Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:27])[C:26]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccccc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) acetyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]1([C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:13][CH3:14])[CH:11]=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1>[OH:12][CH:11]([C:10]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:13][CH3:14])[C:1]#[N:2]
Reactant: [C-]#N
Reactant: CCC(C=O)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(c1ccccc1)(c1ccccc1)C(O)C#N
Temperature: 40 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
17.4 g (91.6 mmol) of p-toluenesulfonic acid H2O, and then 5.9 g (91.6 mmol) of KCN in 25 ml of water, were added at 35° C. to a solution of 19.09 g (84.8 mmol) of 2,2-diphenylbutyraldehyde in 97 ml of THF (abs.). The mixture was then stirred at 40° C. for 4 hours and at room temperature for 16 hours. The mixture was evaporated to 1/3 of the volume, water was added, and the phases were separated. The aqueous phase was then extracted three times with ethyl acetate, and the combined organic phases were washed with 10% strength sodium disulfite solution, dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed on silica gel with n-heptane/acetic acid (20:1). 19.5 g (92%) of 2-hydroxy-3,3-diphenylvaleronitrile were obtained as a pale oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:20]2[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH:28]([CH3:30])[CH3:29])=[CH:22][N:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+]>CS(C)=O>[CH2:31]([N:19]([C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH:28]([CH3:30])[CH3:29])=[CH:22][N:21]=1)[S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH:32]([CH3:34])[CH3:33]
Reactant: COc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Reactant: OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OCC2CCOCC2)cc1
Reaction time: 96 h

Procedure:
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (14.29 mg, 0.123 mmol) and 4-fluoro-N-isobutyl-N-(5-isopropyl-3-methoxypyridin-2-yl)benzenesulfonamide (46.8 mg, 0.123 mmol) in dimethyl sulfoxide (DMSO) (200 μL) stirred in air at room temperature was added sodium hydride (4.92 mg, 0.123 mmol, 60% wt in mineral oil). The reaction mixture was stirred for 4 days then carefully quenched with isopropanol (1 mL) and evaporated in vacuo. The crude sample was purified by mass directed autoprep (formic acid modifier) to give the title product, 42.9 mg. LCMS (2 min, formic) Rt 1.36 min, m/z (ES+) 477 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CS(C)=O>[C:11]([C:7]1[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
8.40 g (40.7 mmol) 2,6-di-tert-butylphenol was dissolved in 100 ml dried DMSO. 8 g (58 mmol) potassium carbonate and 7.6 g (54 mmol) p-fluoronitrobenzene were added into the DMSO solution. The DMSO solution was heated to 100˜120° C. for 12 hrs with stirring. Then the reaction mixture was allowed to cool to room temperature and poured into distilled water. The aqueous solution was acidified to pH 2˜4 and yellow precipitate was collected by filtration. The yellow precipitate was washed with water and dried. The crude yield was 75%. The yellow precipitate was purified by recrystallizing in cyanomethane, mp 157˜160° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][C:22]#[N:23]>>[S:1]1[CH:5]=[C:4](/[CH:6]=[C:21](/[C:13]2[S:12][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=2)\[C:22]#[N:23])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: N#CCc1nc2ccccc2s1
Reactant: O=Cc1csc2ccccc12
Product: N#C/C(=C\c1csc2ccccc12)c1nc2ccccc2s1
Yield: 69.8 %

Procedure:
Benzo[b]thiophene-3-carboxaldehyde (81 mg) was condensed with 2-benzothiazoleacetonitrile (87 mg) through Method B (production step 3), to thereby yield the target product (yield: 111 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=O)=[CH:5][O:4][N:3]=1.Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[OH:16][N:15]=[C:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][CH:5]=1)[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1
Reactant: NO
Reactant: Cc1nocc1C(=O)c1cccs1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nocc1C(=NO)c1cccs1
Yield: 99.9 %

Procedure:
A solution of (3-methyl-1,2-oxazol-4-yl)(2-thienyl)methanone (6.00 g, 31.0 mmol) and hydroxylamine hydrochloride (5.40 g, 77.6 mmol) in pyridine (80 mL) was stirred 5 h at 50° C. then overnight at room temperature. After removal of the solvent in vacuo, addition of water (50 mL) and extraction with ethyl acetate (3×40 mL), the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica gel to afford N-hydroxy-1-(3-methyl-1,2-oxazol-4-yl)-1-(2-thienyl)methanimine [6.45 g, yield 99%; HPLC/MS: m/z=219 (M+H); log P(HCOOH)=1.75].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=S)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:23][NH2:24]>C(O)C>[NH:23]([C:12]1[N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[NH2:24]
Reactant: CC(C)Oc1cccc(-n2c(=S)[nH]c3ccccc3c2=O)c1
Reactant: NN
Solvent: CCO
Product: CC(C)Oc1cccc(-n2c(NN)nc3ccccc3c2=O)c1
Yield: 38.7 %

