N-(2-amino-5-methoxyphenyl)-N-methylmalonamic acid ethyl ester (266 mg). The mixture was stirred at 65° C. for 2.5 hours. The reaction liquid was cooled to room temperature, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol=1:0→10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (176.3 mg) as a white powder.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][S:12][C:13](=[O:22])[C:14]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)=[O:15]>O>[CH3:11][S:12][C:13](=[O:22])[C:14]([C:16]1[N:17]=[C:18]([NH:21][CH:1]=[O:3])[S:19][CH:20]=1)=[O:15]
Reactant: CSC(=O)C(=O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: CSC(=O)C(=O)c1csc(NC=O)n1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A mixture of 40.8 g of acetic anhydride and 18.4 g of formic acid was stirred at 40° to 45° C. for 1 hour. To the resulting mixture was added 20.2 g of 2-(2-aminothiazol-4-yl)thioglyoxylic S-acid metyl ester, with water-cooling, after which the resulting mixture was stirred at 25° C. for 1 hour. Subsequently, 160 ml of water was added dropwise to the thus obtained reaction mixture with ice-cooling, after which the resulting mixture was stirred with water-cooling for 30 minutes, and the deposited crystals were collected by filtration. The crystals were washed successively with water and acetone and then dried to obtain 21.9 g (94.4% yield) of 2-(2-formylaminothiazol-4-yl)thioglyoxylic S-acid methyl ester having a melting point of above 230° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1[S:26](Cl)(=[O:28])=[O:27]>>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1[S:26]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=2)[N:6]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3cc(Cl)c(Cl)cc3Cl)n2)cc1

Procedure:
The title compound was prepared from N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]acetamide (63 mg) and 2,4,5-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white-yellow solid (5,0 mg) with purity >90%: MS (pos) m/z 476.3. 478.3.
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)#[CH:22].C(N(CC)CC)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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:22]#[C:21][C:23]2([OH:31])[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[CH:12][N:11]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc(-c2cccnc2)nc1Cc1ccccc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2cnc(-c3cccnc3)nc2Cc2ccccc2)CN2CCC1CC2
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A mixture of 110 mg of 4-benzyl-5-bromo-2-(3-pyridyl)pyrimidine, 59 mg of 3-ethynyl-3-quinuclidinol, 19 mg of tetrakis(triphenylphosphine)palladium(0), 10 mg of cuprous iodide, 0.14 ml of triethylamine and 1.5 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 100° C. for 2 hours in a nitrogen atmosphere. After cooling as it was, NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 2.5% methanol/ethyl acetate, to give 62 mg of the target compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][P:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:18][C:17]2[CH:16]=[CH:15][C:14]([P:11]([CH3:13])([CH3:10])=[O:12])=[CH:20][CH:19]=2)[CH:7]=1
Reactant: CP(C)(=O)c1ccc(N)cc1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(Nc2ccc(P(C)(C)=O)cc2)n1

Procedure:
To a solution of 4,6-dichloro-2-methylpyrimidine (1.31 mmol) in 1 mL of DMF is added 4-(dimethylphosphoryl) aniline (0.221 g, 1.31 mmol) and potassium carbonate (0.217 g, 1.57 mmol). The mixture is heated at 110° C. until formation of the desired compound. The reaction mixture is basified with saturated sodium bicarbonate solution. The suspension is filtered and washed with ethyl acetate.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].C(N(CC)CC)C.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCCC(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](=[O:5])[S:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCCC(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(=O)Sc1ccccc1
Yield: 90.3 %

Procedure:
3,3-Dimethylbutanoyl chloride (695 μL, 5.0 mmol) in 15 mL toluene was added to a solution of triethylamine (0.70 mL, 5.0 mmol) and thiophenol (0.51 mL, 5.0 mmol) in 10 mL toluene. Reaction monitoring was accomplished by TLC: iso-hexane/ethyl acetate 25:1, Rf=0.63. Workup yielded 941 mg (90%) S-phenyl 3,3-dimethylbutanethioate 5 as pale yellow oil.
Reaction SMILES: [C:1]12[C:18](=[O:19])[O:17][C:15](=[O:16])[C:13]3[C:14]1=[C:5]([C:6]1[C:11]([CH:12]=3)=[CH:10][CH:9]=[CH:8][N:7]=1)[CH:4]=[CH:3][CH:2]=2.[N+:20]([O-])([O-:22])=[O:21].[Na+].O>S(=O)(=O)(O)O>[N+:20]([C:3]1[CH:2]=[C:1]2[C:18](=[O:19])[O:17][C:15](=[O:16])[C:13]3=[CH:12][C:11]4[C:6]([C:5]([CH:4]=1)=[C:14]23)=[N:7][CH:8]=[CH:9][CH:10]=4)([O-:22])=[O:21]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1OC(=O)c2cc3cccnc3c3cccc1c23
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1OC(=O)c2cc3cccnc3c3cc([N+](=O)[O-])cc1c23
Temperature: 65 °C
Yield: 182.5 %

