Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[O:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:41])[CH2:30][CH:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:32]([OH:34])=O)[CH:25]=[CH:26][CH:27]=2)=[N:13][NH:12]1.O=C1C2C(=CC=CC=2)C(CC2C=C(NC(=O)C(C3C=CC=CC=3)CC(O)=O)C=CC=2)=NN1.O>CN(C)C=O>[O:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]2[CH:23]=[C:24]([N:28]3[C:29](=[O:41])[CH2:30][CH:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:32]3=[O:34])[CH:25]=[CH:26][CH:27]=2)=[N:13][NH:12]1
Reactant: O=C(CC(C(=O)O)c1ccccc1)Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Agent: O=C(O)CC(C(=O)Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1)c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CC(c2ccccc2)C(=O)N1c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 3.25 h

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.139 g, 0.429 mmol) and diisopropylethylamine (0.095 g, 0.726 mmol) were added sequentially at ambient temperature to a stirred solution of the above mixture of N-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-phenylsuccinamic acid and N-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-3-phenylsuccinamic acid (0.142 g, 0.33 mmol) in dimethylformamide (2 ml), the mixture was stirred at ambient temperature for 3.25 hours and allowed to stand at ambient temperature for 18 hours, then it was added dropwise to water (10 ml). The mixture was stirred at ambient temperature for 30 minutes, then the resulting solid was collected by filtration, washed with water (5 ml) and hexane (10 ml), and dried in vacuo to give 1-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-3-phenylpyrrolidine-2,5-dione (0.097 g) as an off-white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 3.0 (m, 1H) (ring CH), 3.4 (m partially obscured by water peak, 1H) (ring CH), 4.4–4.55 (m, 3H) (ArCH2—+ring CH), 7.25–7.65 (m, 9H) (9×ArH), 7.9–8.15 (m, 3H) (3×ArH), 8.4 (d, 1H) (ArH), 12.8 (s, 1H) (CONH); m/z (M+H)+. 410, 94.2% purity.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=O)C.[CH2:34]([NH2:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)(=O)C>[NH3:20].[CH2:34]([NH:42][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:3])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)c1oc2cccc(OCCCNC3CCN(Cc4ccccc4)CC3)c2c1C
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCCc2ccccc2)oc2cccc(OCCCNC3CCN(Cc4ccccc4)CC3)c12
Product: N
Temperature: 170 °C
Yield: 25 %

Procedure:
A mixture of 4-(3-(1-benzyl-piperidin-4-ylamino)-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (the compound in Example 100, 15 mg) and phenethylamine (50 μl) was heated at 170° C. for four hours. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography (using dichloromethane:MeOH:ammonia solution (25-28%)=10:1:0.2 as a developing solvent) to give 4-[3-(1-benzyl-piperidin-4-ylamino)-propoxy]-3-methyl-benzofuran-2-carboxylic acid phenethyl-amide (9 mg) as a colorless oil. EI-MS: m/z 525 (M+); 1H-NMR (CDCl3): δ 1.41 (2H, m), 1.85-2.09 (6H, m), 2.51 (1H, m), 2.78 (3H, s), 2.90 (6H, m),3.50 (2H, s), 3.70 (2H, q, J=7 Hz), 4.14 (2H, t, J=6 Hz), 6.61 (1H, d, J=8 Hz), 6.63 (1H, br s), 6.97 (1H, d, J=8 Hz), 7.28 (11H, m).
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:16][OH:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[CH3:27].Cl>O>[OH:17][N:16]=[CH:2][C:3]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[C:21]([CH3:27])[CH:22]=1)=[O:5]
Reactant: COc1ccc(N)cc1C
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(NC(=O)C=NO)cc1C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
Chloral hydrate (11.5 g, 70 mmol) and anhydrous sodium sulfate (60 g, 422 mmol) were added to vigorously stirred water (300 mL). A slurry prepared by mixing hydroxylamine hydrochloride (23.0 g, 331 mmol) and 4-methoxy-3-methylphenylamine (10.0 g, 73 mmol) with aqueous hydrochloric acid (2.4 M, 250 mL) was added to the above mixture. The resulting mixture was refluxed for 20 min and then allowed to stand at room temperature for 16 h. A precipitate formed and was collected by filtration. The solid was washed with water and dried to yield 2-hydroxyimino-N-(4-methoxy-3-methylphenyl)acetamide (6.7 g, 32 mmol, 44%)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][C:30]3[CH:32]=[CH:33][CH:34]=[N:35][C:29]=3[NH:28][C:27]2=[O:36])[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([C:8]([C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]4[CH2:31][C:30]5[CH:32]=[CH:33][CH:34]=[N:35][C:29]=5[NH:28][C:27]4=[O:36])[CH2:24][CH2:25]3)[CH:3]=1)=[O:9])[CH2:11][CH2:12]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Reactant: O=C1Nc2ncccc2CN1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(N3Cc4cccnc4NC3=O)CC2)ncn1)N1CCc2cc(F)ccc21

