Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH2:12][NH:13][C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)=[O:15])[CH:9]=[C:8]([CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[N:1]1([C:6]2[N:11]=[C:10]([CH2:12][NH:13][C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:28][C:27]3[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=3)=[O:15])[CH:9]=[C:8]([CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(CNC(=O)C2CCCN2)nc(-n2ccnc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(CNC(=O)C2CCCN2Cc2ccc(C(F)(F)F)cc2)nc(-n2ccnc2)n1
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a solution of pyrrolidine-2-carboxylic acid (2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-amide (43 mg, 0.15 mmol) in dimethylformamide (1.5 mL) was added 4-(trifluoromethyl)benzaldehyde (22 μL, 0.16 mmol) and acetic acid (0.075 mL) at r.t. The solution was allowed to stir for 2 hrs. To the solution was added sodium triacetoxyborohydride (107 mg, 0.50 mmol) at r.t. The solution was stirred for 16 hrs then concentrated under vacuum. The residue was diluted with DCM, washed with NaOH (1N, 30 mL) and water (30 mL), dried over MgSO4, filtered and concentrated. The product was purified using mass-triggered LCMS to afford 5 mg of 1-(4-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid (2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-amide as a white solid. [M+H]+ 444.96.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[O:7]=[C:1]1[CH2:2][CH2:3][C:4](=[O:6])[N:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CCCCCCN1C(=O)CCC1=O
Yield: 68.3 %

Procedure:
A mixture of succinimide (1, 3.2 g, 31.6 mmol) and ethyl 7-bromoheptanoate (5 g, 21 mmol) in dimethylformamide (30 mL) containing potassium carbonate (3.5 g, 25 mmol) was heated at about 55° to 60° C. for twenty hours. The mixture was then diluted with ether and washed twice with water, once with saturated aqueous sodium chloride, and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave the crude product which was purified by high performance liquid chromatography (HPLC) to give 3.66 g of 7-(2-oxo-5-oxopyrrolidin-1-yl)heptanoic acid, ethyl ester, 2. IR (neat): 1775, 1735, 1700 cm-1 ; PMR (CDCl3): δ 4.10 (q, J=7, 2H), 3.46 (t, J=7, 2H), 2.67 (s, 4H), 2.26 (t, J=7, 2H), 1.77-1.11 (m, 8H), and 1.23 (t, J=7, 3H).
Reaction SMILES: [CH:1]([CH:3]=[O:4])=[O:2].O.C(C=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:24]([O:26][CH:27]=[CH:28][CH:29]=[CH:30][CH3:31])[CH3:25].O1C=CC=CC1>>[CH3:31][CH:30]1[CH:29]=[CH:28][CH:27]([O:26][CH2:24][CH3:25])[O:2][CH:1]1[CH:3]=[O:4]
Reactant: CC=CC=COCC
Reactant: O=CC=O
Agent: C1=CCOC=C1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CCOC1C=CC(C)C(C=O)O1

Procedure:
Monomeric glyoxal was generated by heating a mixture of 8.0 g. of glyoxal hydrate (0.117 mol. of monomer) and 48.0 g. of phosphorus pentoxide over a gentle flame over 35 minutes. The liberated monomer was bubbled (argon stream) into 4.8 g. (0.04 mol) of 1-ethoxy-1,3-pentadiene (purity 92.3%) at 120°. After all the monomer had been generated, the solution was heated at 120° for an additional 45 minutes. Distillation afforded 1.32 g. of the pyran (b.07 = 56°, purity 91%) and 1.86 g. of recovered diene (yield based on diene - 32%, based on glyoxal = 6.6%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1S(O)(=O)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: Cn1c(S(=O)(=O)O)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)nc2ccccc21
Temperature: 155 °C
Yield: 16.6 %

