Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH2:9]1[CH2:14][CH2:13][CH:12]([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][CH2:10]1>C(OCC)(=O)C>[CH:18]1([NH:17][C:16]([NH:15][CH:12]2[CH2:11][CH2:10][CH2:9][CH2:14][CH2:13]2)=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The copolymer was fed into a round-bottomed flask and dissolved in a half amount (25 to 30 mL) of ethyl acetate. Next, N-hydroxysuccinimide and DCC were added thereto followed by dissolution in the residual ethylacetate. The obtained mixture was immersed in ice-water at 4° C. and stirred with a stirrer for 2 hours. Subsequently, it was introduced into a thermostat at 25° C. and stirred therein overnight. The solution was filtered and thus dicyclohexyl urea formed as a by product was removed therefrom. After concentrating under reduced pressure, the residue was purified with diethyl ether. The product thus obtained was taken up by filtration and dried under reduced pressure. The succinylated copolymer thus obtained was stored in a freezer.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:18]([NH:20][CH2:21][CH2:22][O:23][CH3:24])[CH3:19]>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][O:23][CH3:24])=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCNCCOC
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
300 mg (1.12 mol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N-ethyl-2-methoxyethanamine to give after working up and purification 317 mg (80%) of the title compound.
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:23])[C:9]3[C:10]([CH:21]=[CH:22][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[N:11][CH:12]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:14]=3.[CH3:24][S-:25].[Na+]>[Cu]Br>[CH3:24][S:25][C:2]1[C:7]2[C:8](=[O:23])[C:9]3[C:10]([CH:21]=[CH:22][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[N:11][CH:12]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:14]=3
Reactant: O=c1c2cc(-c3ccccc3)cnc2ccc2cccc(Br)c12
Reactant: C[S-]
Agent: [Cu]Br
Agent: [Na+]
Product: CSc1cccc2ccc3ncc(-c4ccccc4)cc3c(=O)c12
Temperature: 140 °C
Reaction time: 72 h

Procedure:
6-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (15 mg, 0.04 mmol), sodium thiomethoxide (15 mg, 0.21 mmol) and copper (I) bromide (23 mg, 0.10 mmol) were combined in a dry flask. The flask was purged with argon and 0.5 mL of N,N-dimethylformamide were added. The solution was stirred and heated to 140° C. After 72 h, the reaction mixture was cooled to room temperature, diluted with EtOAc and washed with 5% HCl, brine and water. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC (30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 9.14 (d, 1H), 8.58 (d, 1M), 7.78 (d, 2H), 7.65 (m, 2H), 7.54 (t, 2H), 7.47 (m, 3H), 7.27 (d, 1H), 2.49 (s, 3H). LRMS (APCI) calculated for C21H16NOS [M+H]+, 330.0; found 330.1.
Reaction SMILES: CS(O[C@H:6]1[C:25]2[C@:20]([CH3:27])([CH:21]=[CH:22][C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:8]([C@H:9]3[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@:12]([O:29][C:30](=[O:32])[CH3:31])([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)[C@H:7]1OS(C)(=O)=O)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[N:38]([C:6]1[C:25]2[C@:20]([CH3:27])([CH:21]=[CH:22][C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:8]([C@H:9]3[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@:12]([O:29][C:30](=[O:32])[CH3:31])([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(N=[N+]=[N-])C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
In a manner similar to that described in Example 1D, treat 6β,7β-dimethanesulfonyloxy-17α-acetoxy-1,4-pregnadiene-3,20-dione with sodium azide in dimethylformamide. Isolate and purify the resultant product in a manner similar to that described in Example 1D to obtain 6-azido-17α-acetoxy-1,4,6-pregnatriene-3,20-dione.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11]C(C)C)[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=1[OH:19])([CH3:4])([CH3:3])[CH3:2].[CH:20]1(C2C=C(C)C=C(C3CCCC3)C=2O)[CH2:24]CC[CH2:21]1>>[C:15]([C:7]1[CH:8]=[C:9]([CH2:11][CH2:21][CH2:20][CH3:24])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:6]=1[OH:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1cc(C2CCCC2)c(O)c(C2CCCC2)c1
Reactant: CC(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CCCCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
2,6-di-tertbutyl-4-isobutylphenol; 2,6-dicyclopentyl-4-methylphenol;
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:23])[N:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[S:6][CH:7]=1.[C:24]([NH:31][CH2:32][C:33](O)=[O:34])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[C:27]([O:26][C:24](=[O:25])[NH:31][CH2:32][C:33](=[O:34])[NH:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:23])[S:6][CH:7]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCc1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Product: CC(C)(C)OC(=O)NCC(=O)NCc1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Yield: 29 %