Procedure:
70 mg (0.25 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 60 mg (0.26 mmol) 3-piperidin-4-yl-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one and 52 μL (0.30 mmol) DIPEA in 5.0 mL DMF were shaken for 2 h at RT. Then the reaction mixture was poured onto water, stirred and the precipitate formed was suction filtered. This was washed with diisopropylether and dried.
Reaction SMILES: CCCCCC.Br[C:8]1[C:9]([O:16][CH3:17])=[N:10][C:11]([O:14][CH3:15])=[N:12][CH:13]=1.[CH:18](OCC)=[O:19].O>CCOCC>[CH:18]([C:8]1[C:9]([O:16][CH3:17])=[N:10][C:11]([O:14][CH3:15])=[N:12][CH:13]=1)=[O:19]
Reactant: COc1ncc(Br)c(OC)n1
Reactant: CCOC=O
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: COc1ncc(C=O)c(OC)n1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 1.6M n-Buli in hexane (48 ml, 73.6 mmol) was added over 5 min. to a stirred suspension of 5-bromo-2,4-dimethoxypyrimidine (16 g; 72.9 mmol) in dry Et2O (240 ml) at -70° C. under an atmosphere of dry N2. Dry ethyl formate (28 g: 377 mmol) was added and the orange solution stirred at -70° C. for 1 h then allowed to warm slowly to ambient temperature. Water (400 ml) was added and the aqueous layer separated and extracted with Et2O (3×200 ml). The ether layer was combined with the extracts and dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography by preloading in SiO2 and eluting with EtOAc-hexane (3:7, v/v). Product fractions were combined and evaporated to give fine white needles, yield 6.89 g, (56%). Mass spectrum m/z 169 (M+H)+Analysis, found: C, 50:1;H,4.5;N,16.9%;C7H8N2O3 requires C,50.00; H,4.79; N, 16.66%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].Cl([O-])=[O:21].[Na+].[Na]>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:18]([OH:21])=[O:19]
Reactant: [O-][Cl+][O-]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C1=C(Cl)c2ccccc2OC1c1ccccc1
Reaction time: 5 h

Procedure:
To a stirred solution of 5.8 g 4-chloro-3-formyl-flav-3-ene in 500 ml tert-butanol and 100 ml 2-methylbut-2-ene at room temperature is added dropwise a solution of 17.9 g sodium chlorite and 17.9 g sodium dihydrogenophosphate in 200 ml water. Stirring is continued for 5 hours. The solution is concentrated in vacuo and water is added to the residue to give a suspension. The mixture is extracted with hexane and the clear organic extracts are discarded. Subsequently, the aqueous suspension is acidified to pH 3 and the mixture is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. The residual solid is recrystallized in a mixture of chloroform and hexane. Pure 4-chloro-3-carboxy-flav-3-ene is obtained as yellow crystals; m.p. 210° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1.[CH3:18][NH:19][NH2:20]>>[CH3:18][N:19]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1)[NH2:20]
Reactant: CNN
Reactant: C=CCCC(=O)N1CCc2nnc(Cl)cc2C1
Product: C=CCCC(=O)N1CCc2nnc(N(C)N)cc2C1

