Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:20](=O)[CH3:21])[CH2:6][C:7](=O)[CH2:8][C@@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])C.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([CH3:32])[CH:26]=1.O>C(O)(=O)C>[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([N:29]2[C:7]([CH2:8][C@@H:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:10])=[CH:6][C:5]([C:4]([OH:3])=[O:23])=[C:20]2[CH3:21])=[C:27]([CH3:32])[CH:26]=1
Reactant: CCOC(=O)C(CC(=O)C[C@H](C)OCc1ccccc1)C(C)=O
Reactant: Cc1cc(Cl)ccc1N
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Cl)ccc1-n1c(C[C@H](C)OCc2ccccc2)cc(C(=O)O)c1C
Temperature: 110 °C
Reaction time: 15 h
Yield: 74.1 %

Procedure:
To a solution of (6S)-2-acetyl-6-(benzyloxy)-4-oxoheptanoic acid ethyl ester (2.5 g, 7.8 mmol) in acetic acid (8 ml), 4-chloro-2-methylaniline (1.1 g, 7.8 mmol) was added, and the mixture was stirred at 110° C. for 15 hours. 15 ml of water was poured to the reaction mixture, and after the organic layer was extracted with diethyl ether, it was washed with 1N aqueous sodium hydroxide solution, water, a saturated aqueous ammonium chloride solution and saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crudely purified by silica gel column chromatography. Subsequently, the product was dissolved in a 5M aqueous sodium hydroxide solution (30 mL) and methanol (40 mL), and the mixture was stirred at 100° C. for 4 hours. After the reaction, 2M hydrochloric acid (80 mL) was added under ice-cooling to neutralize it, and it was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.3 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:22])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[C:16](Br)[C:15]=2[CH:14]=[C:13]([F:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cu][C:24]#[N:25]>CN(C)C=O.[Cu]I>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:22])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[CH:14]=[C:13]([F:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Cc1cc(F)cc2c(Br)coc12)NC(=O)OC(C)(C)C
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(Cc1cc(F)cc2c(C#N)coc12)NC(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 16 h
Yield: 5.8 %

Procedure:
A mixture of 0.20 gm (0.54 mMol) N-tert-butoxycarbonyl 1-(3-bromo-5-fluorobenzofur-7-yl)-2-aminopropane, 0.95 gm (5 mMol) copper(I) iodide, and 0.43 gm (4.78 mMol) copper(I) cyanide in 10 mL dimethylformamide was purged with nitrogen for 15 minutes. The mixture was then heated at 120° C. An additional equivalent of copper(I) iodide and copper(I) cyanide were added and the reaction continued at 120° C. for about 16 hours. After cooling to room temperature the reaction mixture was diluted with dichloromethane and then silica gel was added. The solvents were removed under reduced pressure and the dry silica gel remaining was loaded on the top of a silica gel column. The column was then eluted with a gradient of hexane containing from 17% to 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.010 gm (6%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)[N:10]=[C:5]2[NH:4][CH2:3]1.[H-].[Na+].[N:22]1[C:27]2[CH2:28][CH:29]([CH2:31]OS(C)(=O)=O)[CH2:30][C:26]=2[N:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[N:22]1[C:27]2[CH2:28][CH:29]([CH2:31][N:4]3[C:5]4=[N:10][C:9]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][N:12]=5)=[CH:8][C:7](=[O:17])[N:6]4[CH2:18][C:2]([CH3:19])([CH3:1])[CH2:3]3)[CH2:30][C:26]=2[N:25]=[CH:24][CH:23]=1
Reactant: CC1(C)CNc2nc(-c3ccncn3)cc(=O)n2C1
Reactant: CS(=O)(=O)OCC1Cc2nccnc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CN(CC2Cc3nccnc3C2)c2nc(-c3ccncn3)cc(=O)n2C1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 10.6 %