Procedure:
Prepared in 29% yield (40 mg) as described in general procedure (K) from 3-(4-aminomethylthiazol-2-yl)-1,1-dicyclohexyl-urea (96 mg, 0.28 mmol) and Boc-glycine (60 mg, 0.30 mmol).
Reaction SMILES: [CH3:1][NH2:2].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(OCC)(=O)C>CO>[CH3:1][NH:2][C:5](=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CN
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Monomethylamine (22.43 kg, 722.15 mol, 6 eq.) was added over a 7-hour period to a solution of methyl-4-hydroxyphenylacetate (20.0 kg, 120.35 mol, 1.0 eq.) in methanol (31.7 gal) and stirred overnight at room temperature. Methanol was then displaced under vacuum with ethyl acetate. The resulting slurry (ca. 20 gal) was stirred at +10° C. for 1 hour, then filtered and dried under vacuum at 45° C. to yield of the title compound(18.68 kg, 94% of theory). mp 124-125° C. NMR (300 MHz, d6-DMSO): δ=9.26 (s, 1H), 8.00-7.65 (br s, 1H), 7.21-6.90 (m, 2H), 6.86-6.55 (m, 2H), 3.26 (s, 2H), 2.75-2.45 (m, 3H).
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18]1>C1COCC1>[N:1]1([C:5]2[N:6]=[CH:7][C:8]([C:23]3([OH:26])[CH2:24][CH2:25][C:20]4([O:27][CH2:17][CH2:18][O:19]4)[CH2:21][CH2:22]3)=[CH:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Brc1ccc(N2CCC2)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(N3CCC3)nc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Yield: 42.1 %

Procedure:
2-azetidin-1-yl-5-bromopyridine (64 mg, 0.30 mmol) was dissolved in dry THF (1.5 mL) and cooled to −78° C., followed by the addition of n-BuLi (0.196 mL, 1.6 M in hexanes). Thirty minutes later, a solution of 1,4-cyclohexanedione mono-ethylene ketal (44.6 mg, 0.286 mmol) in dry THF (0.2 mL) was added dropwise at −78° C. with constant stirring. One hour later, the reaction was quenched with NH4Cl (aq) and slowly warmed to rt. The aqueous layer was extracted with CH2Cl2×3, dried, filtered and concentrated to give a crude, which was purified by flash column chromatography (100% EtOAc) to provide 35 mg (43%) of white solid product. MS (M+H+)=291.1.
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.Cl[O:13][N:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.C(N(CC)CC)C>CCOCC>[F:23][C:22]([F:24])([F:25])[C:18]1[CH:17]=[C:16]([C:15]2[CH2:1][C:2]3([C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4](=[O:5])[O:3]3)[O:13][N:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1cccc(C=NOCl)c1
Reactant: C=C1OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1OC2(CC(c3cccc(C(F)(F)F)c3)=NO2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a solution of 109.5 g (0.75 mole) of 3-methylenephthalide and 285 g (1.27 mole) of m-trifluoromethylbenzaldehyde chlorooxime in 3.5 liters of ether was added 128.3 g (1.27 mole) of triethylamine in 250 ml. of ether at 0° C. during 3 hours. The solution was then stirred at room temperature overnight. An infrared spectrum indicated that the reaction was complete. The solid was filtered off. The ethereal solution was washed once with 10% HCl, twice with sodium chloride saturated water, dried over CaSO4 and concentrated under vacuum. Only 19.5 g of impure product was obtained. The solid material which was filtrated from the original reaction solution was stirred with 4 liters of tetrahydrofuran for 4 hours and filtered through a Buchner funnel. The tetrahydrofuran solution obtained was washed once with 10% HCl solution and twice with water saturated with sodium chloride. After being dried and concentrated, the tetrahydrofuran solution gave 140.6 g of pure product, m.p. 170° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])=[CH:11][CH:12]=1)[CH3:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]1[CH:8]=[N:9][C:10]([N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(N(C)C(=O)OC(C)(C)C)nc1
Reactant: NCc1ccccc1
Product: CCOC(=O)CC(NCc1ccccc1)c1ccc(N(C)C(=O)OC(C)(C)C)nc1
Temperature: 95 °C

