Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(OC)(C)C>C(O)CCC>[CH2:21]([NH:28][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CN1CCN(S(=O)(=O)c2ccc(NCc3ccccc3)c([N+](=O)[O-])c2)CC1

Procedure:
17.2 2.8 g (8.756 mmol) of 1-(4-chloro-3-nitrobenzenesulfonyl)-4-methylpiperazine are dissolved in 10 ml of 1-butanol, and 1.913 ml (17.5 mmol) of benzylamine are added. The reaction mixture is heated under reflux for 14 h. After cooling, MTBE is added, the precipitate formed is filtered off with suction and washed with MTBE and dried in vacuo, giving benzyl-[4-(4-methylpiperazine-1-sulfonyl)-2-nitrophenyl]amine; HPLC-MS [M+H]+ 391.2.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.Cl.[CH2:22]([N:25]([CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH3:24].S([O-])([O-])(=O)=O.[Mg+2]>CO.C(N(CC)CC)C>[CH2:31]([N:25]([CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:14][CH:15]=1)[CH2:32][CH3:33]
Reactant: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: CCCN(CCC)CCCCN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCN(CCC)CCCCNCc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (103 mg) obtained in Example 1-1 was dissolved in anhydrous methanol (10 ml) and then added with the hydrochloride (114 mg) of the compound obtained in Example 1-2. Then, the solution was added with triethylamine (0.108 ml) and anhydrous magnesium sulfate (3 g), followed by stirring at room temperature for 1 hour. Anhydrous magnesium sulfate was removed from the solution by filtration through Celite. Then, methanol was distilled off and the resultant was dried using a vacuum pump. The resultant was dissolved in anhydrous methanol (10 ml) and gradually added with sodium borohydride (22.0 mg) under ice-cooling. The solution was warmed back to room temperature and then stirred for 1 hour. After completion of the reaction, methanol was distilled off and the residue was then added with water and chloroform to extract the organic layer. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (60.3 mg) as a pale-yellow viscous liquid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][NH2:22])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:23][C:24]([CH3:26])=O>CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][N:22]=[C:24]([CH3:26])[CH3:23])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)=O
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Solvent: CO
Product: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O

Procedure:
A solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (800 mg, 2.65 mmol) in acetone (10 mL) and methanol (10 mL) was stirred for 20 hours at room temperature, then was concentrated under reduced pressure. The resulting yellow solid was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 5-15% methanol in chloroform) followed by crystallization from acetonitrile to yield 400 mg of acetone O-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}oxime as pale yellow crystals, mp 212-216° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[CH2:9]([O:11][P:12]([O-:16])[O:13][CH2:14][CH3:15])[CH3:10].C[Si](C)(C)Cl>>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][P:12](=[O:16])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: CCOP([O-])OCC
Agent: C[Si](C)(C)Cl
Product: CCOP(=O)(CCc1ccncc1)OCC
Yield: 54.7 %

Procedure:
A dry r. b. flask was loaded with 108 ml of 4-vinylpyridine (1 mole) and 129 ml of diethylphosphite (1 mole) under nitrogen. Dropwise addition of 25 ml of trimethylchlorosilane (0.2 mole) gave exothermic reaction to 53° C. with intermittent ice bath cooling. Once the exotherm subsided the reaction mixture was fitted for vacuum distillation. A possible exotherm was noted during distillation with deposition of solids in the lines. The distillation was shut down, the traps cleaned, and distillation recommenced giving 133 g diethyl 2-(4-pyridyl)ethylphosphonate b0.2 =129°-134° C. as a greenish fluid that turned light yellow on standing. Proton NMR in CDCl3 /TMS showed a 6H absorption at 1.3 ppm, 1.9H quintet at 2.1 ppm, 2H multiplet at 2.9 ppm, 4.2H triplet at 4.1 ppm, 2.1H 1:1 doublet at 7.2 ppm, and a 2.1H singlet at 8.5 ppm.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:12])[CH:18]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2 g, 8.6 mmol) and 3-(chloro)phenylboronic acid (1.35 g, 8.6 mmol) in dioxane/H2O (100 mL, 4:1) was added K2CO3 (2.4 g, 17.2 mmol) and Pd(PPh3)4 (0.19 g, 0.172 mmol), the mixture was stirred at 110° C. for 3 h. The solution was concentrated, partitioned in EtOAc/H2O. The aqueous layer was washed with EtOAc (50 mL) for 3 times. The collected organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give compound 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (1.2 g, 4.54 mmol, 53% yield) as a brown solid.
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]([O:9][C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH2:14][CH:15]=[CH2:16])=[O:11])([CH3:8])[CH3:7].[CH:20]1(O)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:6]([O:9][C:10]([NH:12][C@@H:13]([CH2:14][CH:15]=[CH2:16])[C:17]([O:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18])=[O:11])([CH3:5])([CH3:7])[CH3:8]
Reactant: OC1CCCC1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.9 %

