Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][N:44]([CH2:47][C:48](O)=[O:49])[C:43](=[O:51])[N:42]=1)=[O:39])[C:28]1[CH:36]=[CH:35][C:34]2[O:33][CH2:32][O:31][C:30]=2[CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:48](=[O:49])[CH2:47][N:44]2[CH:45]=[CH:46][C:41]([NH:40][C:38]([O:37][CH2:27][C:28]3[CH:36]=[CH:35][C:34]4[O:33][CH2:32][O:31][C:30]=4[CH:29]=3)=[O:39])=[N:42][C:43]2=[O:51])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)n1)OCc1ccc2c(c1)OCO2

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(piperonyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.76 (brs, 1H), 8.36 (m, 1H), 8.28 (m, 1H), 7.92 (d, 0.6H), 7.86 (d, 0.4H), 7.73 (m, 2H), 7.03 (t, 1H), 7.00 (s, 1H), 6.92 (s, 2H), 6.03 (s, 2H), 5.08 (s, 2H), 4.84 (s, 1.2H), 4.74 (s, 0.8H), 4.47 (s, 0.8H), 4.30 (s, 1.2H), 4.24 (t, 1.2H), 4.08 (t, 0.8H), 4.01 (t, 1.2H), 3.89 (t, 0.8H).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7]C[CH2:5][CH2:4][CH2:3]1.[CH2:8]=[C:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.CC(CCC)=C.CC(=CC(C)(C)C)C.C1(C(CC2C=CC=CC=2)=C)C=CC=CC=1>>[CH3:7][C:2]([CH2:3][CH2:4][CH3:5])=[CH2:1].[CH3:8][C:9](=[CH:10][CH2:11][CH3:12])[CH3:13]
Reactant: C=C1CCCC1
Reactant: C=C1CCCCC1
Agent: C=C(C)CCC
Agent: C=C(Cc1ccccc1)c1ccccc1
Agent: CC(C)=CC(C)(C)C
Product: CCC=C(C)C

Procedure:
Under similar reaction conditions as in Example 5, methylenecyclohexane, methylenecyclopentane, 2-methyl-1-pentene, 2,4,4-trimethyl-2-pentene and 2,3-diphenyl-1-propene underwent the isomerization to the thermodynamically more stable isomers shown in Table 1. The isomerization of 2-methyl-1-pentene afforded only 2-methyl-2-pentene and 4-methyl-2-pentenes were not observed.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccccc1-c1ccc(CO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1-c1ccc(CCl)cc1
Reaction time: 16 h
Yield: 87.9 %

Procedure:
2.0 g (8.25 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate was dissolved in 1.31 g of pyridine and methylene chloride (20 ml). 1.47 g (12.4 mmol) of thionyl chloride was dropwise added thereto at room temperature, followed by stirring as such for 16 hours and under reflux by heating for 5 hours. After the reaction liquid was cooled and concentrated, a saturated aqueous solution of sodium hydrogencarbonate was added thereto, followed by the extraction with methylene chloride. The organic phase was washed with water, dried and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.89 g of the title compound as an oil (yield 88%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH3:12].N1CCCCC1>C(O)C>[CH3:1][N:2]1[C:9]([CH3:8])=[CH:10][C:11]([CH3:12])=[C:4]([C:5]#[N:6])[C:3]1=[O:7]
Reactant: CC(=O)CC(C)=O
Reactant: CNC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)n(C)c(=O)c1C#N
Reaction time: 3 h
Yield: 77.4 %

Procedure:
N-methyl cyanoacetamide (113 g., 1.15 mole), 2,4-pentanedione (115 g., 1.15 mole), piperidine (11.5 ml.) and anhydrous ethanol (250 ml.) are refluxed with stirring for 3 hours. The mixture is allowed to stand overnight at room temperature and the white crystalline precipitate is collected by filtration to give 1-methyl-3-cyano-4,6-dimethylpyrid-2-one, 144 g. (77.4% yield), mp. 202°-205° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4[CH3:19])=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]=1[C:13]1[N:7]2[CH2:6][C:5]3[C:9]([C:8]2=[N:11][N:12]=1)=[CH:10][C:2]([C:26]#[N:27])=[CH:3][CH:4]=3
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(C#N)cc1-2
Temperature: 80 °C
Yield: 6 %

