Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].CC#N>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[CH2:10][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[N:15][CH:16]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: O=C(CCl)Nc1ccc(F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(Cn1cc([N+](=O)[O-])cn1)Nc1ccc(F)cn1
Temperature: 80 °C

Procedure:
A flask was charged with 4-nitro-1H-pyrazole (230 mg, 2.03 mmol), 2-chloro-N-(5-fluoropyridin-2-yl)acetamide (2.24 mmol), Cs2CO3 (729 g, 2.24 mmol) and MeCN (11.5 mL). The resulting reaction mixture was stirred at reflux (80° C.) for 2 h, then allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM. The filtercake was redisolved in DCM and water, the org. layer was separated and the aq. layer was extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4), filtered and concentrated to yield N-(5-fluoropyridin-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide as a crude which was used in the next step without further purification. LC-MS conditions A: tR=0.67 min, [M+H]+=266.32.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][N:10]=1>C1COCC1>[CH3:7][O:8][C:9]1[N:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To lithium aluminium hydride (0.68 g, 18 mmol) suspended in dry THF (10 ml) was added dropwise a solution of methyl 6-methoxynicotinate (1 g, 6 mmol) in dry THF (5 ml). The reaction mixture was stirred for 2 h at r.t. then cooled (ice-bath) and quenched with water (2 ml) followed by the further addition of 1N NaOH (6 ml) and water (2 ml). The cold-bath was removed and the mixture stirred for 30 min at r.t., filtered and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure to give a crude oil which was purified over silica gel (ethyl acetate/n-heptane 1:1): colorless oil 0.45 g (51%);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][C:6]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:15])=[C:8]([CH:16]([CH3:18])[CH3:17])[CH:7]=1.[CH3:23][N:24]([CH:26]=O)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][C:6]1[N:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]([N:15]=[CH:23][N:24]([CH3:26])[CH3:25])=[C:8]([CH:16]([CH3:17])[CH3:18])[CH:7]=1
Reactant: CC(C)c1cc(Oc2ccc(Cl)c(Cl)c2)nc(C(C)C)c1N
Reactant: CN(C)C=O
Product: CC(C)c1cc(Oc2ccc(Cl)c(Cl)c2)nc(C(C)C)c1N=CN(C)C

Procedure:
A 25 ml single-necked round-bottomed flask, fitted with a reflux condenser is charged with dimethylformamidedimethylacetale (1.6 g), DMF (10 ml) and 6-(3,4-dichloro-phenoxy)-2,4-diisopropyl-pyridin-3-ylamine (1.70 g). The reaction mixture is heated under reflux and methanol is distilled off for 2.5 hours. The mixture is then concentrated in vacuo at 50° C. The crude material is crystallised from hexane/toluene acetate 4:1 (v:v): to obtain 1.41 g of the compound as a white solid (MP: 102-103° C.).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[N:27][C:26](Cl)=[CH:25][N:24]=1)=[O:22]>CN(C)C=O.ClCCl>[CH3:19][O:20][C:21]([C:23]1[CH:28]=[N:27][C:26]([O:18][C:15]2[CH:16]=[CH:17][C:10]3[CH2:9][CH2:8][N:7]([CH:3]4[CH2:6][CH2:5][CH2:4]4)[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[CH:25][N:24]=1)=[O:22]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 332 mg, 8.3 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.64 g, 7.5 mmol) in dimethyl formamide (4 ml). After 0.5 hours, a solution of 5-chloro-pyrazine-2-carboxylic acid methyl ester (1.95 g, 11.3 mmol) in dimethyl formamide (8 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and the organic layer was washed with water, brine and dried over magnesium sulfate. The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E122). MS (ES+) m/e 354 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([O:14]C)=[O:13])[N:8]=[CH:9]2)=[CH:4][CH:3]=1>Cl>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([OH:14])=[O:13])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2ccc(Cl)cc2cn1
Agent: Cl
Product: O=C(O)c1cc2ccc(Cl)cc2cn1
Yield: 165.8 %

Procedure:
Methyl 7-chloroisoquinoline-3-carboxylate (0.23 g) was dissolved in concentrated hydrochloric acid (10 ml) to heat the mixture for 18 hours under reflux. The temperature of the reaction mixture was dropped to room temperature, and deposits were collected by filtration and then washed with water to obtain the title compound (0.21 g) as a colorless solic.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Na+].[Na+].I[CH:31]([F:33])[CH3:32].O>C(#N)C>[F:33][CH2:31][CH2:32][N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:14][CH2:13][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]2)[CH2:19][CH2:20]1
Reactant: COc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Reactant: CC(F)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Yield: 88 %

