Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]1[C:17]2=[N:18][CH:19]=[N:20][CH:21]=[C:16]2[C:15]([C:22]2[O:23]C=[CH:25][CH:26]=2)=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[N+](C)=CCl.[Cl-].[OH:33]P([O-])([O-])=O.[K+].[K+].Cl[CH2:41][CH2:42]Cl>CN(C=O)C>[CH2:6]([N:13]1[C:17]2=[N:18][CH:19]=[N:20][CH:21]=[C:16]2[C:15]([C:22]2[O:23][C:41]([CH:42]=[O:33])=[CH:25][CH:26]=2)=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P([O-])([O-])O
Reactant: ClCCCl
Reactant: c1ccc(Cn2nc(-c3ccco3)c3cncnc32)cc1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2nn(Cc3ccccc3)c3ncncc23)o1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
0.74 ml of POCl3 is added at 0° C. to 0.64 ml of DMF. The solidified mixture is allowed to come to room temperature and 14 ml of 1,2-dichloroethane are added. A solution of 2 g of 1-benzyl-3-(2-furyl)pyrazolo[3,4-d]pyrimidine (Rf=0.45, SiO2, toluene/ethyl acetate=1:1) in 14 ml of 1,2-dichloroethane is added dropwise at 15° C. to this solution and it is then warmed to 80° C. After 4 h, the entire batch is added dropwise to further Vilsmeier reagent, which was prepared from 1.5 ml of POCl3 and 1.3 ml of DMF, and stirred at 80° C. for 24 h. The mixture is then added to a 50% aqueous solution of K2HPO4 and briefly heated to 75° C. with stirring. After extraction with ethyl acetate, drying of the organic phase, concentration in a rotary evaporator and chromatography on SiO2, 0.6 g (27% of theory) of an oil is obtained (Rf=0.3, SiO2, toluene/ethyl acetate=1:1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+].O>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: NO
Reactant: Cc1cc(C=O)ccc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C=NO)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
To a solution of 4-bromo-3-methyl-benzaldehyde (4.3 g) (Example I1) in ethanol (50 ml), were added at ambient temperature hydroxylamine hydrochloride (1.75 g), sodium acetate (2.07 g) and water (15 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and the residue diluted with ethyl acetate and aqueous sodium hydroxide (2M). The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 4:1) to give 4-bromo-3-methyl-benzaldehyde oxime (3.65 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.05 (s, 1H), 7.50 (m, 2H), 7.25 (d, 1H), 2.40 (s, 3H) ppm.
Reaction SMILES: C(OC([N:11]1[CH:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23]([NH2:29])=[N:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)[C:13](=[O:30])[C@@H:12]1[CH3:31])=O)C1C=CC=CC=1.[H][H]>[Pd].CO.C(O)(=O)C>[NH2:29][C:23]1[C:22]2[C:27](=[CH:28][C:19]([CH2:18][N:14]3[CH2:15][CH:16]([CH3:17])[NH:11][C@@H:12]([CH3:31])[C:13]3=[O:30])=[CH:20][CH:21]=2)[N:26]=[CH:25][N:24]=1
Reactant: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1
Yield: 153.9 %

Procedure:
Palladium on carbon (10%, 700 mg) is added to a solution of (2S,6RS)-4-(4-amino-quinazolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.62 g, 3.87 mmol) in 20 mL of methanol and 2 mL of acetic acid. The reaction mixture is left to stir in an atmosphere of hydrogen for eight hours. The palladium is filtered off, and the volitale solvents are removed on the rotovap. The crude product (1.7 g, 95%) is isolated as a white solid. The two epimers are separated on silica gel (1% triethylamine/15% methanol/methylene chloride). The minor epimer is assigned as (3S,5R)-1-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one and the major epimer is assigned as (3S,5S)-1-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=2[CH2:6][CH2:5]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:2][CH2:3][CH:4]2[CH2:10][CH2:9][C:8]3[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=3[CH2:6][CH2:5]2)=[CH:26][CH:25]=1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.2 %