Procedure:
To a stirred solution of DMAP (0.057 g, 0.465 mmol) in DCM (20 ml) was added EDC (0.980 g, 5.11 mmol). A solution of Boc-L-allylglycine (1.0 g, 4.65 mmol) in DCM (5 ml) was added and the mixture stirred for 20 minutes at RT. Cyclopentanol (0.506 ml, 5.58 mmol) was then added and the mixture stirred overnight at RT for complete reaction. After concentration of the reaction solvent in vacuo, the residue was subjected to column chromatography eluting with 6% EtOAc in hexanes. Yield=0.907 g, 3.20 mmol, 68.9% yield. m/z 284 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][C:4]=1[F:26])[CH3:2].O[N:28]=[C:29]([O:31][CH2:32][CH3:33])[NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:32]([O:31][C:29]1[N:30]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([F:26])[CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:24][N:28]=1)[CH3:33]
Reactant: CCOC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1noc(C2CC(c3ccc(CC)c(F)c3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
309 mg (0.81 mmol) of the compound from Example 36A and 169 mg (1.62 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were initially charged in 3.1 ml of DMF and reacted with 463 mg (1.22 mmol) of HATU and 0.42 ml (315 mg, 2.44 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 15 minutes; the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was taken up in 3.0 ml of DMF and converted at 180° C. for two minutes in the microwave (Emrys Optimizer). The reaction mixture was purified by means of preparative HPLC. Yield: 108 mg (30% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[C:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[CH:21][N:22]([CH3:24])[CH3:23]
Reactant: O=C(Cc1ccc(F)cc1)c1ccc(Cl)cc1Cl
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(F)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of the ketone product from Step A (6.0 g; 21.3 mmol) in DMF (100 mL) in a dried round bottom flask was added N,N-dimethylformamide dimethyl acetal (11.3 mL; 85.1 mmol) under a N2 atmosphere, and the reaction was stirred at 75° C. for 16 hours. Most of the volatiles were removed in vacuo to afford the crude product as a oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([OH:23])=[O:22])[C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.[CH:36]1([CH2:39]O)[CH2:38][CH2:37]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:36]1([CH2:39][O:22][C:21]([C:20]2[C:15]3[N:14]=[C:13]([C:24](=[O:35])[NH:25][CH:26]4[CH2:31][CH2:30][N:29]([CH:32]([CH3:33])[CH3:34])[CH2:28][CH2:27]4)[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)=[O:23])[CH2:38][CH2:37]1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Reactant: OCC1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)OCC4CC4)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
325.1 mg (0.57 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid were dissolved in 20 mL CH2Cl2. Subsequently 470 μl (5.7 mmol) cyclopropyl-methanol, 152.2 mg (0.74 mmol) DCC and 6.9 mg DMAP were added. The resulting mixture was stirred at room temperature for 16 h. The next day further 100 μl (2.28 mmol) cyclopropyl-methanol, 58.6 mg (0.29 mmol) DCC and 20 mg DMAP were added and the reaction mixture was stirred for 48 h. The solvent was removed under vacuo. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid cyclopropylmethyl ester as a white amorphous solid. The corresponding acetate was obtained by the following procedure: The above described material was dissolved in CH2Cl2 and washed with a saturated NaHCO3-solution. The organic layer was dried over anhydrous MgSO4 and concentrated. The resulting residue was diluted in 20 mL water containing 4 equiv. AcOH and lyophilized.
Reaction SMILES: [C@@H:1]12[O:11][C@@H:2]1CC[C:5]1[C:10]2=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:12](Cl)(Cl)Cl>>[CH3:12][C@@:1]1([C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[O:11][CH2:2]1
Reactant: ClC(Cl)Cl
Reactant: c1ccc2c(c1)CC[C@H]1O[C@@H]21
Product: C[C@]1(c2ccccc2)CO1