Procedure:
To 1-[3-(methyloxy)-4-nitrophenyl]-4-(4-piperidinyl)piperazine (Example 89, step D) (0.958 g, 2.99 mmol) and Na2CO3 (0.470 g, 4.43 mmol) in acetonitrile (20 mL) was added iodofluoroethane (0.500 mL, 6.15 mmol) in one portion. The resultant mixture was heated at 70° C. for 48 h. When complete by TLC, the reaction was poured into H2O (150 mL), extracted with DCM and EtOAc, dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step A (0.972 g, 2.63 mmol, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.43 (m, 2H), 1.70 (d, J=15.0 Hz, 2H), 1.94 (t, J=12.5 Hz, 2H), 2.12-2.21 (m, 1H), 2.50 (t, J=5.0 Hz, 1H), 2.52-2.58 (m, 5H), 2.88 (d, J=10.4 Hz, 2H), 3.35-3.40 (m, 4H), 3.86 (s, 3H), 4.46 (dt, JHF=47.8 Hz, J=4.9 Hz, 2H), 6.47 (d, J=2.4 Hz, 1H), 6.54 (dd, J=9.3, 2.1 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14](Br)[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](N)[CH2:35][CH2:36]C>CC(O)C.O.O>[CH2:1]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14]([C:35]([CH3:36])=[CH2:34])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCCCN
Solvent: O
Solvent: CC(C)O
Product: C=C(C)c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 119.5 %

Procedure:
A mixture of 2,4-bis-benzyloxy-5-bromo-benzoic acid benzyl ester (10.0 g, 20 mmol), potassium isopropenyl trifluoroborate (4.0 g, 27.2 mmol) and n-butylamine (6.0 mL, 60 mmol) in 2-propanol/water (2:1, 200 mL) was purged with N2 for 5 minutes. To this mixture was added [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) (816 mg, 1.09 mmol) and the mixture was heated at reflux for 20 h. The mixture was allowed to cool to ambient then diluted with water (400 mL) and extracted with EtOAc (2×300 mL). The combined organic extracts were washed with 1M aqueous HCl, brine, dried (MgSO4), filtered through a plug of Celite and the filtrate reduced in vacuo to give the title compound (11.1 g) as a brown gum.
Reaction SMILES: Br[C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]C)=[O:32])[C:29]2([CH3:36])[CH3:35])=[C:4]([F:39])[CH:3]=1.[CH3:40][O:41][C:42]1[N:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>>[F:39][C:4]1[CH:3]=[C:2]([C:45]2[CH:46]=[N:47][C:42]([O:41][CH3:40])=[CH:43][CH:44]=2)[CH:38]=[CH:37][C:5]=1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:15][C:10]=2[N:9]=[C:8]1[C@@H:28]1[C@H:30]([C:31]([OH:33])=[O:32])[C:29]1([CH3:36])[CH3:35]
Reactant: COc1ccc(B(O)O)cn1
Reactant: COC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2F)C1(C)C
Product: COc1ccc(-c2ccc(Cn3c([C@@H]4[C@H](C(=O)O)C4(C)C)nc4cc(OCc5ccc6ccccc6n5)ccc43)c(F)c2)cn1

Procedure:
The title compound was prepared using similar methods to those in Example 97 using racemic methyl cis-3-[1-(4-bromo-2-fluorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]-2,2-dimethylcyclopropanecarboxylate and (6-methoxypyridin-3-yl)boronic acid in Step A. MS (ESI): mass calcd. for C36H31FN4O4, 602.23; m/z found, 603.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J=2.5, 1H), 8.20 (d, J=8.5, 1H), 8.11 (d, J=8.5, 1H), 7.83 (d, J=8.2, 1H), 7.76-7.70 (m, 2H), 7.68 (d, J=8.5, 1H), 7.57-7.53 (m, 1H), 7.33-7.23 (m, 4H), 7.14-7.11 (m, 1H), 6.93-6.89 (m, 1H), 6.82 (d, J=8.5, 1H), 5.46 (d, J=17, 1H), 5.43 (s, 2H), 5.41 (d, J=17, 1H), 3.97 (s, 3H), 2.34 (d, J=8.2, 1H), 2.14 (d, J=8.2, 1H), 1.32 (s, 3H), 1.05 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][S:21][CH2:22][CH2:23]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:23][CH2:22][S:21][CH3:20])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(O)cc12
Reactant: CSCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CSCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
Cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methanone (0.76 g) synthesized in Example A82(3) was dissolved in tetrahydrofuran (15 mL), and 2-(methylthio)ethanol (0.26 mL), tributylphosphine (1.5 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.46 g) were added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 12 hr. Hexane (15 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (0.73 g, 76%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]2[N:47]=[C:46]([C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)[CH:45]=[CH:44][N:43]=2)[C:37]([CH3:40])=[N:38][CH:39]=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:33][C:34]3[CH:39]=[N:38][C:37]([CH3:40])=[C:36]([NH:41][C:42]4[N:47]=[C:46]([C:48]5[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=5)[CH:45]=[CH:44][N:43]=4)[CH:35]=3)=[O:15])=[CH:16][CH:17]=2)[CH2:6][CH2:7]1
Reactant: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ncc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a flask was added 4-((4-methylpiperazin-1-yl)methyl)benzoic acid (3.2 g), dicyclohexylcarbodiimide (3.0 g), N-(5-amino-2-methylpyridin-3-yl)-4-(3-pyridyl)pyrimidin-2-amine (3.0 g) and CH2Cl2 (100 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtrated and the filtrate was washed with water (100 mL×2), dried, filtrated, concentrated, and purified through column chromatography to give 4-[(4-methylpiperazin-1-yl)methyl]-N-{6-methyl-5-[(4-(pyrid-3-yl)pyrimid-2-yl)amino]pyrid-3-yl}benzamide (4.0 g).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].Br[CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 60.9 %