Procedure:
A mixture of 3-(3-isopropoxy-phenyl)-2-thioxo-2,3-dihydro-1H-quinazolin-4-one (Example 1) (3.12 g, 10 mmol) and anhydrous hydrazine (3.2 g, 100 mmol) in 100 mL of ethanol was refluxed for 18 hours. The reaction mixture was then cooled and white solid was separated which was filtered to obtain 1.2 g (38%) of title compound as white solid. The filtrate was concentrated and an additional 1.6 g (50.4%) of title compound was isolated by crystallization from ethyl acetate, mp 158°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([CH3:35])[C:33]=1O)[C:29]#[N:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:18][CH2:17]3)[CH2:14][O:15][C:33]3[C:32]([CH3:35])=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=3[CH3:25])[C:11]3[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: OCC(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: Cc1cc(C#N)cc(C)c1O
Product: Cc1cc(C#N)cc(C)c1OCC(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared from 2-[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopropyl-ethanol, 3,5-dimethyl-4-hydroxybenzonitrile (commercially available), tri-n-butylposphine and N′N′N′N-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 60:40). The so-obtained solid was again chromatographed on a preparative HPLC system using a Phenomenex Gemini column eluting with a gradient of acetonitril and water (containing 5% formic acid). White foam (20%). MS (Turbo Spray): m/z=478.149 [M+H].
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:14](O)=[O:15])([CH:5]3[CH3:13])[CH2:3]1)[CH2:9]2>O1CCCC1>[CH3:11][C:8]12[CH2:7][CH:6]3[CH2:12][C:2]([CH3:1])([CH2:3][C:4]([CH2:14][OH:15])([CH:5]3[CH3:13])[CH2:10]1)[CH2:9]2
Reactant: CC1C2CC3(C)CC(C)(C2)CC1(C(=O)O)C3
Solvent: C1CCOC1
Product: CC1C2CC3(C)CC(C)(C2)CC1(CO)C3

Procedure:
To a solution of 3,5,8-trimethyl-1-adamantane carboxylic acid (0.5 g) in tetrahydrofuran (3 mL) was dropwise added BH3.tetrahydrofuran (4.50 mL) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with methanol (3 mL), concentrated and purified by chromatography on silica gel using 0-30% ethyl acetate/hexanes as eluent to provide the title compound.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30]Br>CN(C=O)C.CCOC(C)=O>[F:21][C:18]([F:19])([F:20])[CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:2]([C:3]2([C:4]([O:6][CH3:7])=[O:5])[CH2:30][CH2:29]2)=[O:1])=[CH:9][CH:10]=1
Reactant: COC(=O)CC(=O)c1ccc(OCCCC(F)(F)F)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(C(=O)c2ccc(OCCCC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
To a solution of Intermediate 14A (6.0 g, 19.7 mmol) in DMF (197 mL) was added K2CO3 (8.18 g, 59.2 mmol) followed by 1,2-dibromoethane (2.6 mL, 30 mmol). The reaction mixture was stirred at rt for 2 days. The reaction was reduced in volume in vacuo, then diluted with EtOAc, washed with a 1:1 solution of sat'd aq NaCl and water, dried over anhydrous MgSO4, filtered and concentrated. The product was isolated by silica gel chromatography (220 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 14B (4.2 g, 61%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.45-1.49 (m, 2H), 1.56-1.61 (m, 2H), 2.03-2.14 (m, 2H), 2.26-2.39 (m, 2H), 3.60 (s, 3H), 4.09 (t, J=6.05 Hz, 2H), 6.90-6.94 (m, 2H), 7.86-7.93 (m, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1ccc(-n2ccnc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
A mixture of 4-fluorobenzaldehyde (4.96 g, 40 mmol), imidazole (2.86 g, 42 mmol), and potassium carbonate (6.08 g, 44 mmol) in DMSO (40 ml) was stirred at 110° C. overnight. The reaction mixture was allowed to return to room temperature, and poured into ice water (100 ml). The resulting precipitates were collected by filtration and washed with water and then with ethyl acetate to afford 4-(imidazol-1-yl)benzaldehyde (2.33 g, yield 34%) as a pale yellow crystalline powder.
Reaction SMILES: [C:1]1([C:7](=[O:20])[CH:8]([CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][NH2:22]>C1(C)C=CC=CC=1>[C:1]1([C:7](=[O:20])[CH:8]([CH3:19])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([NH:22][CH3:21])=[O:18])=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Cc1ccc(N=C=O)cc1)C(=O)c1ccccc1
Reactant: CN
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1ccc(CC(C)C(=O)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
A solution of 13.25 g of 4-(3-phenyl-2-methyl-n-propan-3-onyl)-phenyl isocyanate in 20 ml of toluene was added dropwise to a solution of 3 g of methylamine in 100 ml of toluene, at from 20° to 25° C. The mixture was stirred for 6 hours at 40° C., after which the toluene was stripped off under reduced pressure. 13.3 g (90% of theory) of a slightly yellow oil were obtained.
Reaction SMILES: [Br:1][C:2]1(C2C=CC=CN=2)[CH:7]=[CH:6][CH:5]=[C:4](Br)[NH:3]1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:26]=[N:25][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][CH:22]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([C:24]2[N:25]=[N:26][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[CH:22][CH:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccccn2)nn1
Reactant: BrC1=CC=CC(Br)(c2ccccn2)N1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc(-c3ccccn3)nn2)n1

