Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][NH2:41]>COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH:41][CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][CH2:29][NH2:28])=[O:12]
Reactant: NCCCNCCCCNCCCN
Reactant: COc1ccccc1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: COc1ccccc1CC(=O)NCCCNCCCCNCCCN
Reaction time: 48 h

Procedure:
According to the General Procedure using 2-methoxyphenylacetic acid (81 mg. 0.49 mMol), dicyclohexylcarbodiimide (53 mg, 0.26 mMol), and spermine (201 mg, 0.99 mMol) in DME (4 ml), activation during 2.5 h and coupling over 48 h. The produce was eluted over silica gel with the lower layer of dichloromethane/methanol/0.880 ammonia solution (2:1:1). The desired amide was in fractions 6-10 and was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH lower layer, 2:1:1), Rf =0.25, (28 mg, 31%), lyophilisation gave 16 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, 2H2O) 1.35-1.85 (m, 8H, 4×CH2 --CH2), 2.4-2.9 (m, 10H, 5×CH2 --N), 3.25 (t, J=7, 2H, CON2H--CH2 --CH2), 3.5 (s, 2H, Ar--CH2 --CO), 3.83(s, 3H, OCH3), 6.75-7.05 (m, 2H, 2×ArH 3,5), and 7.15-7.35 (m, 2H, 2×ArH 4,6)ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([C@:8]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])([CH3:17])[CH2:9][S:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:7]=1.[OH-].[Li+].Cl>O1CCCC1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([C@:8]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])([CH3:17])[CH2:9][S:10][CH2:11][C:12]([OH:14])=[O:13])[CH:7]=1
Reactant: CCOC(=O)CSC[C@](C)(NCc1ccc(OC)cc1OC)c1cc(Br)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN[C@@](C)(CSCC(=O)O)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of (R)-ethyl 2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)acetate (3 g, 5.99 mmol, Eq: 1.00) in tetrahydrofuran (20 ml), methanol (10 ml), water (5 ml) was added at 23° C. lithium hydroxide (287 mg, 12.0 mmol, Eq: 2.0). The colourless reaction solution was stirred at 23° C. for 2 hours. The reaction mixture was neutralized with 1 N HCl (12.0 ml, 12.0 mmol, Eq: 2.0) (pH=5-6) and evaporated. The residue was triturated with dichloromethane/methanol 9:1 and solid Na2SO4 was added. The solid was filtered off and the filtrate was evaporated to dryness to give the crude (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)acetic acid (3.2 g, 6.1 mmol, 102% yield) as a white foam which was used without further purification. MS (ISN): m/z=470.6 [M−H]− and 472.5 [M+2−H]−.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[OH:5][CH2:6][CH:7]([C:9]1[O:10][CH2:11][CH2:12][N:13]=1)[CH3:8].[N+](C(C)(C)C)(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[O-]S(O)(=O)=O.[OH-].[Na+].[Na+].[Cl-]>O1CCCC1.O.CCCCCCC>[CH2:1]([O:5][CH2:6][CH:7]([C:9]1[O:10][CH2:11][CH2:12][N:13]=1)[CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCCl
Reactant: CC(CO)C1=NCCO1
Agent: CC(C)(C)[N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C=CCOCC(C)C1=NCCO1
Reaction time: 3.5 h
Yield: 99 %

