Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:26]=4)[CH2:21][CH2:20]3)=[O:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCC3)CC2)c1

Procedure:
Example 43 was prepared from 1-(4-chlorophenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.41 (s, 1H), 7.34–7.21 (m, 6H), 6.93 (s, 1H), 6.48 (s, 1H), 3.31–3.24 (m, 2H), 2.94–2.86 (m, 2H), 2.86–2.76 (m, 2H), 2.57–2.37 (m, 4H), 2.33–2.26 (m, 2H), 2.12–2.02 (m, 1H), 1.97–1.87 (m, 3H), 1.82 (s, 1H), 1.79 (s, 1H), 1.70–1.56 (m, 4H), 1.24 (d, 6H, J=7.2 Hz); ESMS m/e: 496.3 (M+H)+; Anal. Calc. for C29H38ClN3O2.0.550 CHCl3: C, 63.18; H, 6.92; N, 7.48. Found: C, 63.22; H, 6.90; N, 7.48.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl>[CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:38])[C:5]2[CH:14]=[C:15]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
134 mg of 3,4-dihydro-2,2-dimethyl-6-(4-nitrobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 15 ml of dichloromethane and 72 mg of m-chloroperbenzoic acid were added. The mixture was stirred at room temperature overnight. After washing in succession with sodium bisulphite solution and sodium bicarbonate solution the organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/methanol (4:1) for the elution. The residue was recrystallized from isopropanol to give 50 mg of 2-[3,4-dihydro-2,2-dimethyl-6-(4-nitrobenzoyl)-2H-1-benzopyran-4-yl]-pyridine N-oxide of melting point 209°-211° C.
Reaction SMILES: [C:1]([C:3]1(O)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1)#[N:2].CCN(S(F)(F)[F:25])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([C:3]1([F:25])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1)#[N:2]
Reactant: N#CC1(O)CCN(C(=O)OCc2ccccc2)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CC1(F)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirred solution of phenylmethyl 3-cyano-3-hydroxy-1-pyrrolidinecarboxylate (1.8 g, 7.31 mmole), in DCM (50 mL) at −78° C. was added DAST dropwise (0.98 mL, 8.04 mmole). After 2 h, Aqueous Na2CO3 was added to the reaction solution and the layers separated. The organic layer was dried over Na2SO4 and concentrated under vacuum. Purification on silica (hexanes/EtOAc, 1:1) provided the title compound (1.0 g, 55%) as a light orange oil: LC-MS (ES) m/e 249 (M+H)+.
Reaction SMILES: [C:1]([N:11]1[CH2:18][C@@H:17]2[C@@H:13]([CH2:14][N:15]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](OCC4C=CC=CC=4)=[O:27])=[CH:21][C:20]=3[F:36])[CH2:16]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([Li])CCC.C([O:47][CH2:48][C@@H:49]1[O:51][CH2:50]1)(=O)CCC.[Cl-].[NH4+]>C1COCC1>[C:1]([N:11]1[CH2:12][C@@H:13]2[C@@H:17]([CH2:16][N:15]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:50][C@H:49]([CH2:48][OH:47])[O:51][C:26]4=[O:27])=[CH:21][C:20]=3[F:36])[CH2:14]2)[CH2:18]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(Nc1ccc(N2C[C@H]3CN(C(=O)OCc4ccccc4)C[C@H]3C2)c(F)c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3ccc(N4C[C@H](CO)OC4=O)cc3F)C[C@@H]2C1
Temperature: -78 °C
Reaction time: 15 h