Procedure:
12.3 g of 3-chloro-5,6,7,8-tetrahydro-6-(4-pentenoyl)pyrido[4,3-c]pyridazine and 50 cc of methylhydrazine are stirred at a bath temperature of 90° for 30 minutes. The crude title compound is obtained in crystalline form upon cooling the mixture with ice. The title compound has a M.P. of 128°-130° (decomp., from isopropanol).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2[C:13]([CH2:12][O:11][C:8]3[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[CH:17][O:16][N:15]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a solution of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (1.0 g, 2.89 mmol) in THF (6.3 mL), water (6.3 mL) and methanol (1.75 mL) was added lithium hydroxide monohydrate (141.4 mg, 5.78 mmol) and the resulting mixture stirred at room temperature for 2 h and then acidified with HCl (4 N) and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title product (360 mg, 38%) which was obtained as white solid. MS: m/e=330.0 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[CH:23]=[N:22][CH:21]=[N:20][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[N:20]=[CH:21][N:22]=[CH:23][C:24]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ncncc21
Product: CC1c2cncnc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:18]#[CH:19]>O1CCOCC1.CCN(CC)CC.[Cu](I)I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:19]#[C:18][CH2:17][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: C#CCOC1CCCCO1
Agent: I[Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cc(C#CCOC2CCCCO2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (2.0 g, 5.80 mmol), tetrahydro-2-(2-propynyloxy)-2H-pyran (2.44 mL, 17.4 mmol), copper iodide (55.0 mg, 0.29 mmol) and bis(triphenylphosphine)palladium (II) dichloride (407 mg, 0.58 mmol) in dioxane (15 mL) and Et3N (15 mL) was heated to reflux for 16 h under nitrogen. The mixture was then allowed to cool to r.t., filtered and the filtrate was diluted with AcOEt. This mixture was washed once with water. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel 60, hexanes/EtOAc 5:1) to give an orange oil, which was recrystallized in hexanes to provide 2-amino-5-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-4-trifluoromethyl-benzoic acid methyl ester (1.50 g, 4.20 mmol, 72%) as a pale brown powder, m.p. 88° C., ESI-MS: m/z 358 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([C:48](=[O:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:44][CH2:43]1.C1CCN2C(=NCCC2)CC1.C(N(CC)CC)C>C(#N)C>[C:48]([N:45]1[CH2:44][CH2:43][N:42]([CH2:41][CH2:40][CH2:39][NH:38][C:13]([C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)=[O:15])[CH2:47][CH2:46]1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: NCCCN1CCN(C(=O)c2ccccc2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(NCCCN1CCN(C(=O)c2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 0.8 g (3.67 mmol.) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 0.84 g (8.8 mmol.) of N-hydroxysuccinimide in acetonitrile (15 ml) was added, at room temperature, 1.41 g (7.36 mmol.) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride. The mixture was stirred for 2 hours. To the reaction system was added a solution of 1.41 g (4.4 mmol.) of 4-(3-aminopropan-1-yl)-1-benzoylpiperazin dihydrochloride, 1.34 g (8.8 mmol.) of 1,8-diazabicyclo[5.4.0]unde-7-cene (DBU) and 1.0 ml (7.17 mmol.) of triethylamine in acetonitrile (15 ml). The mixture was stirred for further 2 hours. The solvent was distilled off under reduced pressure. To the residue was added water, which was subjected to extraction with ethyl acetate (a small volume of ethanol was also used). The organic layer was washed with a saturated aqueous saline solution, dried over magnesium sulfate and subjected to to distillation under reduced pressure. The residue was subjected to fractional purification by means of a column chromatography (methanol/ethyl acetate 30-40%), followed by distilling off the solvent under reduced pressure to afford the object compound as a reddish purple crystalline product. The yield was 0.738 g (45%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[N:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[N:11]=1>C(OCC)C>[CH2:1]([NH:8][C:10]1[N:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Fc1cc(F)nc(F)n1
Solvent: CCOCC
Product: Fc1cc(F)nc(NCc2ccccc2)n1
Reaction time: 1 h