Procedure:
The mixture of 7-(2-iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.64 g), 4-chlorophenol (602 mg), potassium carbonate (1.08 g), and DMF (16 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (toluene) to yield the entitled compound (1.58 g) as crystals.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[C:59]([OH:63])(C)([CH3:61])[CH3:60].[CH2:64]([O:71][C:72]([N:74]1[CH2:79][CH2:78][N:77]([C:80]2[N:89]=[C:88]([O:90][CH2:91]CC=C)[C:87]3[C:82](=[CH:83][CH:84]=[CH:85][CH:86]=3)[N:81]=2)[CH2:76][CH2:75]1)=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.S([O-])([O-])=O.[Na+].[Na+]>O>[CH2:64]([O:71][C:72]([N:74]1[CH2:79][CH2:78][N:77]([C:80]2[N:89]=[C:88]([O:90][CH2:91][CH2:60][C@@H:59]([OH:63])[CH2:61][OH:22])[C:87]3[C:82](=[CH:83][CH:84]=[CH:85][CH:86]=3)[N:81]=2)[CH2:76][CH2:75]1)=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)O
Reactant: C=CCCOc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(c2nc(OCC[C@@H](O)CO)c3ccccc3n2)CC1

Procedure:
To a mixture of AD-mix-β (manufactured by Aldrich Co.) (35.0 g), t-butanol (125 ml) and water (125 ml) is added 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(3-buten-1-yl)oxy]quinazoline [cf. Example 57(2)] (10.46 g) with stirring under ice-cooling, and the mixture is stirred under ice-cooling for 60.5 hours. To the reaction mixture is added sodium sulfite (37.5 g), and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is separated into an organic layer and an aqueous layer, and the aqueous layer is extracted with ethyl acetate. The organic layer is combined with the ethyl acetate extract, and washed with water. The ethyl acetate solution is dried over anhydrous magnesium sulfate, evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography [eluent, chloroform, (chloroform:methanol=50:1, v/v)], and the resulting crystalline product is recrystallized twice from acetone-diethyl ether to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(3R)-(3,4-dihydroxybutan-1-yl)oxy]quinazoline (4.53 g) as crystals.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:6]1[C:3]2[CH:4]=[C:15]([C:14]([O:18][CH3:19])=[O:17])[S:16][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C(F)(F)F)cccc2s1
Temperature: 130 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A mixture of 1.00 g of 2-fluoro-6-(trifluoromethyl)benzaldehyde, 633 mg of methyl thioglycolate, 1.21 g of potassium carbonate and 15 ml of DMF was stirred at 130° C. for 2 hours. The reaction mixture was cooled to room temperature. To the reaction mixture was added water, and then extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with water, followed by saturated aqueous sodium chloride solution. The mixture was dried over magnesium sulfate, and then concentrated under reduced pressure obtain 480 mg of methyl 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylate.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.C[O-:27].[Na+].Br[C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2>C1COCC1>[C:13]([O-:12])(=[O:27])[CH3:16].[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH2:3][C:30]2[CH:31]=[N:32][C:33]3[C:38]([CH:39]=2)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[O-]
Reactant: Brc1cnc2ccccc2c1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC(CCCc2cnc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.7 %

Procedure:
A solution of 1-(t-butoxycarbonyl)-4-(prop-2-en-1-yl)piperidine (from Procedure 5, Step B) (260 mg, 1.15 mmol) in THF (3 mL) under argon was treated with 0.5M 9-BBN solution in THF (2.30 mL, 1.15 mmol). The resulting mixture was stirred at rt for 2 h, then treated with sodium methoxide (68 mg, 1.25 mmol). The resulting mixture was stirred until it was homogeneous (˜15 min) and then was treated with 3-(bromo) quinoline (0.155 mL, 1.15 mmol) and [1,1′-bis(triphenylphosphino)ferrocene)dichloropalladium methylene chloride (41 mg, 0.05 mmol). The resulting mixture was heated at reflux for 30 min, cooled and quenched with 1N NaOH (20 mL). The quenched reaction was extracted with 2×50 mL of ether; the extracts were dried over magnesium sulfate, combined and concentrated. FC (15 g of silica gel, 4:1 v/v hexaneslethyl acetate) afforded the title compound (240 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11](Cl)(=O)[C:12](Cl)=O>CN(C)C=O.ClCCl>[CH2:11]([O:9][C:8]([C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH3:12]
Reactant: Cc1nccnc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1nccnc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-pyrazine-2-carboxylic acid (10 g) (commercially available) and N,N-dimethylformamide (“DMF”) (1 drop) in dichloromethane (20 ml) at ambient temperature was added drop wise oxalyl chloride (2.57 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and the residue dissolved in dichloromethane (20 ml). Triethylamine (4.04 ml) was added to this solution followed by drop wise addition of ethanol (10 ml). The reaction mixture was stirred at ambient temperature for one hour and then concentrated. The residue was purified by chromatography on silica gel (eluent: 0-10% v/v ethyl acetate in iso-hexane) to give 3-methyl-pyrazine-2-carboxylic acid ethyl ester (9.85 g). MH+=167, RT=0.73 min (Method A). 1H-NMR (400 MHz, CDCl3): 8.61 (d, 1H), 8.54 (d, 1H), 4.49 (q, 2H), 2.85 (s, 3H), 1.46 (t, 3H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].I[C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40]>O1CCOCC1>[CH3:42][O:41][C:39](=[O:40])[C:38]1[CH:43]=[CH:44][CH:45]=[CH:46][C:37]=1[C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[CH:14]([N:13]1[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]1[CH2:1][CH3:2])[CH2:15][CH2:16]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CCC2n1c(CC)nc2c(C)cc(C)nc21
Reactant: COC(=O)c1ccccc1I
Solvent: C1COCCO1
Product: CCc1nc2c(C)cc(C)nc2n1C1CCc2cc(-c3ccccc3C(=O)OC)ccc21
Temperature: 25 °C
Yield: 28.7 %