Procedure:
A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (150 mg, 0.47 mmol), 1-methylbenzimidazole-2-sulfonic acid (83.4 mg, 0.39 mmol) and N,N-diisopropylethylamine (175 μl, 0.98 mmol) in acetonitrile (1.5 ml) was heated at 155° C. in the Smith Personal Synthesiser for 2400 seconds and then a further 900 seconds. The reaction mixture was partitioned between dichloromethane (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 95:5:0.5 by volume) to provide the title compound (29 mg, 14%). 1H NMR (400 MHz, CD3OD) δ 1.83-1.86 (m, 4H), 1.96-2.02 (m, 4H), 2.19 (d, 2H), 2.63-2.66 (m, 4H), 2.70 (t, 2H), 3.41 (s, 3H), 3.50 (t, 2H), 3.57 (s, 2H), 3.79-3.82 (m, 2H), 3.97 (t, 2H), 6.91 (d, 2H), 6.97-7.02 (m, 2H), 7.08 (d, 1H), 7.22 (d, 1H), 7.36 (d, 2H). LRMS APCI+ m/z 449 [MH]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([C:7](O)=O)[CH2:6][CH2:5][CH2:4]1.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].P(Cl)(Cl)(Cl)=O>>[F:1][C:2]([F:11])([F:10])[C:3]1([C:7]2[S:15][C:14]([NH2:16])=[N:13][N:12]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: NNC(N)=S
Reactant: O=C(O)C1(C(F)(F)F)CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(C2(C(F)(F)F)CCC2)s1

Procedure:
Commercially available, 1-(trifluoromethyl)cyclobutanecarboxylic acid (Oakwood), thiosemicarbazide (Aldrich) and phosphorus oxychloride (Aldrich) were processed as described for Example 1A to obtain the title compound. MS (ESI+) m/z 224 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[CH:17][S:16][C:10]=2[N:11]=[C:12]([NH2:15])[CH2:13][N:14]=1.[Cl:19]Cl.[OH-].[Na+]>CO.ClCCl>[Cl:19][C:17]1[S:16][C:10]2[N:11]=[C:12]([NH2:15])[CH2:13][N:14]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:9]=2[CH:18]=1
Reactant: ClCl
Reactant: NC1=Nc2sccc2C(c2ccccc2F)=NC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: NC1=Nc2sc(Cl)cc2C(c2ccccc2F)=NC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
19 g of 5-(2-fluoro-phenyl)-3H-thieno[2,3-e][1,4]diazepin-2-ylamine were dissolved in 730 ml of 5% methanol in dichloromethane, treated while stirring well with 327 g of a 2.8% solution of chlorine gas in 5% methanol in dichloromethane and stirred at room temperature under argon for 5 minutes. Thereafter, the reaction mixture was poured into 600 ml of 0.2N sodium hydroxide solution while cooling with ice and extracted. The dichloromethane extracts were dried with sodium sulphate, filtered and the solvent was evaporated in a vacuum. After two fold boiling of the residue in 5% methanol in dichloromethane and filtration there were obtained 7.4 g of 7-chloro-5-(2-fluoro-phenyl)-3H-thieno[2,3-e][1,4]diazepin-2-ylamine of m.p. 215-217° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]([O:12]C)=O)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH2:14]([CH2:16][NH2:17])[OH:15].C>CO.C(O)C>[OH:15][CH2:14][CH2:16][NH:17][C:10](=[O:12])[CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: NCCO
Reactant: COC(=O)Cn1ccnc1[N+](=O)[O-]
Solvent: CO
Solvent: CCO
Product: O=C(Cn1ccnc1[N+](=O)[O-])NCCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
A mixture of 2.50 g (13.5 mmol) of methyl 2-nitroimidazole-1-acetate and 3.0 ml (50.0 mmol) of ethanolamine in 15.0 ml methanol was stirred 20 hr at room temperature. The mixture was diluted with 45 ml ethanol and heated on a stream bath to effect solution. The hot solution was decolorized with charcoal, filtered and evaporated to dryness. The residue was recrystallized from a solution of 150 ml ethyl acetate and 10 ml of methanol to afford 1.81 g (62.4%) of SR-2508 as a white powder, mp 164.5-165.0° C., that was homogeneous by thin layer chromatography on silica gel with 10% methanol in ethyl acetate (Rf 0.16). The solubility of SR-2508 in 0.9% saline solution was approximately 200 mg/ml.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[O:21]
Reactant: Nc1ccc(F)cn1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-5-fluoropyridine (300 mg, 2.60 mmol) in DCM (4.0 mL), DIPEA (1.36 mL, 7.79 mmol) was added, followed by chloracetylchloride (0.23 mL, 2.86 mmol). The resulting dark brown reaction mixture was stirred at rt for 2 h, then quenched with water and diluted with DCM. The org. layer was separated and the aq. layer extracted with DCM (1×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 2-chloro-N-(5-fluoropyridin-2-yl)acetamide as a brown oil which was used in the next step without further purification. LC-MS conditions A: tR=0.60 min, [M+H]+=189.31.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]=[C:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13].C(O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: C=C(C#N)CCC#N
Solvent: CCO
Solvent: CO
Product: N#CCCC(C#N)CSc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 3,4-dichlorobenzenethiol (3.00 ml), methyleneglutaronitrile (2.57 ml), ethanol (25 ml), and triton B (40% methanol solution, 10 drops) was refluxed for 4 hours. After the reaction mixture was concentrated in vacuo, the resulting residue was dissolved in chloroform, washed with water, and dried over MgSO4. The solvent was evaporated at reduced pressure, and the residue was recrystallized from diethyl ether-hexane to give 6.14 g of 2-(3,4-dichlorophenylthiomethyl)glutaronitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:12][CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Reactant: NCCc1cccs1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(NCCc2cccs2)ccnc1Cl