Procedure:
The 3-(6-bromopyridin-2-yl)-6-(pyridin-2-yl)pyridazine was prepared according to the general Stille coupling method, starting from a mixture of 1.6 g (6.74 mmol) of 2,6-dibromobipyridine 42, 3 g (6.74 mmol) of 6-(pyridin-2-yl)-3-(tributylstannyl)pyridazine 39, 546 mg (0.47 mmol) of tetrakis(triphenylphosphine)-palladium(0) and 50 ml of freshly distilled toluene. The mixture is refluxed for 24 h. The residue obtained is chromatographed on a silica gel (eluent: ethyl acetate/petroleum ether=1/9). The brominated product 43 is isolated with a yield of 72%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:32])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([Cl:32])(=[O:17])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccccc1-c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccccc1-c1ccc(F)cc1

Procedure:
4′-Fluorobiphenyl sulfonic acid (3 g) was refluxed in thionyl chloride (30 mL) with a catalytic quantity of DMF (0.5 mL) for 4 hours. Toluene was added and the solvents evaporated under vacuum to give the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([C:7]([F:10])([F:9])[F:8])=O)=O.O.[NH2:12][NH2:13].Cl>CO>[F:8][C:7]([F:10])([F:9])[C:5]1[CH:4]=[C:2]([CH3:1])[NH:13][N:12]=1
Reactant: NN
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc(C(F)(F)F)n[nH]1
Reaction time: 12 h
Yield: 74.5 %

Procedure:
To 1,1,1-trifluoro-2,4-pentadione (15.14 g, 98 mmol) in MeOH (200 ml) was added hydrazine monohydrate (4.92 g, 98 mmol) in MeOH (50 ml) and c.HCl (1.3 ml, 32%). The resulting clear solution was allowed to stir for 12 h. Removal of solvent by distillation up to 200° C. yielded a clear oil which crystallised on cooling. These crystals were dissolved in Et2O, dried over MgSO4, filtered and the solvent removed under reduced pressure. The resulting white solid was sublimed at 80° C. and 10−2 mbar, yielding the pure pyrazole as a white solid (10.91 g, 73 mmol, 74%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:9][C:10]1[CH:22]=[CH:21][C:13]([CH:14]=[CH:15][C:16](OCC)=[O:17])=[CH:12][CH:11]=1>C[O-].[Na+]>[O:4]=[C:3]1[CH2:5][C:16](=[O:17])[CH2:15][CH:14]([C:13]2[CH:12]=[CH:11][C:10]([CH3:9])=[CH:22][CH:21]=2)[CH:2]1[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: CCOC(=O)C=Cc1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1C(=O)CC(=O)CC1c1ccc(C)cc1

Procedure:
To a cooled solution of sodium methoxide (from 2.3 g., sodium and absolute methanol, 40 ml.) was added with shaking methyl acetoacetate (11.8 g.). When homogeneous the mixture was treated with ethyl p-methylcinnamate (19. g.) and then heated under reflux for 18 hrs. After cooling the precipitated sodium enolate salt (formula III) was collected by filtration and washed with acetone. This enolate salt was then converted to the corresponding dione of formula II by dissolving in cold water followed by acidification with 2-N-hydrochloric acid, which afforded crystalline methyl 2,4-dioxo-6-p-tolylcyclohexanecarboxylate.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10]
Reactant: COc1ccccc1CN
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: COc1ccccc1CNc1nc(Cc2ccsc2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 521 mg (3.80 mmol) of 2-methoxybenzylamine to give 62 mg (46% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(=O)(O)[O-]>[Br:24][C:11]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=2)[N:9]([S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:10]=1
Reactant: BrBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(C(F)(F)F)cnc32)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(C(F)(F)F)cnc32)cc1
Yield: 89.1 %