Procedure:
In a three-neck round bottom flask, 24 g allylchloride (0.31 mole), 60 g 2-(3-hydroxy-2-propyl)-2-oxazoline (0.47 mole), 10 g of heptane, and 3.7 g (t-Bu)4NHSO4 phase transfer catalyst in 150 g tetrahydrofuran (THF) are added as the organic phase. The aqueous phase is 93 g NaOH solution prepared by dissolving 50 wt % NaOH into H2O saturated with NaCl. The solution is agitated vigorously by a mechanical stirrer. Reaction is conducted at 40° C. for 3.5 hours. Conversion is over 90% according to GC analysis of crude product. After the reaction, the aqueous layer is decanted and the organic layer is extracted four times with H2O saturated with NaCl. Tetrahydrofuran solvent is stripped off by a rotary evaporator. The remaining solution is filtered and dried over 3 Å molecular sieve. A pure monomer (99%) is obtained by distillation (0.12 mm/31° C.). The structure is identified by NMR and IR analysis.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][CH:6]=1.[CH2:16]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1)[CH3:17]>>[F:14][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([O:18][CH2:16][CH3:17])=[CH:20][C:21]=2[N+:26]([O-:28])=[O:27])=[O:13])=[CH:7][CH:6]=1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1
Product: CCOc1ccc(NC(=O)c2ccc(OCC(F)(F)F)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.05 (s, 1H), 8.84-8.80 (m, 2H), 8.25-8.21 (m, 1H), 7.73 (d, J=3.0, 1H), 7.32-7.28 (m, 1H), 7.01 (d, J=8.7, 1H), 4.86 (q, J=8.4, 2H), 4.11 (q, J=6.9, 2H), 1.46 (t, J=6.9, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH3:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:3]=1[F:19].O.[NH2:21][NH2:22]>CS(C)=O>[F:19][C:3]1[C:4]([N:9]([CH3:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:5][C:6]([CH3:8])=[N:7][C:2]=1[NH:21][NH2:22]
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N(C)CCc2ccncc2)n1
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(NN)c(F)c(N(C)CCc2ccncc2)n1
Reaction time: 8 h
Yield: 63 %

Procedure:
6-Chloro-5-fluoro-N,2-dimethyl-N-[2-(4-pyridinyl)ethyl]-4-pyrimidinamine (350 mg, 1.25 mmol) was dissolved in 4 ml of DMSO and 4 ml of hydrazine monohydrate was added. The mixture was stirred overnight and was purified by RP-HPLC to provide 5-fluoro-6-hydrazino-N,2-dimethyl-N-[2-(4-pyridinyl)ethyl]-4-pyrimidinamine (220 mg, 63%). LCMS: (M+H)+: 277.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:23]([O-])=O)=[C:13]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>O1CCCC1.CO.O.[Fe]>[NH2:23][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][C:13]=1[S:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ccc(OCc2ccccc2)cc1Sc1ccc(O)cc1
Temperature: 25 °C
Yield: 95.6 %

Procedure:
The product of Example 237B (0.390 g, 1.10 mmol), iron powder (0.248 g, 4.41 mmol, 4.0 eq) and ammonium chloride (0.071 g, 1.32 mmol, 1.2 eq) in tetrahydrofuran (6 mL), methanol (6 mL) and water (2 mL) was heated under reflux for 16 hours and then cooled to room temperature. The reaction mixture was filtered through Celite, rinsing with methanol, and the filtrate was evaporated under reduced pressure to provide the title compound (0.340 g, 95%) as a gray powder that was used in subsequent reactions without further purification.
Reaction SMILES: C[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:22])[O:13][CH2:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(C1C=CC(CC(O)=O)=CC=1)(=O)(=O)[NH2:24].BrCC(C1C=CC=CC=1)=O>>[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:22])[O:13][CH2:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:24]
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)COC2=O)cc1
Reactant: NS(=O)(=O)c1ccc(CC(=O)O)cc1
Agent: O=C(CBr)c1ccccc1
Product: NS(=O)(=O)c1ccc(C2=C(c3ccccc3)COC2=O)cc1
Yield: 40 %

