Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[C:14]([O:19][CH3:20])=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:21])[C:7]=2[C:22]=1[O:23][CH3:24].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[C:2]([C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[C:14]([O:19][CH3:20])=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:21])[C:7]=2[C:22]=1[O:23][CH3:24])([OH:26])=[O:1]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COc1cc(C)cc2c1Sc1ccc(CO)c(OC)c1C(=O)OC2
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)cc2c1Sc1ccc(C(=O)O)c(OC)c1C(=O)OC2

Procedure:
560 mg (1.62 mmol) of the compound from Example VI are stirred overnight at 25° C. with 9.13 g (24.3 mmol) of pyridinium dichromate in 20 ml of dimethylformamide. The mixture is poured into water and washed with ether, the ether phase is washed with water and dried over sodium sulphate and, after concentrating in vacuo, the residue is chromatographed on silica gel using methylene chloride/ethanol 10:1.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:24][C:25](=[O:34])[NH:26][O:27]C2CCCCO2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.O>[CH:1]1([CH2:6][C@H:7]([CH2:24][C:25]([NH:26][OH:27])=[O:34])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ncccn1)NOC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ncccn1)NO
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.3 %

Procedure:
A mixture of (5S)-1-{(2R)-2-(cyclopentylmethyl)-4-oxo-4-[(tetrahydro-2H-pyran-2-yloxy)amino]butanoyl}-N-2-pyrimidinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (80 mg, 0.17 mmol) in acetic acid (8 mL) and water (2 mL) was stirred at room temperature for 3 days. The solvent was then removed to provide a residue which was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-70% MeCN:H2O) to afford (5S)-1-[(2R)-2-(cyclopentylmethyl)-4-(hydroxyamino)-4-oxobutanoyl]-N-2-pyrimidinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (24 mg, 35% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (br. s., 2H) 1.37-1.94 (m, 9H) 2.41 (br. s., 1H) 2.64 (br. s., 1H) 3.24 (br. s., 2H) 3.52 (br. s., 1H) 3.83 (br. s., 1H) 5.11 (br. s., 1H) 6.99-7.07 (m, 2H) 8.64 (d, J=4.80 Hz, 2H) 9.21 (br. s., 1H) 10.33 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].Br[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].CN1CCOCC1>O1CCOCC1>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](NCC(=O)OCc1ccccc1)C(C)C
Yield: 21.9 %

Procedure:
A solution of 2.12 g (12.6 mmol) of L-valine methyl ester hydrochloride, 2.0 ml (12.6 mmol) of benzyl bromoacetate, and 3.5 ml (31 mmol) of 4-methylmorpholine in 100 ml of dioxane was heated at reflux for 4 h. After being allowed to cool, the solution was concentrated in vacuo and partitioned between ether and water. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography on silica gel using 20% ethyl acetate in hexane provided 0.77 g (22%) of the desired compound as a colorless oil (Rf 0.24, 20% ethyl acetate in hexane. 1H NMR δ 0.95 (d, J=7 Hz, 6H), 1.96 (br, 1H), 1.98 (octet, J=7 Hz, 1H), 3.08 (d, J=6 Hz, 1H), 3.43 (AA', 2H), 3.71 (s, 3H), 5.16 (s, 2H), 7.36 (m, 5H).
Reaction SMILES: C([O:3][C:4](=[O:9])[C:5]([OH:8])([CH3:7])[CH3:6])C.[H-].[Na+].[CH2:12]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28]Cl)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:12]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:3])=[O:9])=[N:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClCc1nn(Cc2ccccc2)c2ccccc12
Reactant: CCOC(=O)C(C)(C)O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(OCc1nn(Cc2ccccc2)c2ccccc12)C(=O)O
Temperature: 90 °C

Procedure:
Ethyl-2-hydroxyisobutyrate (18.5 g, 140 mmol, 1.2 eq.), toluene (100 mL) and DMF (20 mL) were placed in a three-necked flask fitted with a mechanical stirrer and a reflux condenser under an inert atmosphere. A dispersion of 60% NaH (5.6 g, 140 mmol, 1.2 eq.) was added to the mixture in portions over a period of approximately 1.5 hours. A solution of 1-benzyl-3-chloromethyl-1H-indazole (30 g, 117 mmol, 1 eq.) in toluene (90 mL) and DMF (60 mL) was then added dropwise. The reaction mixture was heated to approximately 90° C. and kept at that temperature until the reaction was complete (checked by TLC, approximately 10 hours). After cooling to room temperature the mixture was washed with acidified water and water. The organic phase was concentrated under reduced pressure and the oily residue obtained was treated with 10 M NaOH (36 mL) at reflux temperature for at least 3 hours. The product, which was precipitated out by the addition of concentrated HCl, was filtered and dried. Yield: 32.3 g of white solid (85%).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=O)=O.[C:17](#[N:21])[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:13][C:8]([F:14])([C:9]([F:12])([F:11])[F:10])[CH2:7][CH:18]([C:17]#[N:21])[C:19]#[N:20]
Reactant: N#CCC#N
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)CC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
In 30 ml of ethylene glycol dimethyl ether, 8.4 g of 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate and 5.9 g of malononitrile were dissolved. Thereto 12.3 g of potassium carbonate was added and the mixture was stirred at room temperature for 8 hours. Thereafter dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.1 g of 2-(2,2,3,3,3-pentafluoropropyl)malononitrile.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.[F:30][C:31]([F:36])([F:35])[CH:32]1[CH2:34][O:33]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:34][CH:32]([OH:33])[C:31]([F:36])([F:35])[F:30])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: FC(F)(F)C1CO1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC(O)C(F)(F)F)CC4)cc3F)ncc2Cl)n[nH]1
Reaction time: 8 h