Procedure:
A mixture of 2,4-dichloro-3-nitropyridine (1.5 g), 2-aminoethylthiophene (1 g) and triethylamine (5 ml) is heated to reflux in EtOH (60 ml). The reaction mixture is cooled, the solvent evaporated and the residue chromatographed on silica gel (10% hexane/CH2Cl2) to yield the desired addition product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)O)[N:10]([CH3:12])[N:11]=1.ClCCl.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH2:13][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][CH:16]=2)[N:10]([CH3:12])[N:11]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cc(NCc3cccc(Cl)c3)nn2C)c2cc(Cl)cnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(NCc2cccc(Cl)c2)cc1Cc1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
[5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (649, 0.033 g, 0.059 mmol) was combined with dichloromethane (5 mL, 0.08 mol) and triethylsilane (200 μL, 1.0 mmol) was added, followed by trifluoroacetic acid (100 μL, 1.0 mmol). The reaction was stirred at room temperature overnight and then concentrated. Ethyl acetate was added and the organic portion was washed with 1 M potassium carbonate, dried over anhydrous sodium sulfate and concentrated. Purification with silica gel flash chromatography eluting with a gradient of methanol (2-20%) and dichloromethane followed by washes with a mixture of ethyl acetate:hexane gave the desired compound (P-0410, 0.0039 g, 17%). (ESI) [M+H+]+=387.30.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:32]=1.C([Sn](CCCC)(CCCC)C=C)CCC.CC(=O)OCC>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16]([CH:31]=[CH2:32])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1nc(C)n2c1C(CCc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)CC2
Temperature: 90 °C

Procedure:
A slightly yellow homogeneous solution of 1-iodo-3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.500 g; 2.802 mmol) in anhydrous DMF (15 ml) was treated successively at rt with tris(dibenzylideneacetone)dipalladium(0) (82 mg; 0.090 mmol), triphenylphosphine (91 mg; 0.350 mmol), and finally with tributyl(vinyl)tin (1.63 ml; 5.604 mmol). The resulting mixture was heated to 90° C., under nitrogen, for 20 h. The reaction mixture was cooled to rt, EA (200 ml) was added, and the resulting solution was washed with water (2×125 ml). The resulting yellow organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give an orange oil. Purification by FC (DCM/MeOH=40/1) gave the pure product 3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-1-vinyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.936 g; 77%). LC-MS: tR=0.88 min.; [M+H]+=436.48 g/mol.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([NH2:10])=[CH:8][C:7]2[O:11][CH2:12][CH2:13][O:14][C:6]=2[CH:5]=1.[CH:16]([NH2:18])=O>>[CH2:13]1[CH2:12][O:11][C:7]2[CH:8]=[C:9]3[C:4]([C:3](=[O:2])[NH:18][CH:16]=[N:10]3)=[CH:5][C:6]=2[O:14]1
Reactant: COC(=O)c1cc2c(cc1N)OCCO2
Reactant: NC=O
Product: O=c1[nH]cnc2cc3c(cc12)OCCO3