Procedure:
5-Azaphenanthrene-1,10-dicarboxylic anhydride (17.0 g, 68.2 mmol) was dissolved in concentrated sulfuric acid (70 mL) and sodium nitrate (2.90 g, 34.1 mmol) was added to the warm solution. This mixture was heated to 65° C. and three additional aliquots of sodium nitrate (2.90 g, 34.1 mmol) were added after 5, 22, and 30 h. Each aliquot caused about a 20° C. temperature rise, with the temperature stabilizing again at about 65° C. The solution was heated for an additional 14 h after the last addition. The clear orange solution was cooled to room temperature and poured into water (500 mL), washing the residue from the reaction flask with water (5×40 mL). The aqueous suspension was allowed to cool to room temperature. The suspended solid was collected on a frit, washed with water (2×50 mL), and dried. This cream colored solid was heated at reflux in acetic acid (100 mL) containing acetic anhydride (10 mL) for 2 h and cooled to room temperature. The solid was collected on a frit, washed with acetic acid (25 mL) and ether (2×25 mL), and dried to give 18.31 g (91%) of the nitro compound as a cream colored solid: mp 268°-269° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.05 (dd, 1H, J=8.0, 4.4 Hz), 8.97 (dd, 1H, J=8.0, 1.5 Hz), 9.11 (d, 1H, J=2.2 Hz), 9.33-9.40 (m, 2H), 10.16 (d, 1H, J=2.2 Hz); MS (CI, CH4) m/e (%) 295 (M+H+, 100), 265 (6), 250 (5).
Reaction SMILES: I.N[C@@H:3]1C(=O)N2[C@@H]1SCC(/C=C/CN1CCC(O)CC1)=C2C(O)=O.[CH:25]1[C:34]2[C:29](=CC=C[CH:33]=2)[CH:28]=[CH:27][C:26]=1[S:35][CH2:36][C:37]([OH:39])=[O:38].S1C2C=CC=CC=2N=C1SCC(O)=O>>[CH3:3][C:28]1[CH:27]=[C:26]([S:35][CH2:36][C:37]([OH:39])=[O:38])[CH:25]=[C:34]([CH3:33])[CH:29]=1
Reactant: O=C(O)CSc1ccc2ccccc2c1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C/CN3CCC(O)CC3)CS[C@H]12
Agent: I
Agent: O=C(O)CSc1nc2ccccc2s1
Product: Cc1cc(C)cc(SCC(=O)O)c1

Procedure:
By operating in an analogous manner to the procedure described in Example 1, (E)-(6R,7R)-7-amino-3-[3-(4-hydroxy-piperidin-1-yl)-propenyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydroiodide was acylated with naphthalen-2-ylsulfanyl-acetic acid, with benzothiazol-2-ylsulfanyl-acetic acid, and with (3,5-dimethyl-phenylsulfanyl)-acetic acid, respectively, to give the following compounds as pale-yellow solids:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([OH:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([O:16][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(Oc1ccc([N+](=O)[O-])cc1)C2

Procedure:
3-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was reacted with 1-fluoro-4-nitrobenzene by method D. The product with the molecular weight of 348.40 (C18H24N2O5) was obtained in this way; MS (ESI): 349 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:17][C:18]([Cl:21])=[CH:19][N:20]=1)(=[O:14])=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[S:12]([NH:15][C:16]1[S:17][C:18]([Cl:21])=[CH:19][N:20]=1)(=[O:13])=[O:14])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ncc(Cl)s2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.8 %

Procedure:
Methyl 3-chloro-4-{[(2,4-dimethoxybenzyl)(5-chloro-1,3-thiazol-2-yl)amino]sulfonyl}benzoate (Preparation 34, 3.2 g, 6.2 mmol, 1 eq) was suspended in 2.5M sodium hydroxide (7.4 ml, 18.6 mmol, 3 eq) and MeOH (40 ml) and the reaction mixture heated at 50° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in 4M HCl in dioxane at 0° C. and the reaction mixture stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration to yield the title compound as a white solid (3.2 g, 9.1 mmol, >100%).
Reaction SMILES: [F:1][C:2]1[CH:40]=[CH:39][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[CH:24]=[C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:22]=[CH:21][C:20]=3[NH:33][C:34](=O)[O:35]CC)=[O:18])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+]>O>[F:1][C:2]1[CH:40]=[CH:39][C:5]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]3[C:17](=[O:18])[C:19]4[C:20](=[CH:21][CH:22]=[C:23]([O:25][CH2:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:24]=4)[NH:33][C:34]3=[O:35])[CH2:12][CH2:13]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Nc1ccc(OCc2ccccc2)cc1C(=O)NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccc(OCc4ccccc4)cc3c2=O)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of 9.3 parts of ethyl [2-[[[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]amino]carbonyl]-4-(phenylmethoxy)phenyl]carbamate and 100 parts of a potassium hydroxide solution 10% in water was stirred in an oil-bath for 8 hours at 100° C. After cooling to room temperature, the precipitated product was filtered off, dried and boiled in 16 parts of methanol. Upon cooling to room temperature, the precipitated product was filtered off and dried in vacuo at 50° C., yielding 7.05 parts (83%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-6-(phenylmethoxy)-2,4-(1H,3H)-quinazolinedione (4).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16]([OH:18])=[O:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccccc2n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2ccccc2n1CC(=O)O