Procedure:
A mixture of 2-ethyl-5,7-dimethyl-3-(5-tributylstannyl-indan-1-yl)-3H-imidazol[4,5-b]pyridine (224 mg, 0.41 mmol), methyl 2-iodobenzoate (131 mg, 0.5 mmol) and PdCl2 (PPh3)2 (28 mg, 0.04 mmol) was heated in anhydrous 1,4-dioxane for 20 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and chromatographed on SiO2 -gel using a gradient of 30% EtOAc/hexanes to 50% EtOAc/hexanes to give 50 mg of a colorless oil. 1H NMR (250 MHz, CDCl3): d 7.80 (1 H, d), 7.55 (t, 1 H), 7.43 (t, 2 H), 7.30 (s, 1 H), 7.10 (d, 2 H), 6.90 (m, 2 H), 6.52 (m, 1H), 3.30 (m, 1 H), 3.15 (m, 1 H), 2.85 (q, 2 H), 2.65 (s, 3 H), 2.57 (s, 3 H), 0.90 (t, 3H.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[S:27]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28]1>>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:14]3[N:15]([C:11]([C:9]4[CH:8]=[CH:7][N:6]=[C:5]([NH:33][CH2:32][C:29]5[CH:30]=[CH:31][S:27][CH:28]=5)[N:10]=4)=[CH:12][N:13]=3)[CH:16]=[CH:17][N:18]=2)[CH2:21][CH2:22]1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: NCc1ccsc1
Product: CN1CCN(c2nccn3c(-c4ccnc(NCc5ccsc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (120 mg, 0.32 mmol) and thiophen-3-ylmethanamine (145 mg, 1.28 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) to afford {4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-3-ylmethyl-amine (Yield 69 mg, 52.8%). 1H NMR (300 MHz, DMSO-d6): δ 8.41 (s, 1H), 8.35 (d, 1H, J=5.4 Hz), 7.94 (t, 1H, J=5.7 Hz), 7.51-7.34 (m, 3H), 7.20-7.12 (m, 2H), 4.56 (d, 2H, J=5.7 Hz), 4.17 (brs, 4H), 2.52-2.44 (m, 4H), 2.23 (s, 3H). LC-MS: [M+H]+ 407.
Reaction SMILES: C(O[C:6]([N:8]([C@@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([F:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)C)=O)(C)(C)C.FC1C2C(S([Cl:43])(=O)=O)=CC=CC=2C=NC=1.C(OC(N([C@@H]1CCNC1)C)=O)(C)(C)C.BrC1C2C(S(Cl)(=O)=O)=CC=CC=2C=NC=1.C(OC(N([C@H]1CCNC1)C)=O)(C)(C)C>>[F:28][C:20]1[C:19]2[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@@H:10]([NH:8][CH3:6])[CH2:11]3)(=[O:16])=[O:17])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:23]=[N:22][CH:21]=1.[ClH:43]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(F)c23)C1
Reactant: O=S(=O)(Cl)c1cccc2cncc(F)c12
Agent: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Product: CN[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(F)c23)C1
Product: Cl

Procedure:
(R)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(4-fluoro-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 22b) can be prepared by using 4-fluoro-5-isoquinolinesulfonyl chloride and (R)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example 1-3, Step A instead of 4-bromo-5-isoquinolinesulfonyl chloride and (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively, and then used in the method of Example 1-3, Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1