Procedure:
To a solution of (2R,3R,4R,5S,65)-2-(Acetoxymethyl)-6-(4-chloro-3-(4-hydroxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (500 mg, 0.91 mmol) in dry DMF (10 mL), was added (2-bromoethoxy)(tert-butyl)dimethylsilane (436 mg, 1.82 mmol) and cesium carbonate (890 mg, 2.73 mmol). The reaction was stirred at r.t. for 36 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (3×10 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 4:6 Acetone:Pet. Ether) to afford title compound (392 mg, 60.85%) as white solid.
Reaction SMILES: CO[CH:3]([CH3:8])[CH2:4][C:5]([NH2:7])=[O:6].[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13]N.[OH-].[Na+]>>[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13][NH:7][C:5](=[O:6])/[CH:4]=[CH:3]/[CH3:8]
Reactant: CN(C)CCCN
Reactant: COC(C)CC(N)=O
Agent: [Na+]
Agent: [OH-]
Product: C/C=C/C(=O)NCCCN(C)C

Procedure:
117.2 g (1.0 mole) of 3-methoxybutyric acid amide are heated with 103.7 g (1.05 mole) of 3-dimethylaminopropylamine for 10 hours in a temperature range of 145°-175° C. The mixture is allowed to cool, 1.5 g of sodium hydroxide are added and the mixture is heated in a high vacuum at 120°-130° C. The methanol is split off within about 30 minutes, vigorous foaming occurring. The temperature is increased and 130 g (0.76 mole=76% of the theoretical yield) of light yellow oil having a Bp0.1 of 132°-134° C. are distilled off.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[F:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O>>[F:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1cccc(F)c1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cccc(F)c3)nc2n(CCC)c1=O
Yield: 74.9 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.95 g (17.5 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.19 g (19.2 mmol) of 3-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 4.67 g (yield 75%) of Compound 36 as a pale yellow powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)(O)[O-].[Na+].Cl[CH2:19][C:20](=[O:22])[CH3:21]>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:19][C:20](=[O:22])[CH3:21])[C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12]
Reactant: CC(=O)CCl
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Cn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 100 °C

Procedure:
166 g (1 mol) of 3-methylxanthine and 110 g (1.3 mol) of sodium bicarbonate are suspended in 500 ml of dimethylformamide, the suspension is heated to 100° C., while stirring, and 111 g (1.2 mol) of chloroacetone are added dropwise over a period of 2 hours. The mixture is then subsequently stirred at 100° C. for two hours and thereafter cooled and the precipitate formed is filtered off with suction and washed five times with 50 ml of dimethylformamide each time. After the product has been taken up in warm 1N sodium hydroxide solution at 60° C., dilute hydrochloric acid is added until the pH reaches 9, the mixture is filtered hot with suction and the residue is washed with water until free from chloride, rinsed with methanol and dried at 80° C. in a drying cabinet.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][C:22]([F:25])([F:24])[O:21][C:20]([F:27])([F:26])[C:19]=2[CH:28]=1>C1(C)C=CC=CC=1>[F:25][C:22]1([F:24])[O:21][C:20]([F:26])([F:27])[C:19]2[CH:28]=[C:15]([NH:14][C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=3[F:13])[CH:16]=[CH:17][C:18]=2[O:23]1
Reactant: Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 5.5 g (0.03 mol) of 2,6-difluorobenzoyl isocyanate in 20 ml of toluene was added dropwise, at 60° C, to 6.7 g (0.03 mol) of 6-amino-2,2,4,4-tetrafluorobenz-1,3-dioxin in 100 ml of toluene. The batch was stirred for 1 hour at 60° C. After it had cooled, the product which had precipitated was filtered off, washed first with toluene and then with petroleum ether and then dried. 8 g (65.5% of theory) of analytically pure 3-(2,2,4,4-tetrafluoro-benz-1,3-dioxin-6-yl)-1-(2,6-difluorobenzoyl)-urea of melting point 231° C were obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@:5]12[O:12][C@@H:9]([CH:10]=[CH:11]1)[C:8](=[O:13])[CH2:7][C:6]2=[O:14])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][CH2:4][C@@:5]12[O:12][C@@H:9]([CH2:10][CH2:11]1)[C:8](=[O:13])[CH2:7][C:6]2=[O:14])[CH3:2]
Reactant: [H][H]
Reactant: CCOC[C@]12C=C[C@H](O1)C(=O)CC2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC[C@]12CC[C@H](O1)C(=O)CC2=O
Yield: 82.9 %