Procedure:
1-(tert-Butyloxycarbonyl-methyl)-1H-indole-2-carboxylic acid ethyl ester was treated with trifluoroacetic acid in dichloromethane to give 1-(carboxy-methyl)-1H-indole-2-carboxylic ethyl ester. Reaction of the latter intermediate with oxalyl chloride in dichloromethane gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]#[N:12].[C:13](Cl)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([NH:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]#[N:12])(=[O:15])[CH3:14]
Reactant: N#Cc1oc2ccccc2c1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1c(C#N)oc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
A solution of 3.86 g (0.024 mole) of 3-amino-2-benzofurancarbonitrile in 50 ml of pyridine is cooled in ice and treated over 15 minutes with 2.0 ml (2.21 g; 0.028 mole) of acetyl chloride. The mixture is stirred in ice an additional two hours and added to 250 g of ice/water. The precipitated crude product is filtered, washed with water, and recrystallized from aqueous methanol to yield 2.8 g (57% yield) of 3-(acetylamino)-2-benzofurancarbonitrile. A sample recrystallized a second time as above is analytically pure, mp 187°-189° C.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH:23][C@@H:24]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[CH:14]=[N:13]2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[ClH:36].C(OC(C)C)(C)C>C(Cl)Cl.C(O)(C)C>[ClH:36].[ClH:36].[N:1]1[C:2]([CH2:10][CH2:11][N:12]2[N:13]=[CH:14][C:15]3[C:20](=[C:19]([NH:23][C@@H:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[CH:18]=[CH:17][CH:16]=3)[C:21]2=[O:22])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2cccc3cnn(CCc4cn5ccccc5n4)c(=O)c23)C1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: O=c1c2c(N[C@@H]3CCNC3)cccc2cnn1CCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of (R)-tert-butyl 3-(3-(2-(imidazo[1,2-a]pyridin-2-yl)ethyl)-4-oxo-3,4-dihydrophthalazin-5-ylamino)pyrrolidine-1-carboxylate from Example 218 (52 mg, 0.110 mmol) in 20 mL of DCM was mixed with 1 mL of HCl containing isopropanol and the reaction mixture was stirred under nitrogen for 12 h at room temperature. The reaction mixture was mixed with diisopropyl ether and the supernatant was discharged. Then, the residue was dissolved in isopropanol and diisopropyl ether was added. The supernatant was discharged. The precipitate was dried to give 24 mg of a yellow salt as solid foam. LC-MS: m/e=357.2 (M+H)+
Reaction SMILES: COC([C:5]1[CH:10]([CH3:11])[CH2:9][C:8](=[O:12])[CH2:7][C:6]=1[OH:13])=O.OS(O)(=O)=O>[OH-].[Na+]>[CH3:11][CH:10]1[CH2:9][C:8](=[O:12])[CH2:7][C:6](=[O:13])[CH2:5]1
Reactant: COC(=O)C1=C(O)CC(=O)CC1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(=O)CC(=O)C1
Temperature: 25 °C
Yield: 48 %

Procedure:
2-Hydroxy-6-methyl-4-oxo-cyclohex-1-enecarboxylic acid methyl ester (600 g, 3.30 mol) is dissolved in NaOH solution (5 M, 3 L) and the solution is refluxed for 2 h. After cooling to RT, the mixture is acidified with H2SO4 (5 M) to pH 7 and extracted with EtOAc (4×1 L). The organic phase is washed with brine and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is recrystallized from hexane to give 5-methyl-cyclohexane-1,3-dione (200 g, 49% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36](B(O)O)[CH:37]=1>COCCOC>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([O:41][CH3:42])=[C:34]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:33]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(Cl)cc1-c1ccccc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 37.5 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 5-chloro-2-methoxy-phenylboronic acid (48 mg, 0.26 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (22 mg, 38%). LC-MS m/e 451.31 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=[C:11](I)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1>C1COCC1.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>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=[C:11]([C:17]3[CH:16]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(I)cc(Oc2cccnc2)c1)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2cccnc2)cc(-c2ccccn2)c1)c1ccc(F)cc1
Yield: 19 %