Procedure:
The title compound was synthesized in a manner similar to that described for 47b from 4-sulfamoylphenylacetic acid and 2-bromoacetophenone in 40% yield. 1H NMR (DMSO-d6) δ 5.43 (s, 2H), 7.36–7.45 (m, 5), 7.76 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.5 Hz, 2H); HRMS calc'd for M+ 315.0557. found 315.0573. Anal. (C16H13NO4S) C, H, N.
Reaction SMILES: N1(O[C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:46]=3[N:47]=[CH:48][N:49]=2)[C@@H:16]2[O:45][C@H:35]([CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C@@H:26]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@H:17]2[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])C2C=CC=CC=2N=N1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[N:50]1([C:11]2[N:49]=[CH:48][N:47]=[C:46]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:16]2[O:45][C@H:35]([CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C@@H:26]([O:27][Si:28]([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:29])[CH3:30])[C@H:17]2[O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21])[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1
Reactant: C1COCCN1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N4CCOCC4)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 85.4 %

Procedure:
As described for the synthesis of 6-(morpholin-1-yl)-9-[2-deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuranosyl]-purine, this morpholino derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-inosine (27) (71.8 mg, 0.099 mmol), and morpholine (17.5 μL, 0.200 mmol) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) in dry DME (1.0 mL) at room temperature over 1 h. No additional purification was needed and 57.5 mg (85% yield) of the title compound was obtained. Rf (3% MeOH in CH2Cl2)=0.68. 1H NMR (500 MHz, CDCl3): δ 8.33 (s, 1H, Ar—H), 8.03 (s, 1H, Ar—H), 6.03 (d, 1H, H-1′, J=5.4), 4.72 (t, 1H, H-2′, J=4.9), 4.32-4.29 (br m, 5H, H-3′ and 2CH2), 4.11 (q, 1H, H-4′, J=3.6), 4.02 (dd, 1H, H-5′, J=11.2, 4.4), 3.83 (t, 4H, 2CH2, J=4.6), 3.77 (dd, 1H, H-5′, J=11.2, 3.2), 0.95, 0.93, 0.80 (3 s, 27H, tert-Bu), 0.124, 0.12, 0.104, 0.10, −0.05, −0.22 (6 s, 18H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 153.9, 152.2, 150.9, 137.7, 120.5, 88.1, 85.4, 75.4, 72.1, 67.0, 62.6, 45.6, 26.1, 25.8, 25.7, 18.5, 18.1, 17.9, −4.4, −4.7, −5.0, −5.4, −5.41.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:5]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]([Cl:3])=[O:21])[CH2:15][CH2:14]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)C1CCN(C(=O)c2ccccc2)CC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
Thionyl chloride (2.0 ml, 3.3 g, 27 mmol) was added to 1-benzoyl-4-piperidinecarboxylic acid (0.31 g, 1.33 mmol) at 25° C. After stirring for 48 hours, the solution was warmed to 30° C. and concentrated under a stream of nitrogen. The 1-benzoyl-4-piperidinecarbonyl chloride, sufficiently pure for subsequent reactions, was obtained as a colorless oil which crystallized during storage at 0° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]=1.[I-:19].[Na+]>CC(C)=O>[I:19][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]=1
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CI

Procedure:
In analogy to the procedure described in example 20 a], 5-chloromethyl-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole (example 9 a]) was treated with sodium iodide in acetone to obtain 5-iodomethyl-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole as yellow solid which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:24])=[N:17][C:18]([O:22][CH3:23])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])=[CH:4][CH:3]=1>C(O)(=O)C.[Pd]>[F:29][C:26]([F:27])([F:28])[CH:25]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[C:16]([CH3:24])=[N:17][C:18]([O:22][CH3:23])=[N:19][C:20]=4[CH3:21])[C:8]3=[N:9][C:10]=2[CH:2]=[CH:3][CH:4]=1)[OH:30]
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(C)n1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1nc(C)c(N2CCCn3c2nc2cccc(C(O)C(F)(F)F)c23)c(C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a solution of 1-[9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (563 mg, 1.27 mmol) in acetic acid (8.5 mL) was added 10% palladium on carbon (50% wet, 56.3 mg), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 2 days. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a solid, which was recrystallized from methanol to give the title compound as colorless crystals (362 mg, 0.889 mmol, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].O.[Sn](Cl)Cl.[OH-].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(/C=C/c2cccc([N+](=O)[O-])c2)n1
Agent: Cl[Sn]Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1csc(/C=C/c2cccc(N)c2)n1
Yield: 81.3 %

