Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH2:23]Cl)=[CH:20][C:14]=2[CH:13]=1)=[O:11].O>CN(C)C=O>[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH2:23][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)=[CH:20][C:14]=2[CH:13]=1)=[O:11]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1cc2cc(OCCCl)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OCCn3ccnc3)ccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
Sodium hydride (0.22 g. of 50% dispersion in mineral oil) was added portionwise with stirring to a solution of imidazole (0.306 g.) in dry N,N-dimethylformamide (10 ml.) and the mixture was stirred at room temperature for 30 minutes and then warmed for a few minutes. 5-(2-Chloroethoxy)benzo[b]thiophene-2-carboxylic acid methyl ester (1.22 g.) was then added and the mixture was heated on a steam bath for 5 hours, and then cooled and poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform gave first mineral oil and some impurity followed by pure product. The product containing fractions were evaporated to give a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 5-[2-(1-imidazolyl)ethoxy]benzo[b]thiophene-2-carboxylic acid methyl ester (0.45 g.), m.p. 127°-129° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].Br[CH2:12][Si:13]1(C2C=CC=CC=2)[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[CH2:15][CH2:14]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][Si@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[CH2:17][CH2:18]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: C=CCCCC1CC[Si](CBr)(c2ccccc2)CC1
Reactant: CCOc1ccc(O)cc1
Product: C=CCCC[C@H]1CC[Si@H](COc2ccc(OCC)cc2)CC1

Procedure:
The general procedure of Example 9 was repeated using 4-ethoxyphenol and 4-bromomethyl1 -(4-pentenyl)-4-phenyl-4-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=O.[OH-].[Na+].[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14]>O>[CH2:11]([N:15]1[C:3](=[O:5])[CH:2]2[CH2:6][CH2:7][CH2:8][N:1]2[C:16]1=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)C1CCCN1
Reactant: CCCCN=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN1C(=O)C2CCCN2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
DL-Proline (2.5 g 0.0217 mole) was dissolved in water (20 ml) containing 2 N NaOH (10.9 ml, 0.0219 equiv) cooled to 0° C. and n-butyl isocyanate (3.27 g 0.33 mole) added dropwise to the stirred solution during 2 hours. The mixture was left at room-temperature overnight, filtered and washed with ether. The aqueous solution was acidified with concentrated hydrochloric acid (30 ml) and heated on the steam-bath for 30 minutes, cooled and continuously extracted with ether for 2 hours. Removal of the solvent gave a clear oil which was distilled under reduced pressure in a Kugelrohr apparatus to yield the product as a colourless oil, b.p. 90° C. at 0.02 mm. Yield 3.5 g=83%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C([O-])([O-])=O.[Na+].[Na+].O1[CH2:27][CH2:26]OCC1.CCOC(C)=O.[Cl-:34].[Na+].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>[Cl:34][C:1]1[N:2]=[N:3][C:4]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:26][CH:27]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: [Cl-]
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(Cl)nn2)cn1
Temperature: 80 °C
Yield: 47 %

Procedure:
A flask was charged with 3,6-dichloropyridzine (Aldrich, 297 mg, 2.0 mmol), 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (499 mg, 2.4 mmol), 2 M Na2CO3 (4 mL) and dioxane (4 mL). Argon was bubbled through the reaction for 60 seconds followed by the addition of Tetrakis(triphenylphosphine)palladium (0) (231 mg, 0.2 mmol). The reaction was heated to 80° C. overnight followed by aqueous work up using EtOAc and brine. The organic layer was dried (MgSO4) and concentrated in vacuo followed by column chromatography purification (20% Ethyl Acetate in Hexanes) resulting in the title compound as a white solid (183 mg, 47%). 1H-NMR (CD3OD): δ 8.23 (1H, s), 8.08 (1H, s), 7.84 (1H, br s), 7.34 (1H, br s), 4.00 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2O)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[OH:30])[N:10]=1.