Procedure:
A mixture of 11-4 (1.7 g, 5.6 mmol) and benzylamine (8 mL, 73.2 mmol) was heated in a sealed-tube at 95° C. for 24 hr. The crude reaction mixture was purified using silica gel flash chromatography (EtOAc/hexanes 1:3 to 1:1) to afford the desired product 11-5 as an oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].CN(C)C=O.Br[CH2:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH2:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nn(CC(=O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (0.7 g), potassium tert-butoxide (1.0 M tetrahydrofuran solution, 1.75 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-bromo-3,3-dimethylbutan-2-one (0.22 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless powder (0.58 g, 92%).
Reaction SMILES: [Na].[Cl:2][C:3]1[N:8]=[C:7](Cl)[C:6]([CH2:10][C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH:5][N:4]=1.[CH:18]([OH:21])([CH3:20])[CH3:19]>>[Cl:2][C:3]1[N:8]=[C:7]([O:21][CH:18]([CH3:20])[CH3:19])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH:5][N:4]=1
Reactant: CC(C)O
Reactant: Cc1ccc(Cc2cnc(Cl)nc2Cl)cn1
Agent: [Na]
Product: Cc1ccc(Cc2cnc(Cl)nc2OC(C)C)cn1
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of 1.38 g (0.06 g-atom) of sodium metal in 25 ml of isopropanol was heated to reflux until complete dissolution of the metal. The alkoxide solution was cooled to -10° and treated dropwise with a solution of 15.0 g (60 mmol) of 2,4-dichloro-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine prepared as in Example 1 in 60 ml of isopropanol. The resulting mixture was allowed to warm to room temperature over 18 hours and was then concentrated. The resulting oil was dissolved in ethyl acetate, filtered, washed with water, dried over magnesium sulfate, filtered, concentrated and dried under vacuum to give 14.5 g (0.052 mol, 87%) of 2-chloro-4-isopropoxy-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine. Recrystallization from ethyl acetate and petroleum ether gave yellow crystals: m.p. 38°-42°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][NH:21][CH2:22][CH3:23])[CH:8]=[C:9]([Cl:11])[CH:10]=1.[CH2:25]([N:32]=[C:33]=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][N:21]([CH2:22][CH3:23])[C:33]([NH:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CCNCc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1
Reactant: O=C=NCc1ccccc1
Product: CCN(Cc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (5-chloro-2′-ethylaminomethyl-5′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and benzyl isocyanate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[S:6].[N+:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[C-:13].[OH-].[K+]>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[S:6][CH:13]=[N:12][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: COC(=S)c1cccc(I)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ncsc1-c1cccc(I)c1
Yield: 75.4 %

