Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([NH:20][C@@H:21]1[CH2:22][CH2:23][C@H:24]([O:27][N:29]2[C:33](=[O:34])[C:32]3[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]2=[O:39])[CH2:25][CH2:26]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4.1 ml (0.0244 mol) of diethyl azodicarboxylate (93%) are added dropwise to a mixture of 5 g (0.0232 mol) of trans-4-(N-BOC-amino)-cyclohexanol (cf. Example 1c), 3.8 g (0.0232 mol) of N-hydroxyphthalimide, 6.1 g (0.0232 mol) of triphenylphosphine and 100 ml of tetrahydrofuran at 20°-30° C. The reaction mixture is further stirred at room temperature for 15 hours and then evaporated in vacuo. To separate off the diethyl 1,2-hydrazinc dicarboxylate and triphenylphosphine oxide, the oily residue is dissolved in ethyl acetate, the solution is cooled to 0° C. and filtered, the filtrate is evaporated and the same operation is repeated once more, but using diethyl ether. The residue obtained after evaporation of the diethyl ether is purified by means of flash chromatography on silica gel using ethyl acetate/hexane mixtures (1:2 and 1:1). After evaporation of the product-containing fractions, the title compound is obtained as a crystalline residue, m.p. 134°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nn(C)cc1N
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (4.8 g, 25.94 mmol) in dry MeOH (100 ml) was thoroughly purged with argon, treated with 10% Pd—C (2.7 g, 2.59 mmol), and again purged with argon. Then the reaction mixture was hydrogenated under a balloon pressure of hydrogen at rt for overnight. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated and dried to give the title compound as gray-white solid (3.4 g, 84%), which was used in the next reaction step without further purification.
Reaction SMILES: C[C@@H](OC([N:12]1[C@@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14](=[O:29])[NH:13]1)=O)C1C=CC=CC=1>[Pd].C1COCC1>[C:23]1([C@H:15]2[C@H:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:12][NH:13][C:14]2=[O:29])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[C@@H](OC(=O)N1NC(=O)[C@@H](c2ccccc2)[C@@H]1c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1NN[C@@H](c2ccccc2)[C@@H]1c1ccccc1
Reaction time: 15.5 h
Yield: 96 %