[C:31](=[O:34])([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].O>C(OCC)C>[OH:30][C:24]1[CH:25]=[C:26]([O:29][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:27]=[CH:28][C:23]=1[C:11]1[N:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:19][CH2:20][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:2]=2[OH:1])[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:5][CH2:4][CH2:3][CH2:2][CH2:7][CH3:6])=[CH:17][C:16]=2[O:34][CH2:31][CH2:25][CH2:24][CH2:23][CH2:28][CH3:27])[N:12]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCCCBr
Reactant: Oc1ccc(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(O)c1
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCOc1ccc(-c2nc(-c3ccc(OCCCCCC)cc3O)nc(-c3ccc(OCCCCCC)cc3OCCCCCC)n2)c(O)c1
Temperature: 120 °C

Procedure:
Under nitrogen, a mixture of 60.8 g (0.150 mol) of 2,4,6-tris(2′,4′-dihydroxyphenyl)-1,3,5-triazine and 87.1 g (0.630 mol) of potassium carbonate in 700 ml of 2-ethoxyethane (Fluka, 99.5%) is added dropwise over the course of 15 minutes to 134.8 (0.800 mol) of 1-bromohexane (Fluka, 98%) which is held at 80° C. The mixture is subsequently heated at 120° C. for 20 h. After cooling, the reaction mixture is poured into 8 l of cold water. After 24 hours at 25° C. the precipitate is filtered off, washed with water (300 ml) and dried. The crude product is chromographed [2.5 kg of silica gel 60 (230-400 mesh), Ø=13 cm; h=60 cm; eluted with hexane/ethyl acetate (39:1)]. Removal of the solvent from the main fraction gives 69.2 g of 2,4-bis(2′-hydroxy-4′-n-hexyloxyphenyl)-6-(2′,4′-di(n-hexyloxy)phenyl)-1,3,5-triazine (Compound 27) of m.p. 85-87° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:11]=1[C:12]([NH2:14])=[O:13].[OH2:26].CC(C)=[O:29]>[Os](=O)(=O)(=O)=O>[OH:26][CH:22]([C:23]([OH:29])([CH3:25])[CH3:24])[CH2:21][CH2:20][O:19][C:15]1[CH:16]=[N:17][CH:18]=[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: O
Reactant: CC(C)=O
Reactant: CC(C)=CCCOc1cncc(Nc2ccc(I)cc2F)c1C(N)=O
Agent: O=[Os](=O)(=O)=O
Product: CC(C)(O)C(O)CCOc1cncc(Nc2ccc(I)cc2F)c1C(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
252 mg of 3-[(2-fluoro-4-iodophenyl)amino]-5-[(4-methylpent-3-en-1-yl)oxy]isonicotinamide (0.554 mmol, 1 eq.) were dissolved in 36 ml of Acetone and 6 ml of water were added to form a suspension. Then 454 mg of N-methyl-morpholino-N-oxide 3.875, 7 eq.) and 555 μl of an osmiumtetroxide solution (2.5 weight % in tert.-butanol, 0.044 mmol, 0.08 eq.) were added and the formed suspension was stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between 50 ml each of water and dichloromethane/isopropanole (4:1). The aqueouse layer was separated and reextracted twice with dichloromethane/isopropanole (4:1). The combined organic layers were washed with brine, dried over a silicone filter and concentrated to afford 272 mg (0.55 mmol, 100%) of the analytically pure target compound which required no further purification.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:21])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1)[N:9]=[CH:8]2.CCOC(C)=O>CN(C=O)C>[OH:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:10]2[N:9]=[CH:8][C:7]3[C:12](=[C:3]([OH:2])[C:4]([CH3:21])=[CH:5][CH:6]=3)[N:11]=2)[CH2:19][CH2:18]1
Reactant: COc1c(C)ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1O
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of trans-4-[(8-methoxy-7-methylquinazolin-2-yl)amino]cyclohexanol (16.7 g, 0.058 mol) in DMF (280 mL) was added NaSEt (11.9 g, 0.142 mol) in one portion at room temperature. The reaction mixture was stirred at 120° C. for 3 h. TLC (EtOAc) indicated the reaction was complete. DMF was removed in vacuo. The residue was taken up with water (200 mL), and the aqueous solution was adjusted to pH 6 with 1 N aq. HCl. The precipitate was filtered, washed with water (60 mL×2) and dried in vacuo to give the title compound (15.1 g, 95%) as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][C:20]#[N:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[CH2:25](O)[CH3:26]>[Ni]>[CH2:25]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]=1)[CH3:26]