Procedure:
Analogously to the method described in Synthesis 10, (1976), 681-682, 47 g (169 mmol) of O-methyl 3-iodothiobenzoate were reacted with ethyl isocyanoacetate in the presence of 1-5% powdered potassium hydroxide in ethanol. Recrystallization from ether yielded 45.8 g (75.4%) of ethyl 5-(3-iodophenyl)-4-thiazolecarboxylate as ochre crystals, melting point 77°-78°.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.[CH3:9][C:10]1([CH3:19])[O:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11]1>O>[CH3:9][C:10]1([CH3:19])[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:13]=2[O:14]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Oc2ccccc2O1
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2O1
Reaction time: 0.25 h

Procedure:
A solution of 70% (conc.) nitric acid (20 ml) and glacial acetic acid (10 ml) cooled at 12° C. was treated by drops with 5 g (33.3 mmole) of the compound of Example 3A at a rate to maintain the temperature at 15°-20° C. Stirring was continued for 15 minutes after addition, then the brown slurry was diluted to 100 ml with water and filtered. The solid was washed with water, taken up in CH2Cl2, dried (Na2SO4) and evaporated to 5.40 g (83%) of pure yellow mononitro title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:14].[OH-].[Na+].[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl>O>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([S:19][C:18]([Cl:22])([Cl:21])[Cl:17])[C:3]1=[O:14]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]n(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)n(SC(Cl)(Cl)Cl)n(-c2ccccc2)c1=O
Yield: 99 %

Procedure:
To a solution of 38.2g (0.2 mole) 4-methyl-1-phenyl urazole in 200 ml water was added a solution of 8g (0.2 mole) sodium hydroxide in 20 ml water. A mixture of 37.2g (0.2 mole) trichloromethylsulfenyl chloride and 3g of an emulsifier solution (as in example 1) in 25 ml water was then added dropwise to the above basic solution while keeping the reaction mixture at 0° C. The reactants were mixed so that the reaction mixture was kept at a pH greater than 7. The precipitate that formed was filtered and the filter cake washed with water. After drying and recrystallizing from benzene there was obtained 67g (99% 4-methyl-1-phenyl-2-(trichloromethylthio)urazole having a melting point of 214° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=1.Cl.O1CCCC1>O>[F:14][C:12]([F:13])([F:15])[CH:11]([C:8]1[S:7][C:6]([CH:2]=[O:1])=[N:10][CH:9]=1)[OH:16]
Reactant: OC(c1cnc(C2OCCO2)s1)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ncc(C(O)C(F)(F)F)s1
Yield: 79.8 %