Procedure:
To a solution of (1S*,5S*)-1-ethoxymethyl-8-oxabicyclo[3.2.1]oct-6-ene-2,4-dione (2.8 g, 0.014 mol) in ethyl acetate (10 ml) is added 10% palladium on carbon (0.056 g), followed by stirring under a 1 bar hydrogen atmosphere for 24 hours. The reaction mixture is then filtered through diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silical gel to afford (1S*,5S*)-1-ethoxymethyl-8-oxabicyclo[3.2.1]octane-2,4-dione (2.3 g) as a pale yellow solid.
Reaction SMILES: C(OP([CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[CH3:16][C:17]1([CH3:32])[CH:19](/[CH:20]=C(\Br)/C(OCCC)=O)[CH:18]1[C:29]([OH:31])=[O:30].[H-].[Na+].P(O)(O)([O-])=O.[Na+]>COCCOC>[CH3:16][C:17]1([CH3:32])[CH:19](/[CH:20]=[C:9](/[F:15])\[C:10](=[O:11])[O:12][CH2:13][CH3:14])[CH:18]1[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCCOC(=O)/C(Br)=C/C1C(C(=O)O)C1(C)C
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)/C(F)=C\C1C(C(=O)O)C1(C)C
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A solution of 7.7 g of ethyl diethyl-phosphono-fluoroacetate (prepared by process of Ann. Chem., 1964, p. 6741), 60 ml of 1,2-dimethoxyethane and 4 g of (1R, trans) 2,2-dimethyl-3-formyl-cyclopropane-carboxylic acid was added over 30 minutes at 2° to 10° C. to a suspension of 2.6 g of a 60% sodium hydride in oil suspension and 60 ml of 1,2-dimethoxyethane and the mixture was stirred at 5° C. for 15 minutes, and then at room temperature for 3 hours. The resulting solution was poured into aqueous monosodium phosphate solution at 5° C. and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness at 40° C. under reduced pressure to obtain 6.5 g of an oil residue. The latter was chromatographed over silica gel and was eluted with a 70-30-1 hexane-ethyl acetate-acetic acid mixture to obtain 4 g of (1R,trans) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxypropenyl]-cyclopropane-1-carboxylic acid
Reaction SMILES: [F-:1].[Cs+].[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1Cl.O>CS(C)=O>[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[F:1]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: [F-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 94.6 %

Procedure:
Cesium fluoride (11.2 g) was added to a solution of 2-chloro-3-nitrobenzoic acid methyl ester (10.6 g, 49.0 mmol) in DMSO (49 mL), and the mixture was stirred at 140° C. for 40 minutes. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed in series with water and saturated saline, and dried over magnesium sulfate. The title compound (9.23 g, 95%) was then obtained by vacuum concentration as a pale yellow solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([NH:20][C:21]1([CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=3)=[CH:34][C:33]=2[Cl:46])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[C:54]([Cl:56])[CH:55]=1)[CH2:51]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C1COCC1>[C:13]([O:17][C:18]([NH:20][C:21]1([CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:51][C:50]4[CH:49]=[C:48]([Cl:47])[CH:55]=[C:54]([Cl:56])[CH:53]=4)[CH:40]=3)=[CH:34][C:33]=2[Cl:46])[CH2:22][O:23][C:24]([CH3:28])([CH3:27])[O:25][CH2:26]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1(CCCc2ccc(Oc3cccc(O)c3)cc2Cl)COC(C)(C)OC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CCCc2ccc(Oc3cccc(OCc4cc(Cl)cc(Cl)c4)c3)cc2Cl)COC(C)(C)OC1
Reaction time: 18 h
Yield: 51.2 %

Procedure:
Diethyl azodicarboxylate (0.31 mL) was added to a THF solution (5 mL) containing the compound of Example 106 (650 mg), 3,5-dichlorobenzyl alcohol (350 mg), triphenylphosphine (530 mg). The mixture was stirred for 18 hours. Subsequently, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the desired product (440 mg) as a colorless powder.