Reactant: CCO
Reactant: N#CCCCc1nn(Cc2ccccc2)c2ccccc12
Agent: [Ni]
Agent: NN
Solvent: O
Product: CCNCCCCc1nn(Cc2ccccc2)c2ccccc12
Temperature: 65 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of 1-benzyl-3-(3-cyanopropyl)indazole (100 mg, 0.35 mM) in ethanol (10 ml) was stirred at room temperature and Raney nickel (approx. 100 mg, wet weight) was added. The resulting suspension was warmed to 65° C. and hydrazine hydrate (0.1 ml, 87 mg) added carefully. The mixture was stirred at 70° C. for a further 2 hr then cooled and filtered through celite. Solvent was removed in vacuo and the residue purified by chromatography on silica (chloroform/methanol 9:1) to give the title product as a clear oil (25 mg, 26%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[C:6](=[O:15])[C:5]=12.[Cl-].[Al+3].[Cl-].[Cl-].[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[C:20]([C:2]1[CH:1]=[C:5]2[N:4]([CH:3]=1)[CH:10]=[CH:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[C:6]2=[O:15])(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=O)Cl
Reactant: O=c1c2ccccc2ccn2cccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)c1cc2c(=O)c3ccccc3ccn2c1

Procedure:
11H-Pyrrolo[2,1-b][3]benzazepin-11-one (1.0 g.) is dissolved in 20 ml. of methylene chloride and 2.66 g. of aluminum chloride is added with cooling. At room temperature there is added little by little 720 mg. of pentanoyl chloride. Fifteen minutes after the addition is complete the mixture is poured onto ice. The organic phase is separated, filtered, dried and concentrated to dryness. The residue is triturated with ether, collected and dried to give 2-pentanoyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [CH2:1]([CH:11]([CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[C:12]([OH:14])=[O:13])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27](O)[CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.C(OCC)(=O)C>[N+:31]([C:30]1[CH:25]=[CH:26][C:27]([O:13][C:12](=[O:14])[CH:11]([CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4])=[CH:28][CH:29]=1)([O-:33])=[O:32]
Reactant: CC(C)=CCC/C(C)=C/CC(C/C=C(\C)CCC=C(C)C)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/CC(C/C=C(\C)CCC=C(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Digeranylacetic acid (300 mg, 0.9 m mol) and p-nitrophenol (139 mg, 1 m mol) were dissolved in acetonitrile-ethyl acetate (1:1) (10 ml), and under ice-cooling, N,N'-dicyclohexylcarbodiimide (227 mg, 1.1 m mols) was added. The mixture was stirred at 0° C. for 3 hours and at room temperature for 15 hours. The crystalline precipitate was removed and the solvent was distilled off under reduced pressure, whereby digeranyl acetic acid p-nitrophenyl ester was obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][OH:10].[SH:11][C:12]1[N:17]2[N:18]=[C:19]([C:21](OC)=[O:22])[N:20]=[C:16]2[N:15]=[C:14]([CH3:25])[CH:13]=1.Cl>CO>[OH:10][NH:9][C:21]([C:19]1[N:20]=[C:16]2[N:15]=[C:14]([CH3:25])[CH:13]=[C:12]([SH:11])[N:17]2[N:18]=1)=[O:22]
Reactant: NO
Reactant: COC(=O)c1nc2nc(C)cc(S)n2n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(S)n2nc(C(=O)NO)nc2n1
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
Triethylamine (1.35 g) (13.37 mmol) are added dropwise at 0° C. to a solution of 0.62 g (8.92 mmol) of hydroxylamine hydrochloride in 15 ml of absolute methanol. The mixture is stirred for 10 minutes and subsequently a solution of 1.0 g (4.46 mmol) of methyl 7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxylate (known from EPOS 303,172) in 30 ml of absolute methanol is added dropwise. After stirring at room temperature for 3 days the beige suspension is made acid (pH 4) with 1N aqueous hydrochloric acid and suction filtered. The filter material is washed with water and diethyl ether and crystallized from methanol/dichloromethane. There are obtained 510 mg of N-hydroxy-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide as beige crystals of m.p. 213° C. (dec.).
