Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.[O:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:32]([CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[O:33])[CH2:17][CH2:18]2)[CH2:7][CH2:6]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(Oc3cc(F)c(F)cc3F)CC2)CC1
Reactant: O=C(O)C1CCOCC1
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3cc(F)c(F)cc3F)CC2)CC1)C1CCOCC1

Procedure:
According to the synthesis of example 19 the title compound was prepared from Trans(4-{2-[4-(2,4,5-trifluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-amine and tetrahydro-pyran-4-carboxylic acid. Preparative HPLC on reversed phase eluting with acetonitrile/water yielded the title compound. MS (m/e): 469.5 (M+H+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[C:19]2[O:18][C:17]([C:20]3([CH3:25])[O:24][CH2:23][CH2:22][O:21]3)=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)[CH3:10]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:9]([C:11]1[C:19]2[O:18][C:17]([C:20]3([CH3:25])[O:24][CH2:23][CH2:22][O:21]3)=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1cccc2cc(C3(C)OCCO3)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cccc2cc(C3(C)OCCO3)oc12
Temperature: 0 °C

Procedure:
28.0 g of recrystallized N-bromosuccinimide were added to a solution of 32.5 g of 7-ethyl-2-(2-methyl-1,3-dioxolan-2-yl)benzofuran in 480 ml of carbon tetrachloride. The resulting suspension was stirred and heated under reflux for 12 hours. The mixture was cooled overnight at 0°C, precipitated succinimide was filtered off and the filtrate was evaporated at 30°C under reduced pressure. There was thus obtained crude 7-(1'-bromoethyl)-2-(2-methyl-1,3-dioxolan-2-yl) benzofuran which was used immediately in the next stage. The structure of this compound was confirmed by spectral data.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH3:5][C:6]1[CH:26]=[CH:25][C:9]([C:10]([C:12]2[C:20]3[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=[C:14]([CH2:21][C:22](Cl)=[O:23])[CH:13]=2)=[S:11])=[CH:8][CH:7]=1>C(#N)C.C(N(CC)CC)C>[CH3:5][C:6]1[CH:26]=[CH:25][C:9]([C:10]([C:12]2[C:20]3[O:19][CH:18]=[CH:17][C:16]=3[CH:15]=[C:14]([CH2:21][C:22]([O:4][CH2:1][CH:2]=[CH2:3])=[O:23])[CH:13]=2)=[S:11])=[CH:8][CH:7]=1
Reactant: C=CCO
Reactant: Cc1ccc(C(=S)c2cc(CC(=O)Cl)cc3c2OCC3)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCOC(=O)Cc1cc(C(=S)c2ccc(C)cc2)c2occc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Allyl alcohol (2.0 ml) was added to a solution of 7-(4-methylthiobenzoyl)-2,3-dihydrobenzofuran-5-ylacetyl chloride (2.0 g) in acetonitrile (100 ml) and triethylamine (2.0 ml). This solution was stirred at room temperature for 12 hours. The solvent was then evaporated to dryness and the residue was taken up in a solution of ethyl acetate/water, washed 3 times with water, the ethyl acetate dried and evaporated to dryness after which the residue was purified by chromatography.
Reaction SMILES: [OH:1][CH:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24](F)[CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[C:28]([CH:29]=1)[O:1][CH:2]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CN(CCC(O)Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)cc1F
Product: CN(CCC(Cc1ccccc1)Oc1cc(Cl)ccc1C#N)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using (3-hydroxy-4-phenylbutyl)methylcarbamic acid, 1,1-dimethylethyl ester, and 4-chloro-2-fluorobenzonitrile.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:20])[O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=[S:22].[NH4+].[OH-].O>C1COCC1>[CH3:1][O:2][CH2:3][CH:4]([CH3:20])[O:5][C:6]1[C:7]([NH:19][C:21]([NH2:23])=[S:22])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COCC(C)Oc1cc(Oc2ccccc2)cnc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCC(C)Oc1cc(Oc2ccccc2)cnc1NC(N)=S
Reaction time: 22 h
Yield: 70 %

Procedure:
3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridine-2-ylamine (0.28 mmol) is dissolved in THF (4 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) is added. The reaction solution is stirred 22 hours. 32% NH4OH (20 eq.) is added and stirred 2 hours at room temperature. Water (60 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridin-2-yl]thiourea is obtained as yellow oil in a yield of 70%. HPLC (method C): 1.93 min; LC-MS (method A): 1.85 min, 334.15 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>O1CCCC1>[N:9]1([C:2]2[CH:7]=[C:6]([N:9]3[CH:13]=[CH:12][N:11]=[CH:10]3)[N:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: c1c[nH]cn1
Reactant: Clc1cc(Cl)ncn1
Solvent: C1CCOC1
Product: c1cn(-c2cc(-n3ccnc3)ncn2)cn1
Yield: 69.3 %