Procedure:
(1S,2R)-3,4-Dihydronaphthalene oxide (Table 6, entry 5) Colorless oil, [α]25D=−38.8° (c 0.91, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:25]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28](=[O:34])[N:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:26]1=[O:42])[CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:31]([C:29]2[C:28](=[O:34])[N:27]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:26](=[O:42])[N:25]([CH2:23][CH3:24])[CH:30]=2)=[O:32])=[CH:20][CH:21]=1
Reactant: COc1cc(OC)c2nccc(Oc3ccc(N)cc3)c2c1
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4c(OC)cc(OC)cc34)cc2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,8-dimethoxy-quinolin-4-yloxy)-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=127-9° C.; LCMS m/z=557 (M+1); 1H NMR (DMSO) δ: 10.93 (s, 1H), 8.87 (s, 1H), 8.45 (d, 1H, J=5 Hz), 7.79 (d, 2H, J=8.8 Hz), 7.41-7.45 (m, 2H), 7.33-7.37 (m, 2H), 7.24- (d, 2H, J=8.8 Hz), 7.10 (d, 1H, J=2.3 Hz), 6.86 (d, 1H, J=2.3 Hz), 6.61 (d, 1H, J=5 Hz), 4.01 (q, 2H, J=7 Hz), 3.94 (s, 3H), 3.89 (s, 3H), 1.29 (t, 3H, J=7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10].[CH3:22][O:23][CH:24]([O:41][CH3:42])[C:25]1[C:30]([O:31][CH2:32][O:33][CH3:34])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=[CH:27][C:26]=1[CH2:39]O>>[CH3:42][O:41][CH:24]([O:23][CH3:22])[C:25]1[C:30]([O:31][CH2:32][O:33][CH3:34])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=[CH:27][C:26]=1[CH2:39][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])=[C:2]([F:1])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(O)cc2)cc1F
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Product: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCOC)c3C(OC)OC)cc2)cc1F

Procedure:
According to a method similar to Example (6-7), from allyl (3-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (3.10 g, 10.9 mmol) obtained in Example (11-3) and [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (3.70 g, 12.0 mmol) obtained in Example (6-6), allyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-3-fluoro-1,1′-biphenyl-4-yl)acetate was obtained as a pale yellow oil (3.89 g, yield: 61%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:27]1[N:28]([CH2:36][CH3:37])[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[N:32][C:31]=12.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]=[C:14]1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:27]2[N:28]([CH2:36][CH3:37])[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][C:31]=23)=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2ccc(Oc3nc4ccccc4[nH]3)cc2)OC1(C)C
Reactant: CCn1nc2cccnc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCn1nc2cccnc2c1-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Yield: 59.1 %

Procedure:
A mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzimidazole (116 mg), 3-bromo-2-ethyl-2H-pyrazolo[4,3-b]pyridine (71 mg), tetrakis(triphenylphosphine)palladium(0) (36.3 mg), cesium carbonate (153 mg) and DME/water (3/1, 4 ml) was subjected to microwave irradiation at 120° C. for 40 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound (66.0 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:18])[C:16]#[CH:17].[H-].[Na+].O>CN(C)C=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:18][CH2:15][C:16]#[CH:17])[N:3]=[CH:4][N:5]=2)=[CH:9][CH:10]=1
Reactant: C#CCO
Reactant: Fc1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2ccc(F)cc2)ncn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 68.9 %