Reaction SMILES: [F:1][C:2](=[C:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1>CS(C)=O.C(N(CC)CC)C.O>[F:1][C:2]([C:3]1[CH:19]=[CH:18][CH:17]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][N:8]=2)[CH:4]=1)=[C:20]1[CH2:25][CH2:24][N:23]([C:33]([NH:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:22][CH2:21]1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: FC(=C1CCNCC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccnc1)N1CCC(=C(F)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Reaction time: 12 h
Yield: 74.6 %

Procedure:
To a solution of 2-(3-(fluoro(piperidin-4-ylidene)methyl)phenoxy)-5-(trifluoromethyl)pyridine (110 mg, 0.312 mmol) and phenyl pyridin-3-ylcarbamate (66.8 mg, 0.312 mmol) in DMSO (2 mL) under N2 was added 3 drops of triethyl amine and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed several times with water to remove the excess DMSO. The title compound was crystallized from CH2Cl2 and hexane to give the pure title compound (110 mg). 1H NMR (500 MHz, CDCl3): δ 2.5 (brs, 2H), 2.6 (brs, 2H), 3.7 (brs, 2H), 3.8 (brs, 2H), 7.0 (d, 1H, J=8.5 Hz), 7.1-7.3 (m, 3H), 7.4 (t, 1H, J=8.5), 7.7 (d, 1H, J=5.5 Hz), 7.9 (d, 1H, J=8 Hz), 8.0 (s, 1H), 8.4 (s, 1H), 9.2 (d, 1H, J=8.5 Hz), 9.6 (brs, 1H), 9.8 (brs, 1H); 13CNMR (125 MHz, CDCl3): 11.4, 14.3, 22.6, 25.5, 27.7, 31.5, 40.8, 44.1, 44.4, 53.4, 111.6, 114.0, 115.5, 119.8, 121.3, 121.4, 121.7, 122.5, 123.8, 125.3, 128.2, 129.6, 133.5, 133.8, 136.8, 140.5, 142.8, 145.3, 151.8, 153.0, 154.7, 156.7, 165.4; m/z (473.3 M+ H+); HPLC: 94.2%.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[C:5]([C:11]([NH2:13])=[O:12])[N:6]([CH3:10])[C:7]=1[CH2:8][CH3:9])#[N:2]>COC(N(C)C)OC>[CH3:5][N:6]([CH:10]=[N:13][C:11]([C:5]1[N:6]([CH3:10])[C:7]([CH2:8][CH3:9])=[C:3]([C:1]#[N:2])[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)=[O:12])[CH3:7]
Reactant: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(N)=O)n1C
Agent: COC(OC)N(C)C
Product: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(=O)N=CN(C)C)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 190.2 %

Procedure:
Prepare a solution of 4-cyano-3-(2′-cyano-biphenyl-4-yl)-5-ethyl-1-methyl-1H-pyrrole-2 carboxylic acid amide (167 mg, 0.47 mmol, prepared in example Am-3) in 2.5 mL of dry dimethoxymethyl-dimethyl-amine and heat to reflux under nitrogen. After 1 hour allow 1 mL of solvent to distill out of the reaction, then cool the mixture to room temperature. Dilute the slurry with 10 mL of hexanes, filter off the resulting product and wash with 5 mL hexanes. Vacuum-dry the solid overnight to give the title compound (183 mg, 95%). MS(ES+, m/e)=410 (M++1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In a 20 mL vial were combined 4-fluoronitrobenzene (1.1 mL, 10 mmol), imidazole (0.68 g, 10 mmol), and sodium carbonate (1.1 g, 11 mmol) in N,N-dimethylformamide (5 mL). The mixture is shaken at 100° C. for 24 hours and then allowed to cool to room temperature and then diluted with water. Concentrated hydrochloric acid is added to bring the pH to 1, and then the mixture is extracted thrice with chloroform (10 mL). The acidic aqueous phase is then treated with 2.5 M sodium hydroxide solution to give a pH of 10. A light yellow solid is collected and washed with water to give 1-(4-nitrophenyl)-1H-imidazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:25][CH2:26][S:27][CH3:28])[NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1.O.O.Cl[Sn]Cl.COC(=O)[C@H](CCSC)NC(=O)C1C=CC(N)=CC=1C1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:25][CH2:26][S:27][CH3:28])[NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1cc(C)cc(C)c1