Procedure:
In anhydrous tetrahydrofuran, 298 mg of 4,6-dichloropyrimidine was substituted with 272 mg of imidazole. The reaction mixture was treated according to the procedure of Example 1 to yield 294 mg of 4,6-bis(1-imidazoly)pyrimidine, recrystallized from a mixture of isopropyl-alcohol and methanol, and having a melting point of 243°-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8].[OH:10]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N+:6]([O-:10])[C:7]=1[Cl:8]
Reactant: OO
Reactant: Oc1cnc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: [O-][n+]1cc(O)cc(Cl)c1Cl

Procedure:
3.28 g (20 mmol) of 5,6-dichloro-3-pyridinol in 15 ml of glacial acetic acid were N-oxidized at 100° C. using 2.14 g (21 mmol) of 35% hydrogen peroxide. When the reaction was complete, the mixture was neutralized, extracted with ethyl acetate and washed until neutral, and the solvent was removed by evaporation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:46]=[CH:45][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:31][C:32](=[O:42])[C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=3)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][C:17]=2[O:43][CH3:44])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>[Pd]>[CH2:1]([O:8][C:9]1[CH:46]=[CH:45][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:31][C:32](=[O:42])[C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:18][C:17]=2[O:43][CH3:44])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)c3ccc([N+](=O)[O-])cc3)C(=O)OC(C)(C)C)cc2OC)cc1
Agent: [Pd]
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)c3ccc(N)cc3)C(=O)OC(C)(C)C)cc2OC)cc1
Reaction time: 8 h
Yield: 73 %

Procedure:
Prepared using General Procedure 9: A stirred solution of 4-(3-(tert-butoxy)-2-(4-nitrobenzamido)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-8 (1.70 g, 2.68 mmol) in THF (30 mL) was degassed under N2 flow. Pd/C (10 wt % 0.17 g, 0.16 mmol) was added and the suspension was degassed under N2 flow. The reaction vessel was flushed with hydrogen gas and the reaction was stirred under an atmosphere of hydrogen overnight. The reaction was diluted with THF (10 mL) and filtered over celite. The material was concentrated and purified by chromatography (EA/hexanes) to afford 1.20 g (73%) of 4-(2-(4-aminobenzamido)-3-(tert-butoxy)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-9. LCMS-ESI (m/z) calculated for C35H44N2O7: 604. Found 605 [M+H]+, tR=3.15 min (Method 4). 1H NMR (400 MHz, DMSO) δ 8.24-8.18 (d, J=7.8 Hz, 1H), 8.05-7.94 (m, 2H), 7.61-7.52 (m, 2H), 7.13-7.04 (m, 4H), 6.93-6.85 (m, 1H), 6.57-6.48 (m, 2H), 5.65 (s, 2H), 4.58-4.50 (m, 1H), 4.12-4.03 (t, J=6.5 Hz, 2H), 3.71 (s, 3H), 3.16-3.03 (m, 2H), 1.79-1.69 (m, 2H), 1.47-1.23 (m, 17H), 0.90-0.82 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([CH3:29])[CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.Cl.[CH3:31][C:32]1([CH2:38][OH:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:39][CH2:38][C:32]1([CH3:31])[CH2:37][CH2:36][N:35]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:22][C:23]=2[CH3:29])[CH2:34][CH2:33]1
Reactant: CC1(CO)CCNCC1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)c(C)c4)C3)o2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC(C)(CO)CC5)c(C)c4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