Procedure:
A mixture of 8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (300 mg) (prepared as in Example 4), zinc cyanide (187 mg), and DMF (5 ml) was degassed with a stream of N2 for 0.5 h. Tetrakis(triphenylphosphine) palladium(0) (20 mg) was added and the reaction heated to 80° C. for 2 days. The reaction mixture was cooled, poured into 10% ammonium hydroxide solution and extracted into EtOAc, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica, eluting with 50% EtOAc/hexane, and recrystallised from EtOAc/hexane to give the title compound (15 mg, 6%). 1H NMR (360 MHz, CDCl3) δ 8.28 (1H, s), 7.69 (1H, dd, J=8.0, 1.4 Hz), 7.54–7.50 (2H, m), 7.48–7.39 (4H, m), 4.05 (2H, s), 2.73 (3H, s), m/z (ES+) 340 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:25]([O:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:8][CH2:9]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccccc1CN1CCC(O)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2[N+](=O)[O-])CC1)c1ccccc1
Yield: 67.1 %

Procedure:
0.5 g (0.00212 mol) of 1-(2-nitro-benzyl)-piperidin-4-ol and 0.595 ml (0.00424 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.295 ml (0.00254 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1 :2). 0.484 g (75%) of 1-(2-nitro-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil. MS: me/e=341 (C19H21N2O4+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[S:10][CH:11]=1.[OH-].[K+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=1
Reactant: CCn1ncc(Br)c1-c1csc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc(Br)c1-c1csc(C(=O)O)c1
Temperature: 50 °C

Procedure:
To a solution of methyl 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.2 g, 0.63 mmol) in THF/H2O (5 mL/1 mL) was added KOH (0.15 g, 2.4 mmol). The reaction mixture was heated to 50° C. for 10 h and then concentrated and diluted with H2O (2 mL). The pH was adjusted to 6 with aqueous HCl. The mixture was extracted with DCM (3×5 mL) and the collected organic fractions were concentrated under vacuum to give crude 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid, which was used directly without further purification. LC-MS (ES) m/z=302 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]=[C:17]([S:25][CH3:26])[N:16]=1>C1COCC1>[CH3:26][S:25][C:17]1[N:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CSc1nc(Cl)cc(C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Oc2cccc(C(F)(F)F)c2)cc(C(F)(F)F)n1

Procedure:
m-(Trifluoromethyl)phenol (1.06 g, 0.0044×1.5 mol) and NaH (0.26 g (ca.60% in mineral oil), 0.0044×1.5 mol) were dissolved in THF, and then 4-chloro-2-methylthio-6-(trifluoromethyl)pyrimidine (Compound No. VII-17) (1.0 g, 0.0044 mol) was added thereto. The resulting solution was refluxed for about 7 hours. The reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate to separate an organic phase. The organic phase was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated. Thereafter, remaining phenol and others were distilled off in a tubular oven (under water flow, 150° C.) to obtain the intermediate compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[C:9](=[O:20])[S:8][C:5]2=[N:6][CH:7]=1.[N:21](OCCC(C)C)=[O:22]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([N:21]=[O:22])[CH2:18][CH2:19]3)=[O:13])[C:9](=[O:20])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)CCON=O
Reactant: O=C(Cn1c(=O)sc2ncc(Cl)cc21)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: O=NN1CCN(C(=O)Cn2c(=O)sc3ncc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of 6-chloro-2-oxo-1-[(1-piperazinyl)carbonylmethyl]-1,2-dihydrothiazolo[5,4-b]pyridine (1.40 g) in chloroform (15 ml) was added isoamyl nitrite (3.0 ml) and the mixture was stirred for 11 hours at room temperature. Precipitated crystals were collected by filtration, washed with chloroform and dried to give colorless crystals of 6-chloro-2-oxo-1-[(4-nitroso-1-piperazinyl)carbonylmethyl]-1,2-dihydrothiazolo[5,4-b]pyridine (1.33 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C([Si](Cl)(C(C)C)C(C)C)(C)C.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([Si:26]([CH3:28])([CH3:27])[N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[CH:3]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Ic1c[nH]c2ncccc12
Agent: CC(C)[Si](Cl)(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)n1cc(I)c2cccnc21