Procedure:
A suspension of 0.5 g (1.94 mmol) of 7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 10 ml of anhydrous dimethylformamide was treated with 155 mg (3.89 mmol) of sodium hydride (50% suspension in mineral oil) and the resulting mixture was stirred for 40 min at 50° C. 0.888 g (3.89 mmol) of methanesulfonic acid 6,7-dihydro-5H-cyclopentapyrazin-6-ylmethyl ester in 2 ml of anhydrous dimethylformamide was added and the reaction mixture stirred at room temperature for 18 h. The solution was treated with water and extracted with ethyl acetate. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with dichloromethane/methanol in the proportions 100/1 to 95/5 to give 80 mg of pure product obtained in the form of free base which was transformed into the hydrochloride salt. Mp: 193-195° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18].O>CC(C)=O>[CH2:18]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Oc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1cc(F)ccc1F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
10 g of 2,5-difluorophenol was dissolved in 120 ml dimethylformaldehyde, 21 g of potassium carbonate and 8.57 ml allyl bromide were added in this order thereto at room temperature and then the resulting mixture was stirred at 80° C. for 1 hour. After water was added to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was subjected to silica gel chromatography (developing solvent: 5% ethyl acetate/n-hexane) to give 13 g of 2,5-difluorophenol allyl ether as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:32]=[CH:31][C:23]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>CO>[N:28]1[CH:29]=[CH:30][C:25]([O:24][C:23]2[CH:22]=[CH:21][C:20]([C:17]3[N:16]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)[O:19][N:18]=3)=[CH:32][CH:31]=2)=[CH:26][CH:27]=1
Reactant: c1ccc(COc2ccc(-c3nc(-c4ccc(Oc5ccncc5)cc4)no3)cc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc(-c2nc(-c3ccc(Oc4ccncc4)cc3)no2)cc1
Temperature: 55 °C
Reaction time: 14 h
Yield: 4 %

Procedure:
In a single neck round bottom flask fitted with a condenser, 4-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenoxy)pyridine (97 mg, 229 μmol) was suspended in methanol (3.0 mL) and THF (3.0 mL) 10% Pd/C (1 mg, 16 μmol) was added The reaction vessel was sealed and the solution was stirred under H2 at 55° C. for 14 hours. The hot solution was filtered through Celite and the pad was washed with methanol (20 mL). The hot solution was filtered through Celite and the pad was washed with methanol (20 mL). The solvent was removed under reduced pressure the solid residue was purified by silica gel column chromatography (EtOAc/Hex 1:2) to give the product as a white solid (3 mg, 4%). 1H NMR (500 MHz, DMSO-d6) δ(ppm): 6.57 (2H, d, J=7.8 Hz), 6.84 (1H, d, J=9.0 Hz), 7.50 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz), 7.75 (2H, d, J=8.8 Hz), 8.08 (2H, d, J=7.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:25][CH:24]1[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1Cc1c[nH]c2ccccc12
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC1Cc1c[nH]c2ccccc12

Procedure:
Intermediate 1 was coupled with 2-(1H-Indol-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 518.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[Cl:28]N1C(=O)CCC1=O.C(Cl)Cl>>[Cl:28][C:19]1[N:18]2[C:13]([C:11]3[CH:10]=[N:9][N:8]([CH:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:5][C:6]#[N:7])[CH:12]=3)=[N:14][C:15]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:16][C:17]2=[N:21][CH:20]=1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cn1cc(-c2cc3ncc(Cl)n3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
3-Cyclopropyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 2) (46 mg, 0.13 mmol) and 1-chloropyrrolidine-2,5-dione (26 mg, 0.19 mmol) were suspended in DCM (1.3 mL, 0.13 mmol) and stirred at ambient temperature for 1 hour. This was immediately purified by silica chromatography using a 0-10% MeOH/EtOAc gradient to afford the title compound (18 mg, 34% yield) as a light yellow solid. MS (apci) m/z=393.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:15][O:16][CH:17]([F:19])[F:18])[C:13]#[N:14].C(N)(N)=[O:26].OO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[F:19][CH:17]([F:18])[O:16][N:15]=[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][O:4][C:3]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:2]=1[CH3:1])[C:13]([NH2:14])=[O:26]
Reactant: NC(N)=O
Reactant: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NOC(F)F)c1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(C)c(OCc2ccccc2C(=NOC(F)F)C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4.72 g of 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-difluoromethoxyimino-acetonitrile in 15 ml of acetone is added dropwise to a solution of 4.88 g of hydrogen peroxide-urea adduct and 0.20 g of potassium carbonate in 15 ml of water and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is then diluted with water and the precipitated crystalline material is filtered off with suction. Chromatography on silica gel with hexane/ethyl acetate (3:1) yields pure 2-(2,5-dimethylphenoxymethyl)-phenylglyoxalic acid amide O-difluoromethyl oxime in the form of white crystals; m.p. 153°-156° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([O:29]C4CCCCO4)[CH2:26][O:27][CH3:28])=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:48].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:48][C:17]([C:19]4[N:20]=[CH:21][C:22]([CH:25]([OH:29])[CH2:26][O:27][CH3:28])=[CH:23][CH:24]=4)=[CH:16][CH:15]=3)[CH2:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: COCC(OC1CCCCO1)c1ccc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-{5-[2-methoxy-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyridin-2-yl}-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.70 g), ammonium acetate (0.42 g) and acetic acid (5 mL) was stirred at 80° C. for 3 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.39 g, yield 69%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 511 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O>>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:15]=[C:7](/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)\[C:8]#[N:9])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: N#CCc1ccccn1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(/C=C(\C#N)c2ccccn2)cc1OC
Yield: 77.4 %