Procedure:
To a stirred solution of 5-trifluoromethyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (53.7 g, 158 mmol) in DCM (250 mL) was added a solution of bromine (16 mL, 316 mmol) in DCM (50 mL) dropwise. No significant exotherm was observed. After an hour at room temperature, the reaction mixture had thickened and stirring ceased. The reaction was deemed complete by tlc and was diluted with 1.2 litres of DCM and 50:50 saturated bicarbonate: saturated sodium thiosulfate aqueous solution. The organic layer was separated and further washed with the 50:50 aqueous mixture, dried over magnesium sulfate and evaporated. The crude yellow solid was triturated with diethyl ether and solid isolated and dried to give the product as a yellow powder (59 g, 59% yield)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([CH2:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1.[CH3:17]OS(OC)(=O)=O>C1COCC1>[CH3:17][O:3][C:4]1([CH2:10][CH:11]=[C:12]([C:13]#[N:14])[C:15]#[N:16])[CH:5]=[CH:6][CH:7]=[CH:8][CH2:9]1
Reactant: N#CC(C#N)=CCC1(O)C=CC=CC1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(CC=C(C#N)C#N)C=CC=CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a suspension of 60% NaH/mineral oil dispersion (2.9 g, 74.7 mmol) in THF (50 ml) was added dropwise (1-hydroxyphenylethylidene)malononitrile (13.8 g, 74.7 mmol) in THF (75 ml) over 25 minutes, followed by dimethylsulfate (7.1 ml, 74.7 mmol) in THF (50 ml) over 20 minutes. The reaction mixture was stirred at room temperature for 30 minutes, then at reflux for 4 hours. 0.5 equivalents of 60% sodium hydride and dimethylsulfate were added and the reaction mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo, the residue was partitioned between ether and water, the organic layer was separated and the aqueous layer was extracted with ether (3×150 ml). The combined organic layers were dried over anhydrous MgSO4 and solvent was removed in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate/hexanes (1/1) to afford 8.4 g (56%) of (1-methoxyphenylethylidene)malononitrile as an amber liquid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccncc1F
Reactant: NCC1COc2ccccc2O1
Product: O=C(O)c1ccncc1NCC1COc2ccccc2O1
Yield: 6 %

Procedure:
The title compound was prepared in 6% yield from 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.43 (br s, 1H), 8.37 (s, 1H), 7.87 (d, 1H, J=5.0 Hz), 7.77 (br s, 1H), 7.57 (d, 1H, J=5.0 Hz), 6.80-6.90 (m, 4H), 4.37-4.48 (m, 2H), 4.02-4.07 (m, 1H), 3.55-3.75 (m, 2H). [M+H] calc'd for C15H14N2O4, 287. Found 287.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:17]=1)(C)(C)C>C(Cl)Cl>[N:24]1[CH:23]=[CH:22][C:21]([C:18]2[N:17]=[C:16]([CH2:15][NH2:14])[O:20][N:19]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCc1nc(-c2ccncc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1nc(-c2ccncc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (6.5 ml) was added to a solution of (3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)carbamic acid tert-butyl ester (Preparation 8, 420 mg, 1.52 mmol in CH2Cl2 (10 ml) and the mixture stirred at rt for 2 h. The solvent was evaporated and the residue dissolved in EtOAc (100 ml). After washing with saturated aqueous Na2CO3 (25 ml), the aqueous phase was re-extracted with 5% MeOH in CH2Cl2 (7×25 ml) and the combined organic phases dried (MgSO4). The solvent was removed to afford the title compound: RT=0.25 min; m/z (ES+)=177.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25]Br>>[F:20][C:21]([F:34])([F:35])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[CH2:25][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(=O)[nH]c1=O
Yield: 49.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (240 mg, yield: 49.4%).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][C:18]([O:20][C@H:21]3[CH2:25][CH2:24][O:23][CH2:22]3)=[O:19])[CH:11]=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH2:40])[CH:32]=[CH:33][C:34]=1[C:35]1[O:39][CH:38]=[N:37][CH:36]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:40][C:8](=[O:26])[NH:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][NH:17][C:18](=[O:19])[O:20][C@H:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH:32]=[CH:33][C:34]=1[C:35]1[O:39][CH:38]=[N:37][CH:36]=1
Reactant: O=C(Nc1cccc(CNC(=O)O[C@H]2CCOC2)c1)Oc1ccccc1
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)Nc2cccc(CNC(=O)O[C@H]3CCOC3)c2)ccc1-c1cnco1
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Added 2e (15 g, 1.0 eq) and 2g (8.58 g, 1.07 eq) into a jacketed reactor of suitable size before adding ethyl acetate (225 ml, 15 vol) and diisopropylethylamine (5.43 g, 1.0 eq), then heated the mixture to reflux (75-85° C.) for 24 hours. Once the reaction was complete, the mixture was cooled to room temperature and stirred for an additional 1 hour. Precipitated solid was filtered, washed with EtOAc 2 times (45 ml, 3 vol each wash), then dried at 58° C. for 18 hours (until a LOD is achieved of less than 1%) to give 17.46 g of crude 2h (90.4% yield, 98.46% a/a) as a white crystalline solid.