Procedure:
was prepared following the protocol of Scheme 20 Step 2, substituting 1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde 46 with 3-iodo-1H-pyrrolo[2,3-b]pyridine and triisopropylsilyl chloride with tert-Butyl-dimethyl-silyl chloride.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:33]([NH:40][C@H:41]([C:50](O)=[O:51])[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CN1CCOCC1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:10])[CH:5]([NH:6][C:50](=[O:51])[CH:41]([NH:40][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C(NC(=O)C(CCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 142.3 %

Procedure:
To an ice-cooled solution of D-valine methyl ester hydrochloride (1000 mg, 3.58 mmol) and HOBt (in DMF (14 mL) was added EDCl (755 mg, 3.94 mmol). After the mixture was stirred for 30 min, N-boc-L-homophenylalanine (600 mg, 3.58 mmol) and N-methylmorpholine (1 mL, 8.95 mmol) were added. The mixture was warmed to room temperature and stirred overnight. The solvent was removed and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic phases were dried over anhydrous Na2SO4. After concentration under reduced pressure, the crude title compound (2000 mg) was obtained and used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]([CH3:16])[N:5]=1)[NH2:3].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:26])=O)=[CH:20][CH:19]=1>C(O)C>[CH3:1][N:2]([C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]=[C:6]([CH3:16])[N:5]=1)[N:3]=[C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1)[CH3:26]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: Cc1nc(-c2ccccc2)cc(N(C)N)n1
Solvent: CCO
Product: CC(=NN(C)c1cc(-c2ccccc2)nc(C)n1)c1ccc(C)cc1

Procedure:
The title compound was prepared from N-methyl-N-(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazine (196 mg, 0.91 mmol) and 4-methylacetophenone (122 μL, 0.91 mmol) in 10 mL of ethanol by a procedure similar to example 8, step 4 yielding 180 mg (60%) of a cream solid. HPLC Purity: 97%.
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][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:24]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)[CH:25]([CH2:29][CH2:30][CH3:31])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CCN1
Product: CCCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 3-propyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 431.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[C:26]2[O:25][CH2:24][C:23](=O)[C:22]=2[CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[C:26]=2[O:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cccc2c1OCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c(OS(=O)(=O)C(F)(F)F)coc12
Temperature: -20 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Trifluoromethanesulfonic anhydride (4.6 g, 16.3 mmol) was added dropwise to a solution of 7-methoxybenzofuran-3(2H)-one (1.8 g, 10.9 mmol), triethylamine (2.2 g, 21.8 mmol), and dichloromethane (40 mL) at −20° C. The resulting mixture was stirred at −20° C. for 2 h. The reaction mixture was neutralized with saturated aqueous NaHCO3 (22 mL). The organic layer was separated, washed with water (40 mL) and brine (40 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column using petroleum ether to afford the title compound as yellow oil (2.3 g, yield 71%). 1H NMR (DMSO-d6, 400 MHz): δ 8.67 (s, 1H), 7.36 (t, 1H), 7.21 (d, 1H), 7.20 (d, 1H), 3.96 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][NH2:14].CCOC(C)=O>C1COCC1>[CH3:13][NH:14][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
4-Nitrobenzoyl chloride (7.00 g, 38 mmol, 1 eq) was dissolved in 50 ml of THF and added to a 2.0 M solution of methylamine in THF (41.5 ml, 83 mmol, 2.2 eq.) at 0° C. Worked up after 3 hours by adding EtOAc and rinsing 3× with 1N NaOH, 1× with brine. The organic layer was dried over MgSO4, then stripped to obtain 2.25 g of off-white solids as product. NMR (300 MHz, DMSO-d6) δ 8.80 (m, 1H), 8.33 (d, 2H, J=7 Hz), 8.06 (d, 2H, J=7 Hz). 2.86 (d, 3H, J=7 Hz).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH3:10].I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:10]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23.0 mL of 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-chloro-phenyl)-acetic acid ethyl ester (1.28 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 mg, 7.13 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.65 g, 90.9%) as a yellow oil: EI-HRMS m/e calcd for C16H21Cl2O2(M+) 280.1230, found 280.1227.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:20][N:21]([CH3:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:14][C:12]2[S:13][C:9]([C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])=[C:10]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:11]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 2.8 %