Procedure:
23.5 g (0.22 mol) of benzylamine were added at -20 C. to a stirred mixture of 13.4 9 (0.1 mol) of 2,4,6-trifluoropyrimidine in 150 ml of diethyl ether within 15 min, and the mixture was stirred at this temperature for 1 hour. After a further hour at 25° C., working up was carried out as in Example 10. 21.4 g (98% of theory) of the title compound of melting point 70°-73° C. were obtained in this way.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH3:12][C:13]1=[C:14]([CH3:20])[C:15]([O:17][C:18]1=O)=[O:16].[ClH:21]>[OH-].[Na+].CC(N(C)C)=O>[CH3:12][C:13]1[C:18](=[O:17])[N:1]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([Cl:21])=[O:9])=[CH:10][CH:11]=2)[C:15](=[O:16])[C:14]=1[CH3:20]
Reactant: Cl
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC1=C(C)C(=O)N(Cc2ccc(C(=O)Cl)cc2)C1=O
Temperature: 90 °C

Procedure:
100 g (0.66 mol) of 4-(aminomethyl)-benzoic acid are dissolved in sodium hydroxide solution (26.4 g of NaOH in 300 ml of water). There is added dropwise to that solution, with stirring, a solution of 83.3 g of dimethylmaleic acid anhydride in 500 ml of dimethylacetamide. The reaction solution is then heated at 90° C. and, after 1.5 hours, 330 ml of aqueous hydrochloric acid (2N) are added. After the addition of hydrochloric acid the solution is cooled to room temperature and the stirrer is switched off. The crystalline product that has precipitated is filtered off, washed with water and dried in vacuo at 60° C. Yield: 155 g (90%). Melting point: 182-183° C. 120 g of that intermediate are suspended in 1000 ml of dry toluene. At 70° C., 50 ml of thionyl chloride are added dropwise. As soon as the evolution of gas has ceased (approx. 2 hours), the temperature is increased to 80° C. for 2 hours. After cooling, the solution is concentrated. The solid residue is recrystallised in toluene and then dried at 60° C. Yield: 155 g (80%). Melting point: 98-99° C. 1H-NMR (CDCl3): 1.98 (s, CH3), 4.72 (s, CH2), 7.45 (d, phenyl), 8.06 (d, phenyl).
Reaction SMILES: [CH:1]12[B:9]([CH2:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2>O1CCCC1>[CH2:10]=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[CH:5]12[BH:9][CH:1]([CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: CC(C)(C)OC(=O)N1CCC(CB2C3CCCC2CCC3)CC1
Solvent: C1CCOC1
Product: B1C2CCCC1CCC2
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
For this the compounds of general formula XV are reacted with tert.-butyl 4-(9-borabicyclo[3.3.1]nonan-9-ylmethyl)-piperidine-1-carboxylate (obtained from the reaction of tert-butyl 4-methylene-piperidine-1-carboxylate with 9-bora-bicyclo[3.3.1]nonane in tetrahydrofuran at reflux temperature) or tert-butyl 4-(9-bora-bicyclo[3.3.1]non-9-ylmethyl)-azepan-1-carboxylate (obtained from the reaction of tert-butyl 4-methylene-azepan-1-carboxylate with 9-bora-bicyclo[3.3.1]nonane in tetrahydrofuran at reflux temperature) in the presence of a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]-palladium-II-dichloride-dichloromethane complex, bis-tri-tert.-butylphosphine-palladium-(0), bis-tri-cyclohexylphosphine-palladium-(0), [1,2-bis(diphenylphosphino)ethane]palladium-II-dichloride or [1,3-bis(diphenylphosphino)propane]palladium-II-dichloride, but preferably [1,1′-bis(diphenylphosphino)ferrocene]-palladium-II-dichloride-dichloromethane complex, as well as a base such as for example sodium carbonate, potassium carbonate, caesium carbonate, triethylamine or N,N-diisopropyl-N-ethyl-amine, but preferably potassium carbonate, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile or N,N-dimethylformamide, optionally with the addition of water, at temperatures between 30° C. and 150° C., but preferably between 50° C. and 120° C., to obtain the compounds of general formula IX.
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[OH-].[K+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:25]([S:1][CH2:2][CH:3]([CH2:4][OH:5])[OH:6])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: OCC(O)CS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCSCC(O)CO
Reaction time: 24 h
Yield: 950.8 %