Procedure:
A mixture of 2.0 g. of 6-amino-3,4-ethylenedioxybenzoic acid methyl ester and 6 ml. of 99% formamide is refluxed for 1.5 hours, then cooled, diluted with 5 ml. of water and the resulting precipitate filtered off, water washed and dried to obtain 6,7-ethylenedioxyquinazolin-4(3H)-one, m.p. 275° C.
Reaction SMILES: [O:1]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]1=2.[CH3:7][C:8]1[C:9]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[N:10][C:11](=[O:14])[NH:12][CH:13]=1>O1CCCC1.CS(C)=O.[Pd]>[OH:1][CH:3]1[CH2:4][CH:5]([N:12]2[CH:13]=[C:8]([CH3:7])[C:9]([N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:10][C:11]2=[O:14])[CH:6]=[CH:2]1
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Reactant: C1CC2=C(C1)O2
Agent: [Pd]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cn(C2C=CC(O)C2)c(=O)nc1-n1cncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.8 %

Procedure:
The equivalent amount of epoxycyclopentene is slowly added at 0° C. to 3.54 g (0.020 mol) of 5-methyl-4-(1,2,4-triazol-1-yl)pyrimidin-2(1H)-one (prepared by reaction of thymine with 1,2,4-triazole/POCl3 /triethylamine) in a mixture of 40 ml of dry tetrahydrofuran and 20 ml of dry dimethylsulfoxide with 5 mol % of the palladium(0) catalyst prepared in situ as above, and the reaction mixture is stirred at room temperature for 12 hours. The resulting suspension is filtered, the filtrate is concentrated and the residue is chromatographed over silica gel using methylene chloride/methanol 9/1. 1.34 g (25.8% of theory) of 1-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]-5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one (Example 1.18.1.) of melting point 198° to 204° C. are obtained. 1H NMR (270 KHz, d6 -DMSO), δ[ppm]: 9.31 (s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 6.25 (m, 1H), 5.92 (m, 1H), 5.52 (m, 1H), 5.28 (d, 1H), 4.71 (m, 1H), 2.87 (m, 1H), 2.30 (s, 3H), 1.47 (m, 1H).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([Br:21])[C:19]=1[OH:20])[CH:15]=[O:16]>>[Br:21][C:18]1[C:19]([O:20][CH:2]([CH3:3])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[C:12]([O:11][CH3:10])[CH:13]=[C:14]([CH:17]=1)[CH:15]=[O:16]
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: CC(C)CCCC(C)Br
Product: COc1cc(C=O)cc(Br)c1OC(C)CCCC(C)C

Procedure:
2-bromo-6-methyl-heptane was reacted with 3-methoxy-4-hydroxy-5-bromo-benzaldehyde to obtain 5-bromo-4-[(1,5-dimethyl-hexyl)-oxy]-m-anisaldehyde (boiling point = 190°-193°C/0.1 mmHg); 2-bromo-6-methyl-heptane was reacted with p-hydroxy-benzonitrile to obtain p-[(1,5-dimethyl-hexyl)-oxy]-benzonitrile (boiling point = 165°-168°C/1.0 mmHg);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CC(C)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][N:11]=2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccc(Br)cc2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1ccc(-c2ncnn2-c2ccc(Br)cc2)cc1