Procedure:
A solution of 1.5 g of (E)-2-[2-(3-nitrophenyl)ethenyl]-4-thiazolecarboxylic acid ethyl ester, 3.87 g of tin(II) chloride monohydrate and 100 ml of ethanol was heated to reflux for 16 hr. The reaction mixture was then poured onto ice-water, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was washed with water, saturated brine and dried (MgSO4). Evaporation of the solvent in vacuo yielded 1.1 g of (E)-2-[2-(3-aminophenyl)ethenyl]-4-thiazolecarboxylic acid ethyl ester; m.p. 112°-113° C. from ethanol.
Reaction SMILES: [C:1]([CH:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:5]([NH:7][CH:8]([C:10]1[C:11](=[O:24])[NH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[N:14][N:15]=1)[CH3:9])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:15]2[C:10]([C:11](=[O:24])[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:3])[CH3:2]
Reactant: CCCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCC(C(C)=O)c1nc(C)c2c(=O)[nH]c(Cc3ccc(C)cc3)nn12

Procedure:
Analogously to Example 1, 910 mg (2.20 mmol) of 2-acetyl-N-{1-[3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}octanamide (Example 25A) and 1.65 g (10.7 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetylheptyl)-5-methyl-2-(4-methylbenzyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [F:1][C:2]([CH3:32])([CH3:31])[CH:3]=[CH:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9][CH2:8]1)=[O:6].[H][H]>CO.[Pd]>[F:1][C:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:11][CH2:12]1)=[O:6]
Reactant: Cc1ccc2c(N3CCN(C(=O)C=CC(C)(C)F)CC3)nc(-c3ccccc3O)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(N3CCN(C(=O)CCC(C)(C)F)CC3)nc(-c3ccccc3O)nc2c1

Procedure:
To 4-fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one (228 mg) in 1.5 mL of methanol was added Pd/C (34 mg, 10% weight Pd on carbon), and the reaction mixture was hydrogenated with a hydrogen balloon for 1 h. The resulting mixture was filtered through Celite, and the solvent was removed to give 4-fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one. LC/MS: m/z 437.4 (M+H)+ at 2.86 min (10%/99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>CCCCCCC.CCOC(C)=O>[C:20]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)#[C:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C#CCCCCCC
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C#N)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC#Cc1ccc(C#N)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-cyano-phenyl ester and 1-octyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (100 mg, 95%); 1H NMR δ (CDCl3): 7.56 (d, J=8.61 Hz, 2H), 7.46 (d, J=8.62 Hz, 2H), 2.43 (t, J=7.44 Hz, 2H), 1.6 (p, J=7.37 Hz, 2H), 1.5-1.4 (m, 2H), 1.38-1.26 (m, 4H), 0.92 (t, J=7.36 Hz, 3H); LCMS m/z: 211.
Reaction SMILES: Cl.[C@@H:2]12[N:9]([CH2:10][C@@H:11]([C:13]3[C:14]([CH3:23])=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[O:17][CH2:16]4)[OH:12])[C@@H:6](CC1)[CH2:5][NH:4][CH2:3]2.[CH3:24][C:25]1[N:30]=[C:29]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)[CH:28]=[CH:27][C:26]=1[CH:36]1[CH2:38][O:37]1>>[OH:12][C@H:11]([C:13]1[CH:21]=[CH:20][C:19]2[C:18](=[O:22])[O:17][CH2:16][C:15]=2[C:14]=1[CH3:23])[CH2:10][N:9]1[CH2:2][CH2:3][N:4]([CH2:38][CH:36]([OH:37])[C:26]2[C:25]([CH3:24])=[N:30][C:29]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:28][CH:27]=2)[CH2:5][CH2:6]1
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Reactant: Cc1nc(-n2cnnn2)ccc1C1CO1
Agent: Cl
Product: Cc1nc(-n2cnnn2)ccc1C(O)CN1CCN(C[C@H](O)c2ccc3c(c2C)COC3=O)CC1