Procedure:
2-Pyridineacetonitrile (1.18 g) was condensed with 3,4-dimethoxybenzaldehyde (1.66 g) through Method B (production step 2), to thereby yield the target product (yield: 2.06 g, 77%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[NH:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH:7]1[N:15]([CH2:16][CH2:17][CH3:18])[C:1](=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: CCCNC1Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(C(=O)CC)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
Propionic acid chloride (2 mL, 2.1 g, 23 mmol) was added dropwise to a solution of indan-2-yl-propylamine (4.0 g, 23 mmol) and triethyl amine in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 2 hours. Aqueous (10%) sodium carbonate was added and the mixture was shaken. The organic phase was dried (magnesium sulfate), filtered and evaporated to yield 4.5 g (85%) of the title compound as an oil.:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH2:13])[C:7]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][N:19]=1.O>N1C=CC=CC=1>[NH2:12][C:10]1[N:9]=[C:8]([NH:13][C:22]([C:21]2[CH:20]=[N:19][C:18]([Cl:17])=[CH:26][CH:25]=2)=[O:23])[C:7]([N+:14]([O-:16])=[O:15])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1
Reactant: Nc1nc(N)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Solvent: O
Product: Nc1nc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c(-c2ccco2)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
A solution of 6-(2-furyl)-5-nitropyrimidine-2,4-diamine (500 mg, 2.26 mmol) in pyridine (10 mL) was treated with 6-chloronicotinoyl chloride (438 mg, 2.49 mmol), stirred for 16 h at 80° C., cooled to room temperature, poured into water (100 mL) and extracted with EtOAc (2×25 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:2)] to give the title compound (430 mg, 82%) as a yellow solid; NMR δH (400 MHz, DMSO) 11.14 (1H, s), 8.86 (1H, d, J 2.5 Hz), 8.27 (1H, dd, J 8.5, 2.5 Hz), 7.93 (1H, m), 7.77 (2H, br s), 7.65 (1H, d, J 7.5 Hz), 7.09 (1H, d, J 4.5 Hz), 6.72-6.70 (1H, m); Retention time 2.41 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:3]=1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C>[Si:27]([O:15][CH2:14][C:13]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])[CH3:16])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)c1cc(N)n(-c2ccccc2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1cc(N)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.6 %