Procedure:
To a flame dried flask cooled to -78° C. and equipped with a nitrogen inlet is introduced cis-3-(carbobenzyloxy)-7-[4-[(carbobenzyloxy)amino]-2-fluorophenyl]-3,7-diazabicyclo[3.3.0]octane (7.25 g, 14.81 mmol), THF (100 mL), and 1.6 M butyl lithium (9.72 mL, 15.55 mmol). The reaction is stirred at -78° C. for 1 hour before (R)-(-)-glycidyl butyrate (2.26 mL, 15.99 mmol) is added slowly and stirred for 2 hours at -78° C. and 15 hours at ambient temperature. Saturated ammonium chloride (50 mL) is added and the aqueous phase is extracted with ethyl acetate (2×50 mL). The extracts are combined, washed with saline (50 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (99/1). The appropriate fractions are combined (Rf =0.13, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 168-171° C.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:29]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[CH2:30][CH2:31][CH3:32]>C1COCC1>[CH2:29]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:35][CH:34]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1ccc(C=O)cc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1ccc(C=CCCCCC(=O)O)cc1
Yield: 51.3 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and p-butylbenzaldehyde (3.24 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (2.67 g, 51%) as a colorless oil (bp 154-157° C./0.05 torr). IR: 3400-2500, 1720 cm-1, 1H-NMR:0.92 (t, 3H), 1.50 (m, 8H), 2.30 (m, 4H), 2.58 (m, 2H), 5.58+6.15 (m, 1H), 6.38 (t, 1H), 7.18 (m, 4H), 10.30 (bs, 1H). Anal. Calcd. for C17H24O2 : C, 78.42, H, 9.29%; Found: C, 78.38, H. 9.29%. Z:E=62:38.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH:21]([N:36]1[CH:41]=[C:40]([O:42][CH3:43])[C:39]([C:44]2[CH:49]=[C:48]([Cl:50])[CH:47]=[CH:46][C:45]=2[C:51]#[N:52])=[CH:38][C:37]1=[O:53])[C:22]([NH:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=1)=[O:23])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[Cl:50][C:48]1[CH:47]=[CH:46][C:45]([C:51]#[N:52])=[C:44]([C:39]2[C:40]([O:42][CH3:43])=[CH:41][N:36]([CH:21]([CH2:20][CH2:19][OH:18])[C:22]([NH:24][C:25]3[CH:35]=[CH:34][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[O:23])[C:37](=[O:53])[CH:38]=2)[CH:49]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COc1cn(C(CCO)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
266 mg (355 μmol) of ethyl 4-[(4-{[tert-butyl(diphenyl)silyl]oxy}-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl)amino]benzoate (racemate) in 7 ml of methanol/water (4/1) were reacted with 232 mg (711 μmol) of caesium carbonate according to General Method 4. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 16.5 mg (9% of theory)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:23])=[C:16]([NH:20][CH:21]=[O:22])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([C:18]1[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:23])=[C:16]([NH:20][CH:21]=[O:22])[C:17]=1[CH3:19])(=[O:26])[CH3:25]
Reactant: Cc1cc2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC(=O)Cl
Product: CC(=O)c1c(C)c(NC=O)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 48 %