Procedure:
A mixture of 1-[2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]-2,2,2-trifluoroethanol (2.56 g), 1M hydrochloric acid (10 mL) and tetrahydrofuran (10 mL) was stirred with heating under reflux for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (1.69 g, yield 80%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). melting point 64-66° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:34][C:33](=[O:35])[N:32]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]4[N:47]=[CH:46][N:45]=[C:44]([C:48](O)=[O:49])[CH:43]=4)[CH2:38][CH2:37]3)[CH2:31][CH2:30][C:29]=2[CH:51]=1.Cl.[CH3:53][C:54]1([CH3:67])[CH2:59][NH:58][CH2:57][C:56]2[C:60]([C:63]([F:66])([F:65])[F:64])=[N:61][NH:62][C:55]1=2>CN(C=O)C>[CH3:53][C:54]1([CH3:67])[CH2:59][N:58]([C:48]([C:44]2[N:45]=[CH:46][N:47]=[C:42]([N:39]3[CH2:38][CH2:37][CH:36]([N:32]4[CH2:31][CH2:30][C:29]5[CH:51]=[C:25]([O:24][CH3:23])[CH:26]=[CH:27][C:28]=5[NH:34][C:33]4=[O:35])[CH2:41][CH2:40]3)[CH:43]=2)=[O:49])[CH2:57][C:56]2[C:60]([C:63]([F:66])([F:64])[F:65])=[N:61][NH:62][C:55]1=2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: CC1(C)CNCc2c(C(F)(F)F)n[nH]c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5c(C(F)(F)F)n[nH]c5C(C)(C)C4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.11 g (0.28 mmol) TBTU were added to 0.10 g (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 90 mg (0.32 mmol) 7,7-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine hydrochloride and 0.12 mL TEA in 1.0 mL DMF and the mixture was stirred for 4 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[CH:36]1([NH:39][C:40]2[CH:45]=[N:44][CH:43]=[C:42]([Sn](C)(C)C)[N:41]=2)[CH2:38][CH2:37]1>CN(C=O)C.C(Cl)Cl.[Cu]I.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>[CH:36]1([NH:39][C:40]2[N:41]=[C:42]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([C:11]5[S:15][C:14]([NH:16][CH2:17][C:18]6[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=6)=[N:13][N:12]=5)[CH:9]=4)[N:4]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:3]=3)[CH:43]=[N:44][CH:45]=2)[CH2:38][CH2:37]1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Reactant: C[Sn](C)(C)c1cncc(NC2CC2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(NC5CC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Temperature: 100 °C
Yield: 23.6 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (543 mg, 0.881 mmol) and N-cyclopropyl-6-(trimethylstannyl)pyrazin-2-amine (350 mg, 1.175 mmol) in DMF (3 mL) followed by copper(i) iodide (223 mg, 1.175 mmol) and Pd(PPh3)4 (67.9 mg, 0.059 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 1 h, then diluted with DCM and washed with H2O. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 20-60% EtOAc in Hex) to give 5-(3-(6-(cyclopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (130 mg, 0.208 mmol, 17.74% for two steps). MS (ESI, pos. ion) m/z: 624 (M+1).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([S:13]([CH2:16]Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1.C(O)(=O)C>O1CCCC1>[CH3:18][O:19][C:20]1[N:21]=[C:22]([CH2:16][S:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:15])=[O:14])[C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COc1ccc([N+](=O)[O-])cn1
Reactant: O=S(=O)(CCl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2ccccc2)n1
Yield: 80 %

Procedure:
A 1M KOt-Bu solution in tetrahydrofuran (50 mL, 50 mmol) is cooled to −40° C., treated portion-wise with a solution of chloromethyl phenyl sulfone (4.39 g, 23.0 mmol) and then with a solution of 2-methoxy-5-nitropyridine (3.55 g, 23.0 mmol) in tetrahydrofuran, stirred for 45 min at −40° C., treated with glacial acetic acid (3.0 g, 50 mmol) and filtered. The filtercake is air-dried to give the title compound as a tan solid, 5.70 g (80% yield), mp 147–149° C., identified by mass spectral and HNMR analyses.
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[O:9][CH2:10][C:11]([NH:13][C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25]CC2C=CC=CC=2)[N:18]=1)=[O:12].Br.C(O)(=O)C>C(Cl)(Cl)Cl>[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][O:9][C:2]2[C:1]([CH3:33])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=2[CH3:8])[NH:15][CH:16]=1
Reactant: Cc1cc(C)c(OCC(=O)Nc2nc(-c3ccccc3OCc3ccccc3)c[nH]2)c(C)c1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(C)c(OCC(=O)Nc2nc(-c3ccccc3O)c[nH]2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To 2-(mesityloxy)-N-[4-(2-benzyloxyphenyl)-1H-imidazol-2-yl]acetamide (Compound 1) (530 mg; 1.2 mmol) obtained in Example 1, 25% hydrobromic acid/acetic acid solution (8.0 mL) was added, and the mixture was stirred for 1 hour at 60° C. To the reaction solution, chloroform (100 mL) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure. The resulting crystals were dispersed in diethyl ether, collected by filtration and dried to give 180 mg of the title compound (yield 43%) expressed by the following formula (Ex. 2).