Procedure:
A thick-walled glass hydrogenation tube was charged with diastereomer B of 1-[((R)-α-methylbenzyl)oxycarbonyl]-trans-4,5-diphenyl-3-pyrazolidinone [from Example 139A/139B] (226 mg, 0.586 mmol), 15.0 mL THF and 5% Pd/C catalyst (112 mg) and was shaken on a Parr apparatus under an atmosphere of hydrogen at c. 50 psi pressure for 15.5 hr. The catalyst was filtered off using Celite and washed with THF. The tiltrate was evaporated in vacuo to obtain 134 mg (96%) of a white foam: 1H NMR (CDCl3) δ 3.99 (d, J=l 1 Hz, 1H), 4.66 (br s, 1H), 4.74 (d, J=11 Hz, 1H), 7.20-7.39 (m, 1 OH), 8.63 (br s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[C:8]1([CH:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:15]([C:17](O)=[O:18])[NH2:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>C(OCC)C>[NH2:16][CH:15]([CH:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:17][OH:18]
Reactant: N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: NC(CO)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a solution of 1M-lithium aluminium hydride in diethyl ether (40ml) was added β,β-diphenylalanine hydrochloride (3.70g, Example 1b) over a period of 1h. The solution was heated at reflux for 1h, cooled to room temperature and to the solution was cautiously added 2M-sodium hydroxide (40ml). After filtering the solution through Celite, the residue was washed with ethyl acetate and the organic phase of the combined filtrates was washed with water, saturated brine and dried (MgSO4). The solid which formed on removal of the solvent in vacuo was washed with hexane to give 2-amino-3,3-diphenylpropan-1-ol 2.52g, mp 107°-8° C. 1H NMR (360MHz, CDCl3) d 7.36-7.14 (10H, m), 3.79 (1H, d, J=10.5Hz), 3.6 (1H, m), 3.57 (1H, dd, J=10.7Hz and 3.3Hz), 3.31 (1H, dd, J=10.7Hz and 6.7Hz), m/z (CI+) 228 (M+H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[C:20](=[O:29])[N:19]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.I[CH3:38]>C1COCC1>[CH2:11]([C:18]1([CH3:38])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[C:20](=[O:29])[N:19]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)N(C(=O)OC(C)(C)C)C2=O
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)(Cc1ccccc1)N(C(=O)OC(C)(C)C)C2=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Lithium bis(trimethysilyl)amide (5.04 mL, 5.04 mmol, 1 M in THF) was added to a solution of the tert-butyl 3-benzyl-5-methoxy-1-oxoisoindoline-2-carboxylate (example 1.3, 890 mg, 2.52 mmol) in THF (8 mL) at −78° C. After stirring the solution at −78° C. for 1 hr, iodomethane (465 mg, 3.27 mmol) was added, this was stirred at −78° C. for 1.5 hours. LC/MS showed complete conversion. Quenched the reaction mixture with saturated NaCl solution, then extracted with ethyl acetate, the combined organic layer was washed 1× with saturated NaCl solution. The organic phase was dried on Na2SO4 and the solvent was evaporated. The residue was purified by flash-chromatography on silica gel with 25-40% ethyl acetate in hexane, 750 mg (2.04 mmol, 81%) of the product was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([N:23]2[CH2:37][C:26]3=[C:27]4[N:32]([N:33]=[C:25]3[CH2:24]2)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]4)=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][C:30]1[C:29]([CH3:36])=[N:28][C:27]2[N:32]([N:33]=[C:25]3[CH2:24][N:23]([C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH:14]=[C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:22])[CH2:37][C:26]3=2)[C:31]=1[CH3:34]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1C=C1CCN(C(=O)OC(C)(C)C)CC1)C3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1C=C1CCNCC1)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A mixture of 4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (80 mg; 0.15 mmol; 1 eq.) and TFA (1 mL) in DCM (1 mL) was stirred at room temperature for 30 min then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH and extracted with DCM (2×). The combined organics were dried over magnesium sulfate and concentrated in vacuo to afford the title compound (40 mg, 62%) as a white solid. 1H NMR (CDCl3) δ 7.41-7.25 (m, 4H), 6.33 (s, 1H), 5.01-5.00 (m, 2H), 4.47-4.45 (m, 2H), 2.90 (s, 2H), 2.85-2.78 (m, 5H), 2.69 (s, 1H), 2.61 (s, 2H), 2.41-2.38 (m, 2H), 2.26-2.23 (m, 2H). HPLC (max plot) 96%, Rt 2.63 min. UPLC/MS: (MS+) 422.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[NH:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.IC.[C:24]([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]([CH3:24])[C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1-n1c(=O)[nH]c2ccc(F)cc2c1=O
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)c2cc(F)ccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A mixture of 3-(3-bromo-2-methylphenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione (742 mg, 2.13 mmol), iodomethane (0.159 mL, 2.55 mmol) and Cs2CO3 (1.039 g, 3.19 mmol) in THF (20 mL) was stirred at room temperature overnight. The mixture was filtered and concentrated. The residue was dissolved in DCM and washed sequentially with saturated aqueous NaHCO3 and water, dried and concentrated to provide 3-(3-bromo-2-methylphenyl)-6-fluoro-1-methylquinazoline-2,4(1H,3H)-dione (742 mg, 96% yield). Mass spectrum m/z 363, 365 (M+H)+.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[N:17]=3)[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6].[ClH:34]>O.CO.C1COCC1>[ClH:22].[ClH:34].[ClH:22].[Cl:22][C:21]1[C:16]([C:13]2[S:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:5]([OH:6])=[O:4])[C:15]=3[CH:14]=2)=[N:17][C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[N:19][CH:20]=1
Reactant: COC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)O)cccc4s3)n2)CC1
Temperature: 70 °C
Yield: 94 %