Procedure:
Using N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide obtained in Example 58 and acetyl chloride, the title compound was obtained in the same manner as in Example 38. Yield: 48%. Melting point: 177-179° C. (ethyl acetate-hexane).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[CH2:8]([O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:15][CH:14]=1)=[O:12])[CH3:9].[N:39]1([CH2:44][C:45](=O)[CH2:46][CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[CH:43]=[CH:42][N:41]=[CH:40]1>CN(C)C=O>[N:39]1([CH2:44]/[C:45](/[CH2:46][CH2:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)=[CH:19]\[C:16]2[CH:15]=[CH:14][C:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])=[CH:18][CH:17]=2)[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: COc1ccc(CCCC(=O)Cn2ccnc2)cc1
Reactant: CCOC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(/C=C(/CCCc2ccc(OC)cc2)Cn2ccnc2)cc1
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of potassium t-butoxide (5.0 g, 0.045 mol) in dry dimethylformamide (20 ml) at room temperature under a nitrogen atmosphere was treated with [[4-(ethoxycarbonyl)phenyl]methyl]triphenylphosphonium bromide (20.0 g, 0.0396 mol) in portions over 5 minutes. The resulting red suspension was stirred for 5 minutes and then treated dropwise with a solution of 1-(1H-imidazol-1-yl)-5-(4-methoxyphenyl)-2-pentanone (Example 8d; 4.0 g, 0.0155 mol) in dry dimethylformamidie (4 ml) over 5 minutes. The mixture was then heated at 120° C. for 1 hour. On cooling the reaction mixture was poured onto ice water (200 ml) and extracted with ethyl acetate (2×50 ml). The extracts were combined, washed with water, dried over magnesium sulfate and the solvent was evaporated off under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, 5% methanol in dichloromethane) to initially yield the less polar isomer, ethyl 4-[2-(1H-imidazol-1-ylmethyl)-5-(4-methoxyphenyl)-1Z-pentenyl]benzoate as a pale yellow oil having the following structural chracteristics:
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:11]1[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][NH:8][CH2:9][CH:10]12
Reactant: c1ccc(CN2CC3CCCNC3C2)cc1
Agent: [Pd]
Solvent: CO
Product: C1CNC2CNCC2C1

Procedure:
69 g (0.32 mol) of 6-benzyl-octahydropyrrolo[3,4-b]pyridine are hydrogenated in 450 ml of methanol over 7 g of palladium-on-active charcoal (5% strength) at 90° C./90 bar in the course of 3 hours. The catalyst is then filtered off, the filtrate is concentrated and the residue is distilled. 33.8 g (84% of theory) of a colorless solid having a melting point of 65°-67° C. and a boiling point of 78° C./9 mbar are obtained.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:10]2[NH:9][C:2](=[O:3])[O:13][C:12](=[O:14])[C:11]=2[CH:15]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Yield: 92.4 %

Procedure:
Trichloromethyl chloroformate (4.8 mL, 300 mmol) was added to a stirred solution of Compound 57 (6.84 g, 40 mmol) in dry dioxane at room temperature and the solution was refluxed for 4 h. The solution was cooled in an ice bath and the solids formed were filtered. The solids were washed by ether and dried under vacuum at room temperature to yield 7.3 g (92%) of white solids. 1H NMR (DMSO-d6): δ 7.47 (d, J=8.6 Hz, 1H), 7.70 (dd, J=8.6, 1.8 Hz, 1H), 7.82 (d, J=1.1, 1H), 11.63 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.[C:21](Cl)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Reactant: CCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (3 ml) was suspended 60% sodium hydride (20 mg). The compound 1 (124 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, valeryl chloride (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-valerylquinoline (compound 5, 120 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][C:8]1[O:32][C:11]2=[C:12]3[O:17][CH:16]([CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15][CH2:14][C:13]3=[CH:30][CH:31]=[C:10]2[C:9]=1[CH3:33].C(O)(=O)C(O)=O>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH:16]1[CH2:15][CH2:14][C:13]2=[CH:30][CH:31]=[C:10]3[CH:9]([CH3:33])[CH:8]([CH3:7])[O:32][C:11]3=[C:12]2[O:17]1
Reactant: Cc1oc2c3c(ccc2c1C)CCC(CNCCCNc1ncccn1)O3
Agent: O=C(O)C(=O)O
Product: CC1Oc2c(ccc3c2OC(CNCCCNc2ncccn2)CC3)C1C
Yield: 3.3 %