Procedure:
To a solution of 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol (0.208 g, 0.85 mmol) in DMF (2.0 mL) was added imidazole (0.32 g, 4.7 mmol) and TBSCl (0.39 g, 2.6 mmol). The resulting mixture was stirred at RT for 5 h. Solvent was removed under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by chromatography to afford 3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-amine (0.125 g, 42% yield) as a light yellow oil. MS (ESI) m/z: 346.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](Cl)=[O:13])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O[NH:16][C:17](=[NH:37])[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[C:23]2[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][N:16]=[C:17]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[C:23]4[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:37]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(C(=O)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarbonyl chloride (D33; 94 mg, 0.4 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 114 mg, 0.360 mmol) and triethylamine (0.084 ml, 0.600 mmol) in dry DMF (1.5 ml) at 0° and the mixture was allowed to warm to room temperature and stirred for 45 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[C:40]([CH3:41])=[C:39]([C:42]#[CH:43])[N:38]=[C:37]1[CH3:44]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:43]#[C:42][C:39]2[N:38]=[C:37]([CH3:44])[N:36]([C:30]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=3[F:28])[C:40]=2[CH3:41])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#Cc1nc(C)n(-c2ccc(F)cc2F)c1C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-4-iodo-pyridine (0.21 g, 1 mmol) was dissolved in 10 mL of dry THF and 0.29 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (5 mg, 0.03 eq) and bis(triphenylphosphine)palladium(II)chloride (24 mg, 0.05 eq) were added, and the reaction mixture was stirred at room temperature for 10 min. 1-(2,4-Difluoro-phenyl)-4-ethynyl-2,5-dimethyl-1H-imidazole (0.16 g, 1 mmol) and Copper(I)iodide (3 mg, 0.02 eq) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 10 mL water and extracted three times with ethyl acetate (10 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (n-heptane/ethyl acetate 1:1) and recrystallized from diethyl ether. The desired product was obtained as a white solid (0.1 g, 42%), MS: m/e=344.0 (M+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:17][O-:18].[Na+]>CO>[F:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5]([O:18][CH3:17])=[CH:6][CH:7]=1
Reactant: Fc1ccc(F)c(NCC2CCOCC2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(NCC2CCOCC2)n1
Temperature: 25 °C

Procedure:
To a solution of 3,6-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (5 g, 21.91 mmol) in MeOH (35 mL) was added sodium methoxide (25 wt. % in MeOH, 15.03 mL, 65.7 mmol). The resulting mixture was heated in a steel bomb at about 135° C. for ˜18 hr. The mixture then was cooled to ambient temperature and concentrated in vacuo. The resulting residue was taken up in water (˜250 mL) yielding a precipitate, which was collected by filteration, and then washed with water. The solid then was dissolved in toluene (10 mL)/DCM (10 mL), decanted from the dark brownish film and concentrated in vacuo. The resulting residue was dried in high vacuo providing crude 3-fluoro-6-methoxy-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a nearly colorless oil, which was directly used in the next reaction without further purification. Yield: 4.96 g. LCMS (m/z): 241.1 [M+H]+; Retention time=0.87 min.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:18]#[N:19])[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[I:22]Cl>>[I:22][C:15]1[N:13]2[CH:14]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=3)[CH:10]=[C:11]([C:18]#[N:19])[C:12]2=[N:17][CH:16]=1
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Reactant: ClI
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Yield: 99 %

Procedure:
Prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine (example C.23 step 3) (900 mg, 4 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as a light yellow solid (1.3 g, 99%). MS (ISP) 414.1 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8](=[O:20])[CH2:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]=2[O:13][CH2:14]C(C)C)=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:20])[CH2:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]=2[O:13][CH3:14])=[CH:21][CH:22]=1
Reactant: CC(C)COC1=C(Cc2ccc(Cl)cc2)C(=O)CC(C)(C)C1
Solvent: CO
Product: COC1=C(Cc2ccc(Cl)cc2)C(=O)CC(C)(C)C1
Yield: 73.2 %

Procedure:
A solution of 154 g of the 2-(4-chlorobenzyl)-3-(2-methylpropoxy)-5,5-dimethylcyclohex-2-en-1-one obtained in Example 1 in 1200 ml methanol containing 3 g p-toluenesulphonic acid was refluxed for 2 hours. The reaction mixture was then extracted with 3 liters water and 1 liter diethyl ether and re-extracted with a further 1 liter diethyl ether. The organic phases were then back-washed first with 200 ml 10% aqueous sodium hydroxide and then with 100 ml saturated sodium chloride solution, dried over anhydrous magnesium sulphate and flashed. The residue was then crystallised in 60/80 petroleum, filtered and air-dried to give 98 g 2-(4-chlorobenzyl)-3-methoxy-5,5-dimethylcyclohex-2-en-1-one as a white solid, m.pt. 62°-63° C. Yield: 73%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:16][C:17](=[O:30])[CH2:18][O:19][C:20]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]2[C:21]=1[CH2:22][CH2:23][CH2:24]2>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:29][C:26]3[CH:27]=[CH:28][C:20]([O:19][CH2:18][C:17]([OH:30])=[O:16])=[C:21]4[C:25]=3[CH2:24][CH2:23][CH2:22]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(Cl)cc3)on2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole and 12C. mp 112-114° C.; MS m/z 430 (M+1).