Procedure:
Aqueous 2 N LiOH (1.1 mL, 2.2 mmol) is added to a stirred solution of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methyl ester (280 mg, 0.610 mmol) in water (3 mL), MeOH (6 mL) and THF (12 mL). The mixture is heat at 70° C. for 2 hours. While at 70° C., 5 N HCl (1 mL) is added to the solution, then the solution is allowed to cool to room temperature. After concentration, the yellow solid is suspended in THF (20 mL), sonicated, filtered, and dried to give the title compound as a solid (320 mg, 94% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[C:12](O)[C:11]2[C:6](=[N:7][C:8]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:10]=2)[N:5]=1.O=P(Cl)(Cl)[Cl:27].N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl>[Cl:27][C:12]1[C:11]2[C:6](=[N:7][C:8]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:13]=1
Reactant: COCc1cc(O)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: COCc1cc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]napthyridin-4-ol (191 mg, 0.569 mmol) is dissolved in a solution of chloroform (15 mL), POCl3 (0.212 mL, 2.28 mmol) and 2,6-lutidine (0.256 mL, 2.28 mmol). The reaction is heated at reflux overnight. The mixture is concentrated under reduced pressure. The resulting residue is dissolved in EtOAc (50 mL) and extracted with water (50 mL), saturated NaHCO3(aq) (50 mL) and brine (50 mL). The organic extract is dried over Na2SO4 and the solvent removed under reduced pressure. The crude product is purified by column chromatography on silica gel eluting with hexanes/EtOAc (1:1) to yield the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH2:28].CN(C)C=O.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C>[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:28][C:20](=[O:22])[C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6.65 g. of Nα -benzyloxycarbonyl-D-phenylalanine (0.022 mol) and 4.38 g. (0.022 mol) of L-leucine methyl ester hydrochloride in 60 ml. of spectrograde dimethylformamide is chilled in ice and treated with 3.0 ml. of triethylamine (2.24 g.). 1-Hydroxybentriazole, 3.3 g., and dicyclohexylcarbodiimide, 5 g., are added and the reaction stirred at room temperature overnight and for 24 hours longer at room temperature. The mixture is filtered and the solvent evaporated under reduced pressure. The residue is dissolved in 200 ml. of ethyl acetate and washed with 0.1N hydrochloric acid, saturated salt solution, 5% sodium bicarbonate solution, saturated salt solution and water. The ethyl acetate solution is dried over magnesium sulfate, filtered and evaporated to a crystalline residue. The product is recrystallized twice from ethyl acetate and petroleum ether; 7.3 g.; m.p. 125°-126° C.; [α]D23 -20.3° (c 1.02, methanol).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[N:6]1([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[O:14][CH2:15][CH2:16][OH:17])[CH:10]=[CH:9][N:8]=[CH:7]1.Cl>C(#N)C>[N:6]1([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[O:14][CH2:15][CH2:16][O:17][S:1](=[O:4])(=[O:3])[NH2:2])[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1cccc(-n2ccnc2)c1
Agent: Cl
Solvent: CC#N
Product: NS(=O)(=O)OCCOc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
A solution of sulfamoyl chloride (0.0275 mole) in 60 ml of acetonitrile was treated dropwise with a solution of 5.1 g (0.025 mole) of 2-[3(1H-imidazol-1-yl)phenoxy]ethanol in 100 ml of acetonitrile. The mixture was stirred at ambient temperature under nitrogen for 20 hr. The mixture was concentrated under vacuum, and the residue was partitioned between ethyl acetate and dilute potassium carbonate solution. The organic fraction was again concentrated under vacuum to a crystalline residue. This residue was dissolved in warm 95% ethanol and treated with 1 equivalent of anhydrous hydrogen chloride. The solution was chilled and the precipitate was collected and dried to give 4.0 g (50%) of the title compound as a pinkish powder, monohydrochloride, mp 149.0°-150.0° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:19]=[N+:20]=[N-:21])(C)C>>[C:1]1([C:7]2[N:19]=[N:20][NH:21][C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C(#Cc1ccccc1)c1ccccc1
Product: c1ccc(-c2nn[nH]c2-c2ccccc2)cc1
Temperature: 150 °C
Yield: 27.4 %

Procedure:
A mixture of 50 g (0.28 moles) of diphenylacetylene and 33 g (0.28 moles) of trimethylsilylazide was heated at 150°C for several days. The cooled reaction mixture was extracted with hot dilute NaOH. This was washed with toluene while still warm, cooled, and acidified. The precipitate was recrystallized from toluene to give 17 g of 4,5-diphenyl-1,2,3(1H)-triazole, m.p. 131°C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:14])=[C:7]([C:10]([F:13])=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[OH:15][CH2:16][CH2:17][CH:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1.CCN(C(C)C)C(C)C>C1COCC1.[Cl-].[Na+].O>[C:8]([C:7]1[C:6]([CH3:14])=[C:5]([C:3](=[O:4])[CH2:2][N:23]2[CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:19][CH:18]2[CH2:17][CH2:16][OH:15])[CH:12]=[CH:11][C:10]=1[F:13])#[N:9]
Reactant: Cc1c(C(=O)CBr)ccc(F)c1C#N
Reactant: CC(C)(C)OC(=O)N1CCNC(CCO)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2CCO)ccc(F)c1C#N
Reaction time: 8 h

Procedure:
3-(2-Bromoacetyl)-6-fluoro-2-methylbenzonitrile (prepared as described above, 5.11 g, 20.0 mmol) was dissolved in THF (100 mL), then known, commercially available compound tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (4.60 g, 20.0 mmol) was added, followed by Hunig's base (6.96 mL, 39.9 mmol) and the mixture was stirred overnight. The reaction mixed was poured into brine and extracted with ethyl acetate (twice), dried over Na2SO4, filtered and concentrated. The product was purified by MPLC chromatography using a 330 g ISCO Redi Sep column and 5% MeOH/DCM solvent system-to yield tert-butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-oxoethyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate: LC-MS (IE, m/z): 406 [M+1]+;
Reaction SMILES: [CH:1]([C:4]1([CH3:24])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:18]3[N:17]=[C:16]([CH3:19])[N:15]([CH3:20])[C:14]=3[CH:13]=[CH:12][C:11]=2[C:21]([OH:23])=O)=[N:5]1)([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH:1]([C:4]1([CH3:24])[C:8](=[O:9])[N:7]2[C:21](=[O:23])[C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH3:20])[C:16]([CH3:19])=[N:17][C:18]=4[C:10]=3[C:6]2=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc2c(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)ccc2n1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc2c3c(ccc2n1C)C(=O)N1C(=O)C(C)(C(C)C)N=C31
Reaction time: 3 h
Yield: 23.6 %