73C (0.12 g, 0.31 mmol) and (4-methylpiperidin-4-yl)methanol hydrochloride (0.051 g, 0.31 mmol) were mixed with DCM (3 ml). Triethylamine (0.085 ml, 0.61 mmol) and then sodium triacetoxyborohydride (0.129 g, 0.61 mmol) were added. The mixture was stirred at RT overnight and then diluted with DCM (10 ml). The mixture was washed with aqueous NaHCO3 (sat. 4 ml) and then the organic solution was filtered through a phase separator. The solvent was removed by evaporation and the residue was purified by silica gel chromatography eluting the product with 1-3% methanol in DCM where the methanol contained ammonia (2 M). The product was triturated from DCM/diethylether. There was obtained 102 mg (66%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3): δ 0.95 (s, 3H), 1.32 (m, 2H), 1.53 (m, 2H), 2.30 (m, 2H), 2.34 (s, 3H), 2.53 (m, 2H), 3.38 (m, 2H), 3.42 (s, 2H), 3.89 (s, 3H), 4.32 (m, 1H), 4.63 (m, 1H), 4.72 (m, 1H), 5.04 (m, 2H), 5.10 (m, 1H), 6.55 (d, 2H), 6.59 (s, 1H), 7.03 (d, 2H), 7.19 (m, 2H), 8.10 (d, 2H), MS (APCI+) m/z 507 [M+H]+, LC purity: 98%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O1CCOCC1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: ClC(c1ccccc1)c1cc2ccccc2o1
Solvent: C1COCCO1
Product: CN1CCN(C(c2ccccc2)c2cc3ccccc3o2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
25.4 g of α(benzofuran-2-yl)benzyl chloride dissolved in 150 ml of dioxane are added slowly at about 60°-70° C. to 26 g of 1-methyl-piperazine in 150 ml of dioxane. After the addition, the mixture is stirred at about 70° C. for a further two hours. The solvent is removed under reduced pressure, the residue is then dissolved in 5% sodium bicarbonate and extracted with ethyl ether. After washing the ether phase with water and drying with sodium sulphate, the hydrochloride is precipitated by bubbling in anhydrous hydrochloric acid gas: M.P. 186°-188° C. (isopropanol).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br:18]Br>C(O)C>[Br:18][CH2:14][C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:15]
Reactant: CC(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: CCO
Product: O=C(CBr)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of 1-[4-(4-fluorophenoxy)phenyl]ethanone (17.7 g, 0.077 mol) in 220 ml of ethanol is cooled down to approximately 0° C. Bromine (4.8 ml, 0.096 mol) is added dropwise with a syringe. The temperature is allowed to return to ambient temperature, followed by stirring for 2 hours. After evaporation of the solvent then stirring for 10 hours in isopentane, the residue is filtered on frit and dried under a vacuum chamber bell jar. A beige-coloured powder is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.C([O-])(O)=O.[Na+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CCO>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:6]2[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=3)[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2,4-dichloro-6-(3-chloro-4-fluoro-phenyl)-pyrimidine (0.12 mol) and NaHCO3 (1.95 g, 0.023 mol) in EtOH at 0° C., add piperazine-l-carboxylic acid tert-butyl ester (0.013 mol). Remove the ice bath and stir at room temperature for 16 h. Concentrate under reduced pressure and partition between EtOAc and brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:34][CH3:35])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1)[CH3:21]>C(OCC)(=O)C>[CH2:34]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][NH:33][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:29][CH2:30]1)[CH3:35]
Reactant: CCN(CC)CCC1CCN(CCN)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CCOC(C)=O
Product: CCN(CC)CCC1CCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 10 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[2-(diethylamino)ethyl]-piperidin-1-yl]ethanamine in a yield of 10% of theory. Colourless crystals, m.p. 170°-172° C. (ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[CH:25])[CH3:21].C(N(CC)CC)C>[Cu]I.C1COCC1>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[C:25][C:16]1[S:17][C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:19])=[CH:3][C:2]=2[F:1])[CH:15]=1)[CH3:21]
Reactant: C#CCN(CC)CC
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 40 °C
Yield: 84.8 %