Procedure:
5-[(1R)-1-Hydroxy-2-(4-{2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 34 starting from (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1(3H)-one (INTERMEDIATE 12) and 6-methyl-5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl) pyridine (INTERMEDIATE 34).
Reaction SMILES: C(=O)([O-])[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][C:14](=[O:23])[C@@H:13]2[CH2:24][CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>>[CH2:28]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[C@@H:13]([CH2:24][CH3:25])[C:14]1=[O:23])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CC[C@H]1C(=O)Nc2ccc(F)cc2N1S(=O)(=O)c1ccc(OC(=O)[O-])cc1
Agent: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Product: CC[C@H]1C(=O)N(Cc2ccccc2)c2ccc(F)cc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]sulfonyl}phenyl carbonate (see Example 20) was treated with benzyl bromide according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-1-benzyl-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−30° (c=0.0058 G/ML, DMSO); MS (ESI) m/z 441 ([M+H]+); MS (ESI) m/z 439 ([M−H]−); Anal. Calcd for C23H21FN2O4S: C, 62.71; H, 4.81; N, 6.36. Found: C, 62.23; H, 4.49; N, 6.23.
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([Br:31])=[CH:26][N:25]=2)=[N:8][CH:9]=[C:10]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1.[OH-].[NH4+:33]>O.S(=O)(=O)(O)O>[Br:31][C:27]1[CH:28]=[C:29]([CH3:30])[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[C:7]3=[N:8][CH:9]=[C:10]([CH2:12][C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)[CH:11]=[C:6]3[N:5]=[N:33]2)=[N:25][CH:26]=1
Reactant: [NH4+]
Reactant: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2cccnc2)cc1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cnc1CCCCn1nnc2cc(Cc3cccnc3)cnc21
Temperature: 4 °C

Procedure:
Sodium nitrite (0.33 g) in water (20 ml) was added over 15 minutes to a solution of 3-amino-2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(pyrid-3-ylmethyl)pyridine (2.0 g) in molar sulphuric acid (100 ml) stirred at 4° C. The solution was then allowed to warm to room temperature, basified with concentrated ammonium hydroxide solution and extracted with chloroform (3 x 100 ml). The chloroform extracts were combined, dried over magnesium sulphate, and the solvent removed to give a product which was recrystallised from acetonitrile to give the title compound (1.49 g) as prims, m.p. 114°-115° C.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: FC(F)(F)C(F)(F)CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 21.1 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.4 g of 1-iodo-3,3,4,4,4-pentafluorobutane were dissolved in 5 ml of dimethyl sulfoxide, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 7 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.45 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,4,4,4-pentafluorobutyl)malononitrile (hereinafter, referred to as the present compound (68)).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH:10]=[C:9]2[C:20](=[O:23])[CH2:21][CH3:22].[N:29]([Si](C)(C)C)=[N+:30]=[N-:31].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]1[NH:31][N:30]=[N:29][N:19]=1)[CH:10]=[C:9]2[C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)c1cn(CCCC#N)c2ccc(OCc3c(Cl)cccc3Cl)cc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCC(=O)c1cn(CCCc2nnn[nH]2)c2ccc(OCc3c(Cl)cccc3Cl)cc12
Yield: 46.4 %

Procedure:
To a solution of 4-[5-(2,6-dichlorobenzyloxy)-3-propionyl-indol-1-yl]butyronitrile (0.034 g, 0.08 mmol) in toluene (3 mL) was added azidotrimethylsilane (0.033 mL, 0.25 mmol) and dibutyltin oxide (0.006 g, 0.02 mmol). The reaction was refluxed for 16 h. The solvent was removed under reduced pressure and the crude product was purified by HPLC to yield a white solid (0.017 g, 46%). MS(ES) m/e 458.0 [M+H]+.