Procedure:
A mixture of 4-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-1,2-dimethyl-5-benzimidazolecarboxylic acid (0,942 g, 2.87 mmol), dicyclohexylcarbodiimide (0,590 g, 2.87 mmol) and tetrahydrofuran is stirred for 3 hours at reflux temperature, cooled and concentrated in vacuo. The residue is chromatographed (silica gel, ethyl acetate eluent) to afford the title product as a white powder (0.210 g, 23.6%), mp 258°-263° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[N:13]1[CH:14]=[CH:15][C:16]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)=[N:17][C:12]=1[NH:11][C:3]1[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cncnc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(N)cc1Nc1nccc(-c2cncnc2)n1
Reaction time: 2 h

Procedure:
Stannous chloride dihydrate (3.6 g, 16 mmol) was dissolved in 10 mL of concentrated hydrochloric acid. The solution was added to N-(2-methyl-5-nitrophenyl)-4,5′-bipyrimidin-2-amine with violent stirring. The mixture was poured into ice-cold water after being stirred for 2 hours. It was then neutralized to pH>8 with sodium carbonate and extracted with ethyl acetate for 4 times. The pooled extracts were washed with brine, dried over magnesium sulfate and finally concentrated under reduced pressure to obtain 0.7 g of the title compound. MS (M+1)=279.13.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]1([F:29])[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1>>[F:29][C:13]1([CH2:12][NH:11][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:17][CH2:18]1
Reactant: NCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(O)c1ccc(O)cc1
Product: O=C(NCC1(F)CCN(C(=O)OCc2ccccc2)CC1)c1ccc(O)cc1

Procedure:
4-Hydroxy benzoic acid was coupled to benzyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate according to the procedure for EXAMPLE 1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[OH:32]>>[OH:32][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:26]1[NH:25][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N[C@H]2CCCC[C@@H]2O)cn1
Yield: 91 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (1S,2S)-2-amino-cyclohexanol hydrochloride (1:1) instead of 2-aminoethyl isopropylether, to the title compound (240 mg, 91%) which was obtained as a white solid. MS: m/e=408.3 [M+H]+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:35])[N:24]([CH:32]([CH3:34])[CH3:33])[CH2:25][CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH:20]=[C:19]([Cl:36])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:36][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=1)[C:23]([N:24]([CH:32]([CH3:33])[CH3:34])[CH2:25][CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)=[O:35]
Reactant: CC(C)N(CCn1cncn1)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCn1cncn1)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-{3-chloro-5-[isopropyl-(2-[1,2,4]triazol-1-yl-ethyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.097 g) in dichloromethane (5 ml) was added trifluoroacetic acid (2 ml) and the mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue subjected to preparative hplc to give the title compound (0.093 g) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:21])(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCCO)c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCC=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 4-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]butanol (85.7 mg, 0.23 mmol, as prepared in the preceding step), N,N-diisopropylethylamine (86 uL, 0.49 mmol), anhydrous dimethyl sulfoxide (50 uL, 0.70 mmol) and anhydrous dichloromethane (1 mL) was cooled to 0° C. under nitrogen. Sulfur trioxide pyridine complex was added in portions over 8 minutes. The solution was stirred at 0° C. for 3 hours and at ambient temperature for 1 hour. The reaction was diluted with dichloromethane (25 mL) and extracted with 5% aqueous citric acid (10 mL). The aqueous layer was extracted with dichloromethane (10 mL). The combined organic layers were washed with 5% aqueous citric acid (25 mL), and the aqueous layer was extracted. The combined organic layers were washed with pH 7 buffer (25 mL) and brine (25 mL) and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to give the title compound as a colorless oil (86.0 mg, 100%). This product was used in the next step without purification. 1H-NMR (300 MHz, CDCl3) δ 9.81 (t, 1H, J=1.3 Hz), 7.82 (dd, 1H, J=1.7, 7.9 Hz), 7.62 (ddd, 1H, J=1.7, 7.4, 8.4 Hz), 7.09 (d, 1H, J=8.4 Hz), 6.99-7.05 (m, 1H), 6.55 (br s, 1H), 6.51 (br s, 1H), 6.42 (t, 1H, J=2 Hz), 4.02 (s, 3H), 3.88 (t, 2H, J=6.0 Hz), 2.62 (td, 2H, J=1.3, 7.0 Hz), 2.24 (s, 3H), 2.01-2.15 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C18H20O6S: 387.1 (M+Na). Found: 387.0.