Procedure:
To a solution of methyl 4- hydroxybenzoate (33.2 g) in acetone (300 ml) were added geranyl bromide (44.5 g) and potassium carbonate (55.2 g). The mixture was refluxed with heating for 2 hours. The reaction solution, after water (200 ml) were added thereto, was extracted with chloroform (400 ml). The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum to yield a raw product of methyl 4-geranyloxybenzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:11]1([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH:11]1([N:16]2[CH2:17][CH2:18][N:19]([C:2]3[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=3)[CH2:20][CH2:21]2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: C1CCC(N2CCNCC2)C1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccnc(N2CCN(C3CCCC3)CC2)c1
Temperature: 95 °C
Yield: 29.5 %

Procedure:
A mixture of 5.6 g (35 mmol) 2-chloro-4-nitropyridine, 5.75 g (37 mmol) 1-cyclo-pentyl piperazine and 4.59 g (35 mmol) N,N-diisopropylethylamine in 35 ml DMF and 12 ml water was heated to 95° C. for 3 h. After evaporation to dryness the residue was taken up in 150 ml NaHCO3 aq. and 150 ml ethyl acetate. The aqueous phase was extracted two times with 150 ml ethyl acetate each and the combined organic phases were washed twice with 100 ml NaHCO3 aq each and 100 ml NaCl aq. sat. and dried with MgSO4 and evaporated to dryness. The residue was purified with column chromatography to yield 2.85 g (29%) 1-cyclopentyl-4-(4-nitro-pyridin-2-yl)-piperazine (m/e): 277.3 (MH+; 100%) and 4.47 g (47%) 1-(2-chloro-pyridin-4-yl)-4-cyclopentyl-piperazine (m/e): 266.3 (MH+; 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[O:12][CH3:13].C(N(CC)CC)C.ClCCl.[C:24](Cl)(=[O:26])[CH3:25]>O>[C:24]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[O:12][CH3:13])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: COc1cccc2cc(O)cnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cccc2cc(OC(C)=O)cnc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
175 mg of 3-hydroxy-8-methoxy quinoline [compound (V)] prepared in example 6 and 132 mg of triethyl amine were added to 10 ml of dichloromethane. After cooled to 0° C., 0.1 ml of acetyl chloride was slowly added dropwise. The solution was agitated for 1 hour, and water was added to the solution. The solution was extracted with dichloromethane and washed with water. The dichloromethane layer was dried with anhydrous magnesium sulfate. The dichloromethane was removed by vacuum distillation to give 195 mg of 3-acetoxy-8-methoxy quinoline as an oil.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccc(F)cc2F)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccc(F)cc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A solution of (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.62 g, 1.24 mmol) in methanol (12.4 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2-5% methanol/dichloromethane gradient) afforded (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.46 g, 80%) as an off-white solid: HR-ES-MS m/z calculated for C22H26N4O5F2 [M+H]+ 465.1944, observed 465.1944; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 1.34-1.50 (m, 1H), 1.50-1.67 (m, 1H), 1.67-1.89 (m, 1H), 3.21-3.32 (m, 2H), 3.78 (br. s., 1H), 3.87 (dd, J=13.6, 7.5 Hz, 1H), 4.09 (dd, J=13.6, 3.6 Hz, 1H), 4.22 (d, J=18.4 Hz, 1H), 4.60 (d, J=18.4 Hz, 1H), 4.71 (t, J=5.4 Hz, 1H), 4.81-4.99 (m, 3H), 6.41 (d, J=2.1 Hz, 1H), 7.12-7.26 (m, 1H), 7.48-7.66 (m, 3H), 10.78 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]#[C:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1.Cl.[CH:23]([NH2:25])=[NH:24]>C(#N)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:25]=[CH:23][N:24]=2)=[CH:4][CH:3]=1
Reactant: O=C(C#CCCCOC1CCCCO1)c1ccc(Cl)cc1
Reactant: N=CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Clc1ccc(-c2cc(CCCOC3CCCCO3)ncn2)cc1
Yield: 82.4 %

Procedure:
A mixture of 3.60 g (11.73 mmol) of 1-(4-chlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hex-2-yn-1-one, prepared in stage 5.2., of 9.45 g (117 mmol) of formamidine hydrochloride and of 25 g (234 mmol) of sodium carbonate in suspension in 108 ml of acetonitrile and 0.1 ml of water is stirred at 40° C. for 5 hours. The mixture is subsequently taken up in 600 ml of water and 400 ml of a saturated aqueous sodium carbonate solution. The organic phase is separated by settling, washed with 200 ml of water and 200 ml of a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 70/30 mixture of n-hexane and of ethyl acetate, to produce 3.22 g (9.67 mmol) of product in the form of a yellowish oil.