Procedure:
The mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (50.0 mg, 0.12 mmol) and 2-(trifluoromethyl)oxirane (67.8 mg, 0.60 mmol) in 2 mL of DMF was stirred overnight. The reaction mixture was purified by preparative RP-HPLC to afford 3-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)-1,1,1-trifluoropropan-2-ol. ESMS m/z 528.2 (M+H+).
Reaction SMILES: CO[C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[NH:10][CH2:11][C:12]([O-:14])=[O:13])=[O:4].[Na+].[S-:16][C:17]#[N:18].[Na+].O.Cl[Si](C)(C)C>CN1CCCC1=O>[O:4]=[C:3]1[NH:18][C:17](=[S:16])[N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][C:5]1=2
Reactant: N#C[S-]
Reactant: COC(=O)C1=C(NCC(=O)[O-])CCC1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)Cn1c2c(c(=O)[nH]c1=S)CCC2
Temperature: 117 °C
Yield: 82.6 %

Procedure:
Sodium ({2-[(Methyloxy)carbonyl]-1-cyclopenten-1-yl}amino)acetate (60 g) and sodium thiocyanate (26.6 g) were stirred in N-methylpyrrolidinone (240 ml) and water (2.94 ml) under a nitrogen atmosphere. Chlorotrimethylsilane (73.8 g) was added and the mixture heated to 117±3° C. After 3 hours at this temperature the reaction mixture was cooled to 90° C. and water (480 ml) was added. The mixture was cooled to 2° C. and the product isolated by filtration. It was washed with water (2×120 ml) then acetone (2×60 ml) and dried at 60° C. in an oven under reduced pressure to yield the title compound as an off-white solid (50.69 g, 83%). 1H NMR (d6 DMSO) δ 2.00 (2H, quintet), 2.60 (2H, t), 2.87 (2H, t), 4.95 (2H, broad s), 12.57 (1H, broad s), 13.26 (1H, broad s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:19])[C@H:9]([CH2:17][OH:18])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1[N:24]=[CH:23][N:22]([C:25](N2C=NC=C2)=[O:26])[CH:21]=1>C(Cl)Cl>[N:22]1([C:25]([O:18][CH2:17][C@@H:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:19])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:26])[CH:21]=[CH:20][N:24]=[CH:23]1
Reactant: COC(=O)CCC[C@@H](CO)N(C)C(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COC(=O)CCC[C@@H](COC(=O)n1ccnc1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of (S)-methyl 5-(tert-butoxycarbonyl(methyl)amino)-6-hydroxyhexanoate (4.4 g, 16 mmol) in DCM (50 mL) was added CDI (3.1 g, 19 mmol). The reaction was complete in 30 min. DCM was removed. The residue was purified on silica gel column (hexanes/EtOAc 1:1) to give (S)-2-(tert-butoxycarbonyl(methyl)amino)-6-methoxy-6-oxohexyl 1H-imidazole-1-carboxylate (5.1 g, 85%) as a colorless oil. LRMS (M+Na+) m/z 392.1
Reaction SMILES: ClC1C=CC(C([N:8]2[CH2:13][CH2:12][C:11]3[C:14]4[C:15]([S:43][C:10]=3[CH2:9]2)=[N:16][C:17]([CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[C:18]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:19]=4[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([O:30][CH3:31])[CH:21]=2)=O)=CC=1.[OH-].[K+].C(O)C>O>[CH2:41]([N:38]([CH2:37][C:17]1[N:16]=[C:15]2[S:43][C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[C:14]2=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([O:30][CH3:31])[CH:21]=2)[C:18]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:39][CH3:40])[CH3:42]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC(C)C)c(OC)c1)CCN(C(=O)c1ccc(Cl)cc1)C3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC(C)C)c(OC)c1)CCNC3
Reaction time: 5 h
Yield: 92.8 %