Procedure:
Intermediate 16-a (0.072 mol) was dissolved in methylbenzene (250 ml)/H (100 ml). The solution was cooled to -70° C. Diisobutylaluminium hydride, 1.5M solution in hexane (0.1 mol) was added dropwise and the mixture was stirred for 1 hour at -70° C. Methanol (15 ml) was added dropwise and the reaction mixture was allowed to warm to room temperature. The mixture was poured out into water, acidified with hydrochloric acid and extracted with diethyl ether. The separated organic layer was dried, filtered and the solvent evaporated. The residue was dissolved in methanol (150 ml). N-2-pyrimidinyl-1,3-propanediamine (0.06 mol) was added and the mixture was hydrogenated with palladium-on-charcoal (small amount) as a catalyst in the presence of thiophene, 4% solution (10 ml). After uptake of H2 (1 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 90/10). Three fraction groups were collected and the solvent was evaporated, yielding residues (1), (2) and (3) (12 g). A sample of residue (3) (3.6 g) was dissolved in 2-propanone and converted into the ethanedioic acid salt (1:2) with a solution of ethanedioic acid.H2O (0.020 mol) in 2-propanone. The precipitate was filtered off and dried, yielding 4.5 g (46.1%) of (±)-N-[(7,8-dihydro-2,3-dimethyl-6H-furo[3,2-h][1]benzopyran-8-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine ethanedioate(1:2); mp. 208.8° C. (comp. 7-a). Residue (2) was repurified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 85/15). The desired fractions were collected and the solvent was evaporated. The residue (1.8 g) was dissolved in ethanol and converted into the ethanedioic acid salt (1:2) with ethanedioic acid (0.010 mol). The precipitate was filtered off and dried, yielding 1.1 g (3.3%) (±)-N-2-pyrimidinyl-N'-[(3,6,7,8-tetrahydro-2,3-dimethyl-2H-furo[3,2-h][1]benzopyran-8-yl)methyl]-1,3-propanediamine ethanedioate (1:2); mp. 171.2° C. (comp. 8-a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C@H:20]3[CH2:25][N:24]([CH2:26][CH3:27])[CH2:23][CH2:22][NH:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:35]([N:21]1[CH2:22][CH2:23][N:24]([CH2:26][CH3:27])[CH2:25][C@@H:20]1[C:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[O:11])[CH2:17][CH2:16]1)=[O:19])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CCN1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCN(C(C)=O)[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
N-(3,4-Dichlorophenyl)-4-{[(2R)-4-ethylpiperazin-2-yl]carbonyl}piperazine-1-carboxamide (70 mg) in chloroform (1 ml) was cooled in an ice bath, triethylamine (19 ul) added, followed by acetyl chloride (10 ul) and the mixture stirred for 2 hours at 0° C. The mixture was diluted with CH2Cl2, washed with saturated aqueous sodium bicarbonate, the organic phase dried (MgSO4), evaporated and the residue purified on a 4 g Redisep® SiO2 column, eluting with 0-50% MeOH/CH2Cl2 to give the title compound as a colourless solid (35 mg, 45%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O.CCN(S(F)(F)[F:19])CC>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][F:19]
Reactant: OCCCCCCCCCCBr
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCCCCCCCCCCBr

Procedure:
Repetition of the procedure described in Example 2 but using 1.00 g (4.23 mmol) of 10-bromodecanol and 0.5287 ml (4.23 mmol) of DAST in 50 mL methylene chloride affords the crude of 10-bromo-1-fluoro-decane. Purification by flash chromatography gives the 10-bromo-1-fluoro-decane (826 mg 3 82%) as a clear colorless liquid: Rf=0.73 hexane/ethyl acetate (7:3, v/v); IR (film) δ2850-3000 (alkane CH); and 1H-NMR (CDCl3) δ1.25-2.95 (m, 16H), 3.36 (t, J=6 Hz, 2H), 4.40 (dt, J=48 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[C:12]([N:16]2[C:20](=[O:21])[N:19]([CH:22]([F:24])[F:23])[C:18]([CH3:25])=[N:17]2)=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].C[O-].[Na+].[CH2:29](O)[CH:30]=C>C(OCC)C>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[C:12]([N:16]2[C:20](=[O:21])[N:19]([CH:22]([F:24])[F:23])[C:18]([CH3:25])=[N:17]2)=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8][CH2:9][CH:29]=[CH2:30])=[O:7]
Reactant: COC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl
Reactant: C=CCO
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: C=CCOC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl

Procedure:
Under a dry nitrogen atmosphere, a stirred solution of 0.5 g (0.0013 mole) of methyl 2-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate (Compound 2) and approximately 0.01 g of sodium methoxide in 30 mL of 2-propen-1-ol was heated at reflux. After approximately 5 mL of methanol was collected in a Dean-Stark trap, the reaction mixture was cooled slightly, and the remaining solvent removed by distillation under reduced pressure leaving a residue. This residue was dissolved in diethyl ether and washed with water. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 0.55 g of 2-propenyl 2-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate as an oil, Compound B2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:19](C(O)=O)[C:20]([OH:22])=[O:21])[CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:15]=[C:16]([CH3:17])[CH3:18])[CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=1
Reactant: COc1cccc(COc2ccc(C(C=C(C)C)C(C(=O)O)C(=O)O)cc2)c1
Solvent: Cc1ccccc1
Product: COc1cccc(COc2ccc(C(C=C(C)C)CC(=O)O)cc2)c1
Yield: 64.7 %

Procedure:
A suspension of compound 33.3 (0.136 mmol) in toluene was refluxed for 16 h. After removing the solvent, the residue was purified using silica gel column chromatography (TFA/Dichloromethane/ethyl acetate=1/5/40) to give compound 33 as a white solid (0.088 mmol). MS ESI m/e: 339 (M−H) 1H NMR (500 MHz) (DMSO-d6) δ 11.97 (1H, s); 7.31 (1H, t, J=10 Hz); 7.14 (2H, d, J=11 Hz); 6.99 (2H, m); 6.87 (3H, m); 5.22 (1H, s). 5.03 (2H, s); 3.75 (1H, m); 3.75 (3H, s); 2.44-2.53 (2H, m); 1.63 (3H, s); 1.62 (3H, s).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[NH2:19])=[CH:3][C:4]=2[N:5]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a 100 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.5 g, 0.0046 mol—Preparation 2), 3-aminophenylboronic acid (0.67 g, 0.0051 mol), sodium carbonate (0.98 g, 0.0092 mol) toluene (30 mL), ethanol (10 mL) and water (5 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.14 g, 0.0002 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to provide the title compound (1.1 g, 70%). 1H NMR (300 MHz, DMSO-d6): δ 9.02 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.01-6.99 (m, 2H), 6.68-6.17 (m, 1H), 5.33 (br s, 2H), 4.52 (br s, 4H), 3.79 (t, J=4.8 Hz, 4H). LC-MS (ESI): Calculated mass: 341.1; Observed mass [M+H]+: 342.1. (RT=0.73 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][C:7](=[N:9][OH:10])[NH2:8].[C:15]([O-])(=O)[CH3:16].[Na+].C(OC(=O)C)(=O)C>COCCOCCOC>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][C:7]1[N:8]=[C:15]([CH3:16])[O:10][N:9]=1
Reactant: Cc1c(Cl)cccc1OCC(N)=NO
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(COc2cccc(Cl)c2C)no1
Yield: 56.6 %

Procedure:
7.0 g (32.6 mmol) of 3-chloro-2-methyl-phenoxy-acetamide oxime and 14.0 g (142.8 mmol) of sodium acetate are introduced into 80 ml of diglyme and the mixture is treated with 8.6 g (84.2 mmol) of acetic anhydride. The reaction mixture is stirred at reflux temperature until the reaction is complete (approximately 2 hours). The entire batch is subsequently concentrated, the product is treated with water, and the mixture is extracted using ethyl acetate. After the solvent has been distilled off, the crude product which remains is chromatographed over a silica gel column (silica gel 60 Merck, particle size: 0.040 to 0.063 mm) using methylene chloride as the eluent. 4.4 g (56.5% of theory) of 3-(3-chloro-2-methyl-phenoxymethyl)-5-methyl-1,2,4-oxadiazole are obtained.