Procedure:
A mixture of 1 eq. (175 mg, 0.402 mmol) of 4-fluoro-N-[3-iodo-5-(pyridin-3-yloxy)-phenyl]-benzamide 1.15 eq. (170 mg, 0.463 mmol) of 2-tributyltinpyridine, and 0.04 eq. (11 mg, 0.10 mmol) of bis-(triphenylphosphine)dichloropalladium in 2 mL of THF was irradiated for in a microwave for 10 minutes an 170° C. The reaction mixture was filtered and concentrated in vacuo. Purification by chromatography over silica with 50% EtOAC/Hexane to 75% EtOAc/Hexane as the gradient eluant afforded 30 mg of a solid (4-fluoro-N-[3-pyridin-2-yl-5-(pyridin-3-yloxy)-phenyl]-benzamide, (19% yield). Mpt 160-162° C. MS (M+1) 386.1.
Reaction SMILES: [F:1][C:2]([F:18])([S:14](F)(=[O:16])=[O:15])[C:3]([F:13])([F:12])[O:4][C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7].C[Si](C)(C)[O-:21].[K+:24].O1CCCC1>OCC(CO)O>[F:1][C:2]([F:18])([S:14]([O-:21])(=[O:16])=[O:15])[C:3]([F:13])([F:12])[O:4][C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7].[K+:24]
Reactant: C[Si](C)(C)[O-]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Agent: [K+]
Solvent: OCC(O)CO
Solvent: C1CCOC1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Yield: 65 %

Procedure:
The procedure of Example 1 was followed using perfluoro-3-oxapentanesulfonyl fluoride (7.95 g, 25 mmol), potassium trimethylsilanolate (3.2 g, 25 mmol) and dry tetrahydrofuran (100 mL) while heating at reflux for 1.5 h. Potassium perfluoro-3-oxapentanesulfonate (3.79 g initially and 1.74 g by concentrating the filtrate under vacuum; total 5.53 g, 65% yield) was isolated as a white solid: 19F NMR (fluorotrichloromethane) δ -79.4 (m, CF2, 2F), -83.2 (s, CF3, 3F), -84.9 (m, CF2, 2F), -115.0 ppm (m, CF2, 2F); Positive ion Fast Atom Bombardment MS (Glycerol matrix, Cs⊕ ion bombardment) m/e 393, 747, 1101, 1455, 1809 for M+K⊕ to M5 +K⊕.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:35]([NH:37]O)=[NH:36])=[CH:31][N:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:27][N:37]=[C:35]([C:32]5[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=5)[N:36]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: N=C(NO)c1cnc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Product: Nc1ncc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(Cl)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) (205 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (150 mg, 57%). MS (EI) 526.1 [(M)+]; mp 279° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=3)[C:10]2=[S:29])=[CH:5][C:4]=1[F:30].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(O)(C(F)(F)F)=O.C(#N)C>C1(C)C=CC=CC=1>[F:30][C:4]1[CH:5]=[C:6]([N:9]2[C:13]([CH3:14])([CH3:15])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:27])([F:28])[F:26])[CH:18]=3)[C:10]2=[S:29])[CH:7]=[CH:8][C:3]=1[CH2:2][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CCl)c(F)c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CN2CCCC2)c(F)c1
Reaction time: 0.17 h

Procedure:
Compound 6 was prepared according to General Method 2. A solution of 4-(3-(4-(chloromethyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.21 mmol) and pyrrolidine (78 mg, 1.05 mmol) in toluene (10 mL) was refluxed for 12 h. The solvent was removed and residue was purified by silica gel chromatography (eluant: 60% ethyl acetate in hexane) to obtain 13 mg of 4-(3-(3-fluoro-4-((pyrrolidin-1-yl)methyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-trifluoromethyl)benzonitrile, HPLC, Column: SUNFIRE C18, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 7.491 min, M+1, 491.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.Br[CH:13]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]1=[O:15]>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:13]2[CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]2=[O:15])=[CH:7][CH:6]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C1NCCCCC1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NCCCCC1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
54 g (1.0 mol) of sodium methylate and 144.6 g (1.0 mol) of 4-chlorothiophenol are initially introduced into 500 mL of methanol, and a methanolic solution of 192 g (1.0 mol) of α-bromocaprolactam is added dropwise at room temperature. After the exothermic reaction has ceased, the mixture is stirred for a further 3 hours at room temperature, the precipitated sodium bromide is then filtered off under suction and the mother liquor is evaporated down in vacuo. The precipitated crystals are filtered off under suction.