Procedure:
A mixture of the compound (8.9 g) obtained in Example 48A, 4N KOH (18 ml) and ethanol (150 ml) was stirred under refluxing conditions for 5 hours. The reaction mixture was poured over water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (4:1, v/v) to yield ethyl 2-diethylaminomethyl-4-(4-isopropoxy-3-methoxyphenyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (6.5 g, 88%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals.
Reaction SMILES: [C:1](Cl)(=O)C.CO.[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]([C:17]([OH:19])=[O:18])[NH:8]1>CN(C=O)C>[CH3:1][O:18][C:17]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][NH:8]1)=[O:19]
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)C1Cc2ccccc2CN1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
Acetyl chloride (0.88 g) was added to methanol (100 ml) with stirring at 0° C. After 10 minutes, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (J. Am. Chem. Soc., 1962, 48, 4487-4494) (2.0 g) was added; the reaction was allowed to warm to room temperature and stirred overnight. DMF (1 ml) was then added and stirring was then continued for a further 24 h. The solvent was removed in vacuo; dichloromethane was added and the solid thus formed was filtered off and partitioned between dichloromethane (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml). The organic phase was dried (magnesium sulphate), filtered, and the filtrate evaporated in vacuo to yield the title compound as a pale yellow oil (1.0 g).
Reaction SMILES: Cl[CH2:2][C:3](=[CH2:16])[CH2:4][CH:5]1[O:9][C:8](=[O:10])[CH:7]=[C:6]1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=1>>[Cl:25][C:22]1[N:21]=[CH:20][C:19]([CH2:18][NH:17][CH2:2][C:3](=[CH2:16])[CH2:4][CH:5]2[O:9][C:8](=[O:10])[CH:7]=[C:6]2[N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:24][CH:23]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: C=C(CCl)CC1OC(=O)C=C1N1CCCC1
Product: C=C(CNCc1ccc(Cl)nc1)CC1OC(=O)C=C1N1CCCC1

Procedure:
If, in the preparation process 2 according to the invention for preparing the novel compounds of the general formula (I), the compound of the formula (III) used is, for example, 5-[2-(chloromethyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one and the compound of the general formula (IV) is 3-aminomethyl-6-chloropyridine, this can be reacted in a first reaction step to give 5-[2-({[(6-chloropyridin-3-yl)methyl]amino}methyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one as compound of the general formula (V) which is then subjected to an intramolecular cyclization in the second reaction step (reaction scheme VI):
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([C:20]2[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=2)C=CC=CC=1>>[C:20]1([CH3:14])[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: Cc1ccc(NC(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 4-benzylpiperidine and 4-phenylphenyl isocyanate. 1H NMR (400 MHz, CDCl3): 7.31-7.12 (m, 7H), 7.07 (d, J=8.0 Hz, 2H), 6.32 (s, 1H), 4.06-4.00 (m, 2H), 2.79 (td, J=13, 2.5 Hz, 2H), 2.56 (d, J=6.8 Hz, 2H), 2.28 (s, 3H), 1.79-0.165 (m, 3H), 1.30-1.18 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1.C1COCC1.[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].CC[O-].[Na+]>CCOC(C)=O>[CH2:32]([O:31][C:29](=[O:30])[C:28](=[O:34])[CH2:19][C:18]([C:8]1[N:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=1)=[O:20])[CH3:33]
Reactant: CC(=O)c1ccc(-c2ccccc2)n1Cc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(-c2ccccc2)n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 1-[1-(4-fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]ethanone AV-8-1 (0.628 g, 2.14 mmol), dry THF (10 mL), diethyl oxalate (0.41 mL, 3.00 mmol) and NaOEt (0.204 g, 3.00 mmol). The resulting mixture was stirred 1 h at ambient temperature. The mixture was diluted with EtOAc and washed with 1N HCl, H2O (2×) and brine. Drying (MgSO4) filtration and removal of the solvent in vacuo gave 4-[1-(4-fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AV-9-1 as an oil. This material was used without further purification. 1H NMR (CDCl3) δ 1.38 (3H, t, j=7.1 Hz), 4.38 (2H, q, j=7.1 Hz), 5.65 (2H, s), 6.38 (1H, d, j=4.1 Hz), 6.79 to 6.94 (4H, m), 7.29 (2H, m), 7.39 (3H, m).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:23].[N:24](OCCC(C)C)=O>C(Cl)(Cl)Cl.C(O)(=O)C>[NH:23]1[C:3]2[C:2](=[C:7]([C:8]3[N:9]=[C:10]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:11]4[S:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:6]=[CH:5][CH:4]=2)[CH:1]=[N:24]1
Reactant: CC(C)CCON=O
Reactant: Cc1c(N)cccc1-c1nc(N2CCOCC2)c2sccc2n1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: c1cc(-c2nc(N3CCOCC3)c3sccc3n2)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Reaction of 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine under Suzuki conditions yielded 2-methyl-3-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine. To a solution of 2-methyl-3-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine (80 mg) in chloroform (8 mL) and acetic acid (4 mL) was added isoamyl nitrite (36 μL). The reaction mixture was stirred for 1 day at room temperature. The mixture was then quenched with sodium bicarbonate solution and extracted in to chloroform and reduced in vacuo. The residue was purified using flash chromatography to yield 270. MS: ESI MH+ 338
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)#[CH:13]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[C:13][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][CH:3]=2)=[CH:15][CH:16]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Brc1cncc2ccccc12
Product: COc1ccc(C#Cc2cncc3ccccc23)cc1
Reaction time: 4 h
Yield: 58.7 %