Procedure:
To a stirred solution of 40.0 grams (0.037 mole) 3-mercapto-1,2-propanediol in 300 milliliters of 95% ethanol, 24.9 grams (0.44 mole) of KOH was added under an inert atmosphere of nitrogen. Then, a solution of 135.0 grams (0.44 mole) bromohexadecane in 100 milliliters of 95% ethanol was added dropwise over a one-hour period, and the reaction allowed to proceed at room temperature with vigorous stirring for 24 hours. The precipitate was filtered, taken up in one liter of boiling methanol and cooled to 0° Centigrade for twelve hours. The precipitate was filtered and allowed to air dry, producing 117 grams (95%) of product (mp 72°-74° Centigrade).
Reaction SMILES: C([C:3]1[C:4]([OH:32])=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=[O:13])[C:9]([C:14]1[CH:30]=[CH:29][C:17]([C:18]([NH:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:19])=[CH:16][CH:15]=1)=[C:8]2[CH3:31])=O.OC1C=CC2N=C(C3C=CC(C(N4CCN(C)CC4)=O)=CC=3)C=CC=2C=1C=O>CS(O)(=O)=O>[OH:32][C:4]1[CH:3]=[C:12]2[C:7]([C:8]([CH3:31])=[C:9]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:20][CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[O:19])=[CH:29][CH:30]=3)[C:10](=[O:13])[O:11]2)=[CH:6][CH:5]=1
Reactant: Cc1c(-c2ccc(C(=O)NCCN3CCOCC3)cc2)c(=O)oc2c(C=O)c(O)ccc12
Agent: CN1CCN(C(=O)c2ccc(-c3ccc4c(C=O)c(O)ccc4n3)cc2)CC1
Agent: CS(=O)(=O)O
Product: Cc1c(-c2ccc(C(=O)NCCN3CCOCC3)cc2)c(=O)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.9 %

Procedure:
Compound 4 (5 g, 21.2 mmol) and compound 5 (5.6 g, 24.3 mmol) were stirred at 0° C. CH3SO3H (50 mL) was added dropwise. Then the mixture was stirred at RT for 16 h. The reaction mixture was poured into crush ice, extracted by DCM. The DCM layer was washed with sat.Na2HPO4, dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel column (DCM:EtOH=50:1), afforded compound 6 (1.2 g, 18%) as light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]#[N:11])=[C:8]([F:12])[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>C(COC)OC.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>[CH2:1]([O:3][C:4]1[C:9]([C:10]#[N:11])=[C:8]([F:12])[C:7]([C:32]2[N:28]=[CH:29][NH:30][CH:31]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1C#N
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: [Na+]
Solvent: COCCOC
Product: CCOc1ccc(-c2c[nH]cn2)c(F)c1C#N
Temperature: 85 °C
Yield: 46.1 %

Procedure:
To a sealed tube was added the above tert-butyl ester intermediate (25.5 mg, 0.103 mmol), 6-ethoxy-2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (60 mg, 0.206 mmol) and tetrakis(triphenylphosphine)palladium(0) (23.85 mg, 0.0206 mmol) in 1 mL of dimethoxyethane, followed by the addition of 0.5 mL of 20% Na2CO3. The mixture was heated at 85° C. for 4 h. LCMS showed both de-boc and boc-protected imidazole compounds formed. The reaction mixture was filtered, concentrated and the residue was purified by silica gel chromatography eluting with 2-5% MeOH/CH2Cl2. The boc-protected intermediate was not found during the column process, the de-boc intermediate was found and the fractions were collected and concentrated to afford 11 mg (46.1%) of 6-ethoxy-2-fluoro-3-(1H-imidazol-4-yl)-benzonitrile.