Procedure:
Compound 454 (125 mg, 0.450 mmol) was dissolved in DMF (2 mL), and 4-(dimethylamino)benzoic acid (296 mg, 1.80 mmol), EDC hydrochloride (344 mg, 1.80 mmol) and 1-hydroxybenzotriazole monohydrate (276 mg, 1.80 mmol) were added thereto, followed by stirring at 80° C. for 2 hours. Water (200 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=9:1), followed by reslurrying with ethanol to afford the entitled Compound 465 (5.30 mg, 3%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5]O.N1C=CC=CC=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][Br:20]
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)c(OC)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(CBr)c(OC)c1
Temperature: 4 °C
Reaction time: 0.75 h

Procedure:
2 g (11.77 mmol) of 2,4-dimethoxybenzyl alcohol (Aldrich, Steinheim, FRG) are dissolved in 30 ml of abs. toluene, and this solution is treated with 0.3 ml of pyridine. The clear solution is cooled down to approximately 4° C. and 1.12 ml (0.992 equivalents) of PBr3 in 6 ml of abs. toluene are added dropwise to it over the space of 30 min. After a further 45 min, the reaction solution is poured onto ice-water and the whole is extracted with ether. The organic phase is washed, in succession, with water, sat. sodium bicarbonate solution and saline (all being cold). The combined aqueous phases are reextracted with ether. The combined organic phases are dried over Na2SO4 and the ether is removed on a RE at about 30° C. The toluene solution which remains, and which contains the title compound, is immediately subjected to further use. TLC (hexane:ethyl acetate, 1:1): decomposition.
Reaction SMILES: Cl.Cl.[F:3][C@H:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[C@H:6]([CH3:19])[CH2:5]1.C(OC([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C@H:32]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:33](O)=[O:34])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[ClH:42].[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C@@H:32]([C@@H:28]2[CH2:29][CH2:30][CH2:31][NH:27]2)[C:33]([N:16]2[CH2:15][CH2:14][N:13]([C:12]3[C:7]4[C@H:6]([CH3:19])[CH2:5][C@@H:4]([F:3])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:18][CH2:17]2)=[O:34])=[CH:37][CH:38]=1
Reactant: C[C@@H]1C[C@@H](F)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.7 %

Procedure:
(5R,7R)-7-Fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine di-hydrochloride (0.050 g, 0.16 mmol) was combined with (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.055 g, 0.16 mmol) in dichloromethane (10 mL). Diisopropylethylamine (0.1 mL, 0.57 mmol) and HBTU (0.061 g, 0.16 mmol) were added, and the mixture was stirred at ambient temperature for 1 hour. The solvent was removed by concentration in vacuo and the residue was purified by column chromatography on SiO2, eluting with 2:1 hexanes/ethyl acetate. The product was dissolved in dioxane (1 mL) and treated with a solution of 4M HCl in dioxane (2 mL). After stirring at ambient temperature for 2 hours, the mixture was concentrated in vacuo to yield (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone hydrochloride (0.060 g, 81% yield). MS (APCI+) [M+H] 458.2.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].C[O-].[Na+].[C:10](OC)(=[O:15])[C:11]([O:13][CH3:14])=[O:12]>CO>[CH3:14][O:13][C:11](=[O:12])[C:10](=[O:15])[CH2:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)C1CC1
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
To a solution of cyclopropyl methyl ketone (5 g, 59.4 mmol) in MeOH (75 mL) was added sodium methoxide (4.8 g, 54.0 mmol) at rt. After a 15 min stirring, dimethyl oxalate (7 g, 59.4 mmol) was added. The reaction mixture was stirred for 16 h at rt and concentrated. The residue was taken up in a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5) to provide 5 g of the title compound. Rf=0.59 (hexane/EtOAc, 4:1); 1H NMR (300 MHz, CDCl3) δ ppm 1.00-1.30 (m, 4H), 1.80-1.95 (m, 1H), 3.85 (s, 3H), 6.48 (s, 1H), 14.2-15.0 (br. s, 1H).