Agent: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1cc(C)cc(C)c1

Procedure:
4-nitro-2-(3,5-dimethylphenyl)benzoyl methionine methyl ester (0.11 g, 0.26 mmol) was taken up in ethyl acetate (3.0 ml). To this mixture was added SnCl2.2H2O (0.30 g, 1.30 mmol) and the reaction was heated under nitrogen at reflux for 6 h. The mixture was worked up as described for 4-amino-2-phenylbenzoyl methionine methyl ester in Example 2, to give 0.15 g of a yellow film that was wet with solvent. The material was otherwise pure by NMR and was used without further purification. 1H NMR (CDCl3)1.60-1.70 (1 H, m), 1.80-1.90 (1 H, m), 1.99 (3 H, s), 2.05 (2 H, t, J=7.6 Hz), 2.33 (6 H, s), 3.64 (3 H, s), 3.93 (2 H, br s), 4.61-4.64 (1 H, m), 5.82 (1 H, d, J=7.7 Hz), 6.49 (1 H, d, J=2.3 Hz), 6.62 (1 H, dd, J=8.4 Hz, 2.4 Hz), 6.98 (2 H, s), 7.00 (1 H, s), 7.65 (1 H, d, J=8.3 Hz); 13C NMR (CDCl3) 15.08, 21.17, 29.28, 31.49, 51.70, 52.18, 113.30, 115.94, 123.55, 126.36, 129.32, 131.23, 138.15, 140.72, 141.92, 148.40, 168.45, 172.01.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([NH:26][CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([NH:26][CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95.9 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(methylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 7, 380 mg, 1.00 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (5 ml) and the mixture was stirred at room temperature for 3.5 hours. The solvent was removed under reduced pressure and the residue azeotroped with toluene (×2). The residue was dissolved in ethyl acetate and washed sequentially with a saturated aqueous solution of sodium citrate then brine. The organic layer was dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was crystallised from hexane to afford the title compound as a white solid (310 mg).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CI.[Br:9][C:10]1[N:11]=[C:12]([C:19]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[N:25]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:24]3=[O:40])=[O:20])[N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12>CN(C=O)C>[Br:9][C:10]1[N:11]=[C:12]([C:19]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:1])[C:26](=[O:31])[N:25]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C:24]3=[O:40])=[O:20])[N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc2[nH]c(=O)n(Cc3ccc(F)cc3)c(=O)c2c1)c1nc(Br)c2ccccn12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
1.87 g (5.7 mmol) of caesium carbonate and 0.39 ml (6.2 mmol) of methyl iodide are added, at ambient temperature under an inert atmosphere, to 2.6 g (5.17 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione in 50 ml of anhydrous DMF. The reaction medium is stirred for 18 hours at ambient temperature and then filtered. The precipitate is rinsed with water and then dried under reduced pressure at 50° C. overnight. 2.54 g of a yellow solid are obtained.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=O.[NH2:17][C:18]([NH2:20])=[S:19].CC(O)=O>O1CCOCC1>[CH:14]([C:6]1[C:5]([C:3]2[NH:17][C:18](=[S:19])[NH:20][CH:2]=2)=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: NC(N)=S
Reactant: CC(C)c1nn2ccccc2c1C(=O)CCl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)c1nn2ccccc2c1-c1c[nH]c(=S)[nH]1
Yield: 121 %

Procedure:
A mixture of 200 mg (0.63 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone, 100 mg of thiourea and 100 μl of HOAc were stirred in 1.5 ml of dioxane at 60-700 C for 30 minutes. 197 mg of 4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1H-imidazole-2(3H)-thione was obtained after workup. Compound 1085.