Procedure:
In 7 ml of N,N-dimethylformamide were dissolved 199 mg of 4-chloro-6-(4-fluorophenyl)pyrimidine and 64 mg of 2-propyn-1-ol, to which 46 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 150 mg of 4-(4-fluorophenyl)-6-(2-propynyloxy)pyrimidine (the present compound (58)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[CH3:30].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:26]4[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=4)[CH2:32][CH2:33]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(-c4ccccc4)n3)CC2)cc1C

Procedure:
60 mg (71%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (50 mg, 0.170 mmol), 1-(3,4-dimethylphenyl)piperazine (32 mg, 0.170 mmol), DIPEA (0.030 mL, 0.170 mmol) and NaBH(OAc)3 (108 mg, 0.510 mmol).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>Cl.C(OCC)C>[O:7]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: C1=COCCC1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Phenol (10 g, 106 mmol) was dissolved in 3,4-dihydro-2H-pyran (29 mL, 318 mmol) and one drop concentrated HCl was added at RT. The reaction was stirred at RT overnight. Ethyl ether (500 mL) was added to dilute the reaction. The organic layer was washed with water (2×100 mL), saturated sodium bicarbonate (2×100 mL), brine (2×100 mL) and dried over MgSO4. Evaporation gave title compound (17 g, 100%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[CH:35]=[CH:34][C:33]2[C:32](=[O:36])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:37])[C:24]=2[CH:23]=1>>[CH:23]1[C:24]2[C:25](=[O:37])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32](=[O:36])[C:33]=2[CH:34]=[CH:35][C:22]=1[CH2:21][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2ccc3c(c2)C(=O)c2ccccc2C3=O)c(=O)[nH]c1=O
Yield: 36.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-chloromethyl anthraquinone were reacted by the same way with the example 1 to obtain the titled compound (175 mg, yield: 36.3%).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Na+].[OH2:11]>>[OH:11][C:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:9])=[O:8])=[CH:3][N:4]=1
Reactant: O
Reactant: O=C([O-])c1cccnc1
Agent: [Na+]
Product: O=C(O)c1ccc(O)nc1
Temperature: 30 °C
Reaction time: 7 h

Procedure:
A 3-liter reaction vessel was filled with 2250 ml of 5 percent sodium nicotinate solution (pH 6.5) and was heated to 30° C. A suspension of Achromobacter xylosoxydans DSM 2783 cells in 120 ml of water was added and the reaction mixture was aerated intensively while stirring it well. The pH, the temperature and the oxygen concentration in the reaction mixture were measured and regulated continuously. After 7 hours, the concentration of the dissolved oxygen rose. At this point, the reaction was completed. The reaction suspension was centrifuged off and the cells in the sediment were used for the next charge. The clear supernatant was brought to pH 1.5 with concentrated sulfuric acid and the 6-hydroxynicotinic acid obtained was drained off and dried. 121 g of white product was obtained which, according to HPLC analysis, contained 98.6 percent of 6-hydroxynicotinic acid. This corresponded to a 6-hydroxynicotinic acid yield of 93.7 percent, related to the nicotinic acid used.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([CH3:24])[N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].[CH2:27]1[O:29][C@@H:28]1[CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([CH3:24])[N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:30][C@@H:28]1[CH2:27][O:29]1)[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1O
Reactant: OC[C@@H]1CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
To a solution of 2-ethyl-4-[5-(4-isobutyl-6-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (79 mg, 0.224 mmol) in THF (6 mL), (R)-(+)-glycidol (25 mg, 0.335 mmol) and triphenyl phosphine (88 mg, 0.335 mmol) are added. The mixture is stirred and cooled to 0° C. before DEAD (58 mg, 0.335 mmol, as a 40% solution in toluene) is added. The mixture is warmed to rt and stirring is continued for 4 h. Another portion of (R)-(+)-glycidol (8 mg, 0.112 mmol), triphenyl phosphine (30 mg, 0.112 mmol) and DEAD (19 mg, 0.112 mmol) is added. Stirring is continued for 4 h before the solvent is evaporated. The crude product is purified on prep. TLC using heptane:EA 7:3 to give 2-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-4-isobutyl-6-methyl-pyridine (46 mg) as a yellow oil; LC-MS: tR=1.17 min, [M+H]+=408.19.