Procedure:
According to Scheme 29 Step 1: The title compound was prepared from 4-bromoisoquinoline (1 eq, 5.30 mmol, 1.10 g) and 1-ethynyl-4-methoxybenzene (1 eq, 5.30 mmol, 0.70 g) according to the procedure described for Example 13 Step 1. Reaction conditions: 70° C. for 4 hours. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column SiO2, cyclohexane/AcOEt 90/10 to 80/20) to afford 4-(2-(4-methoxyphenyl)ethynyl)isoquinoline (3.11 mmol, 0.81 g, 59%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:14]Br>C(O)(=O)C>[Br:14][CH:11]([CH3:12])[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:13]
Reactant: BrBr
Reactant: CCC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 1-(3-nitrophenyl)propan-1-one (1.41 g, 7.90 mmol) in acetic acid (20 mL) was added bromine dropwise (1.27 g, 7.93 mmol) and the mixture was stirred at room temperature for 24 h. The mixture was poured into ice-cold water and the organic layer was extracted with DCM. The organic extract was washed with sat. aq. NaHCO3 and brine, dried over anhydrous MgSO4, and filtered. Evaporation of the solvent under reduced pressure afforded 11z as a white solid which was used in the next step without further purification (1.78 g, 87%). 1H NMR matches literature data.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH3:18])=[O:16].O>C(Cl)(Cl)(Cl)Cl>[C:2]1([C:1]([C:14]2[O:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccco1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(C(=O)c2ccccc2)o1

Procedure:
Anhydrous ferric chloride 10.42 g, 0.0026 mole) and benzoyl chloride II-1(29.65 g, were dissolved in CCl4 (40 ml and added dropwise with methyl furan-2-carboxylate I-1 (24 g. 0.19 mole). The reaction mixture was then heated under refluxing for 16 hrs, and after cooling was added with water(120 ml). The mixture was extracted with CCl4 , then the CCl4 layer was washed with water, 5% sodium bicarbonate solution, and then with water, till neutral, then dried over anhydrous Magnesium sulfate and filtered. The solvent of the filtrate was evaporated under reduced pressure, the residue was recrystallized from isopropanol, and then from methanol to give compound V-1. Yield 18.75 g(42.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.Br[CH2:14][CH2:15][OH:16]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:14][CH2:15][OH:16])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: OCCBr
Product: Cc1cc(C)n2nc(SCCO)nc2n1
Yield: 84 %

Procedure:
The compound of the first step was prepared according to the experimentals described for Example 1 above from of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol and 2-bromoethanol in 84% yield; EM (calc.): 224.1; MS (ESI) m/e: 225.0 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.09 (s, 1H), 5.05 (s, 1H), 3.70 (t, 2H), 3.30 (t, 2H), 2.66 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [C:1]([CH:6]1[CH2:11][C:10](O)([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]1=[O:17])(=[O:5])[CH2:2][CH2:3][CH3:4].B(F)(F)F.O(CC)CC>C1C=CC=CC=1>[C:1]([C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][C:7]=1[OH:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C1CC(O)(C(=O)OC)C=CC1=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCC(=O)c1cc(C(=O)OC)ccc1O
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 5-butyryl-1-hydroxy-4-oxocyclohex-2-ene-1-carboxylate in benzene was added BF3.O(Et)2 (1.3 mL, 10 mmol). The mixture was stirred for 0.25 h and then quenched with saturated sodium bicarbonate followed by extraction with dichloromethane. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford methyl 3-butyryl-4-hydroxybenzoate which was used without further purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[O:23][CH:24]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH:24]=2)[N:3]=1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cncs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1

Procedure:
250 mg (0.964 mmol) of 2-amino-6-sulfanyl-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, together with 242 mg (1.060 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 243 mg (2.892 mmol) of sodium bicarbonate, were stirred in 5 ml DMF at room temperature for 1 h. The reaction mixture was added to water, and the resulting precipitate was filtered off and washed with diethyl ether. Drying under reduced pressure gave 53 mg (12% of theory) of the target compound.