Procedure:
A stirred mixture of 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (965 mg, 2.50 mmol), N,N-diethylprop-2-yn-1-amine (417 mg, 3.75 mmol), copper(I) iodide (24 mg, 0.125 mmol), triethylamine (8.7 mL, 63 mmol), and THF (20 mL) was sparged with N2 for 5 minutes, then tetrakis(triphenyl -phosphine)palladium(0) (144 mg, 0.125 mmol) was added. The sealed reaction was heated to 40° C. for 18 hours. The mixture was concentrated, and then purified by Biotage Flash 40M silica gel chromatography system, eluting with EtOAc followed by 5% MeOH in EtOAc. The product was obtained as a waxy solid (783 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=6 Hz, 1H), 7.59 (s, 1H), 7.03 (t, J=9 Hz, 1H), 6.53 (m, 3H), 3.86 (br s, 2H), 3.78 (s, 2H), 2.73 (q, J=7 Hz, 4H), 1.19 (t, J=7 Hz, 6H). LRMS (ESI pos) m/e 370 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[N:9]1([C:14](N2C=CN=C2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1>C(Cl)Cl>[N:9]1([C:14]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: OCc1ccncc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(OCc1ccncc1)n1ccnc1
Yield: 80.7 %

Procedure:
A solution of (pyridin-4-yl)methanol (2.0 g, 18.3 mmol) and di(1H-imidazol-1-yl)methanone (5.94 g, 36.6 mmol) in 20 mL CH2Cl2 was heated overnight at 50° C. The reaction was quenched with water, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 10-70% EtOAc in CH2Cl2 gave (pyridin-4-yl)methyl 1H-imidazole-1-carboxylate (3 g, 81%). LC/MS: m/z 204.3 (M+H)+ at 0.38 min (v). 1H NMR (400 MHz, CDCl3) d 8.69 (dd, J=4.4, 1.6 Hz, 2H), 8.20 (t, J=0.9 Hz, 1H), 7.47 (t, J=1.5 Hz, 1H), 7.34 (dd, J=4.4, 1.6 Hz, 2H), 7.11 (dd, J=1.6, 0.8 Hz, 1H), 5.45 (s, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Cl:17][C:18]1[CH:19]=[C:20]([OH:31])[CH:21]=[N:22][C:23]=1[O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:31][C:20]2[CH:21]=[N:22][C:23]([O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])=[C:18]([Cl:17])[CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: C[C@H](Oc1ncc(O)cc1Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
tert-Butyl 5-chloro-2,4-difluorobenzoate (Preparation 59, 8.3 g, 33.4 mmol) was added to a solution of 5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-ol (Preparation 231, 16.2 g, 66.8 mmol) and potassium carbonate (27.8 g, 200 mmol) in dimethyl sulfoxide (100 mL). The reaction mixture was stirred at room temperature for 18 hours then quenched with an aqueous solution of sodium hydroxide (1 M, 100 mL). A white precipitate formed and was collected by filtration to give the title compound as a white solid (9.2 g).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][C:12]=2[CH:15]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(Br)ccc2o1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
13.8 g (100 mmol) Na2CO3 are added to a solution of 4.02 g (20.0 mmol) 5-bromo-salicylaldehyde and 2.26 mL (20.0 mmol, 98%) ethyl bromoacetate in 50 mL DMF. The reaction mixture is heated to 80° C. and stirred for 2 h at this temperature. It is diluted with 200 mL water, the aqueous phase is extracted three times with 100 mL tert-butylmethylether and the combined organic extracts are washed twice with 50 mL water. The organic phase is dried over MgSO4, filtered through activated charcoal and the solvent is eliminated i.vac.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:38]>CO>[ClH:38].[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCC(N)(CO)CO

Procedure:
2-Acetamido-1,3-diacetoxy-2-icosylpropane (1.5 g) was dissolved in 40 ml of methanol and 9.6 ml of a 1 N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was neutralized with a 1 N aqueous hydrochloric acid solution and the reaction mixture was concentrated under reduced pressure. The concentrate was washed with water and ethyl acetate:hexane=1:1 in order to give 817 mg of 2-amino-2-icosyl-1,3-propanediol hydrochloride.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]([CH3:28])([CH3:27])[C:23]([NH:25][NH2:26])=[O:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:26][NH:25][C:23](=[O:24])[C:22]([CH3:28])([CH3:27])[CH3:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 2,2-dimethylpropanehydrazide 253 (0.137 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 254 (0.32 g, 94%) as a white foam.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[OH:15])=[N+:2]=[N-:3].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:2]=[N-:3]
Reactant: BrCc1ccccc1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(N=[N+]=[N-])c(OCc2ccccc2)c1
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 97 %

Procedure:
To a solution of 4-azido-N-ethyl-3-hydroxybenzamide (3.44 g) obtained in Example 133b) in DMF (50 ml) were added benzyl bromide (2.4 ml) and potassium carbonate (2.76 g), and the reaction mixture was stirred at 55° C. for 3.5 hr. The reaction mixture was allowed to cool to room temperature, water was added and the resulting precipitate was collected by filtration and washed with water to give the title compound as a brown powder (4.81 g, 97%).
Reaction SMILES: [Br:1]Br.[C:3]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[C:12]#[N:13])[NH2:8])#[N:4].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][NH:8][C:7]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[C:5]([C:3]#[N:4])[CH:6]=1
Reactant: N#Cc1ccc(N)cc1C#N
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(NBr)cc1C#N
Temperature: 25 °C

Procedure:
A solution of 6.7 g of bromine in 5 ml of acetic acid is slowly added dropwise at room temperature to a mixture of 5.7 g of 3,4-dicyanoaniline, 3.6 g of sodium acetate and 25 ml of acetic acid. When the addition of bromine is complete, the mixture is further stirred at room temperature until no more educt can be detected in a thin-layer chromatogram. The acetic acid is then removed in vacuo in a rotary evaporator. The residue is taken up in warm water and the product is isolated by filtration. The filter cake is washed well with water and dried in vacuo at 70° C., affording bromo-3,4-dicyanoaniline as a grey product which dissolves in dimethyl formamide to give an almost colourless solution. A thin-layer chromatogram shows the product to be a mixture of isomers. Rf values of the two main products: 0.43 and 0.55 respectively [determined on ready prepared silica gel plates 6 OF-254, MERCK Darmstadt; eluant:toluene/ethanol (4:1)].