Procedure:
A mixture of 9.0 g. of 1-(p-bromophenyl)-5-(p-nitrophenyl)-1H-1,2,4-triazole, 18.0 g. of sodium hydrosulfite, 40 ml. of water and 150 ml. of acetone is stirred at room temperature overnight. The acetone is removed in vacuo and the residue is extracted with hot chloroform. Cooling produces 2.1 g. of the desired product as pale yellow crystals, mp. 128°-130° C.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1N)([CH3:3])[CH3:2].N([O-])=O.[Na+].CCCCCC.[BrH:22]>O.[Cu]Br>[Br:22][C:5]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: Br
Reactant: Cc1cccc(C(C)C)c1N
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: Cc1cccc(C(C)C)c1Br
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
2-isopropyl-6-methylanilin (14.9 g, 0.1 mol) was solved in conc hydrobromic acid (40 ml) and the mixture was cooled to 5° C. Sodium nitrite (7.0 g, 0.1 mol) in water (15 ml) was added so that the temperature was below 10° C. A solution of copper(I)bromide in conc hydrobromic acid (10 ml) was added to the reaction mixture and the temperature was allowed to raise to room temperature. The mixture was stirred for 1 h. at room temperature and 30 min at 40° C. Hexane was added and the organic layer was separated and evaporated under reduced pressure. Purification by column chromatography on silica gel using hexane as eluent gave 6.9 g (32%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:15]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[C:25]3[CH2:42][CH2:41][CH2:40][C:26]=3[N:27]=[C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[C:35](OCC)=[O:36])[N:29]=2)[CH:19]=1)([CH3:17])[CH3:16]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:9])[C:35]([C@@H:31]2[CH2:32][CH2:33][CH2:34][N:30]2[C:28]2[N:29]=[C:24]([NH:23][C:20]3[CH:19]=[C:18]([CH:15]([CH3:16])[CH3:17])[NH:22][N:21]=3)[C:25]3[CH2:42][CH2:41][CH2:40][C:26]=3[N:27]=2)=[O:36])=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Reactant: CNc1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)N(C)c3ccc(F)nc3)nc3c2CCC3)n[nH]1
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
To a solution of 6-fluoro-N-methyl-pyridin-3-amine (1.05 g, 8.34 mmol) in THF (15 mL) was added isopropylmagnesium chloride (2M in THF) (4.15 mL, 8.34 mmol) dropwise at 0° C. The reaction mixture was stirred at the same temperature for 30 min. followed by the dropwise addition of solution of ethyl (2S)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxylate (0.8 g, 2.083 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The progress of reaction was monitored by LCMS. The reaction mixture was quenched with saturated solution of ammonium chloride (30 mL) and extracted with EtOAc (2×30 mL). The organic layer was washed with water (40 mL) followed by brine (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude which was purified by reverse phase HPLC to afford (2S)—N-(6-fluoro-3-pyridyl)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-N-methylpyrrolidine-2-carboxamide (190 mg) as solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 1.19-1.30 (m, 6H), 1.80-2.30 (m, 6H), 2.58-2.68 (m, 2H), 2.70-2.88 (m, 2H), 2.91-3.00 (m, 1H), 3.28 (s, 3H), 3.61-3.78 (m, 1H), 3.79-3.90 (m, 1H), 4.40 (brs, 1H), 6.18 (s, 1H), 6.66 (s, 1H), 7.00 (brs, 1H), 8.01 (brs, 1H), 8.20 (s, 1H). The other enantiomer was obtained by using the chiral (R) starting material.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][CH:4]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C)C=O>[C:11]1(=[O:21])[N:15]([CH2:2][C:3]2[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][CH:4]=2)[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1cccc(CCl)n1
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
A mixture of 6-chloromethyl-2-pyridinecarbonitrile (2.75 g) and potassium phthalimide (3.35 g) in N,N-dimethylformamide (27.5 ml) was stirred at ambient temperature for 4 hours. After the solvent was evaporated in vacuo, water (50 ml) was added to the residue and the resulting precipitate was collected by filtration to give 6-phthalimidomethyl-2-pyridinecarbonitrile (4.60 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1COCC1.Br[CH2:28][C:29]#[N:30]>O>[C:29]([CH2:28][N:12]([C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9][CH:10]=1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])#[N:30]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)Nc1ccnn1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC#N)c1ccnn1-c1ccccc1
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a mixture of tert-butyl (1-phenyl-1H-pyrazol-5-yl)carbamate (3.80 g), 60% NaH (0.422 g) and THF (60.0 mL) was added bromoacetonitrile (1.93 g) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added water, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.38 g).