Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([CH3:9])[N:8]=1)[NH2:2].[CH:16](=O)[CH2:17][CH3:18]>Cl.CO>[CH3:9][C:7]1[N:8]=[C:3]([NH:1][N:2]=[CH:16][CH2:17][CH3:18])[N:4]=[N:5][C:6]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCC=O
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Agent: Cl
Solvent: CO
Product: CCC=NNc1nnc(-c2ccccc2)c(C)n1
Reaction time: 0.08 h

Procedure:
C.hydrochloric acid (1 drop) was added to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (4.12 g) and propionaldehyde (4 ml) in methanol (15 ml) at room temperature, and the stirring was continued for 5 minutes. The reaction mixture was evaporated and the resultant residue was triturated with diethyl ether. The precipitates were collected by filtration to give 5-methyl-6-phenyl-3-(2-propylidenehydrazino)-1,2,4-triazine (3.89 g).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:11]([C:21]23[CH2:30][CH:25]4[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]4)[CH2:22]2)[CH2:28]3)=[CH:10][C:9]=1[C:31]#[CH:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:11]([C:21]23[CH2:22][CH:23]4[CH2:29][CH:27]([CH2:26][CH:25]([CH2:24]4)[CH2:30]2)[CH2:28]3)=[CH:10][C:9]=1[C:31]#[C:32][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#Cc1cc(C23CC4CC(CC(C4)C2)C3)c(OCCCCCC)cc1OCCCCCC
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCCCCCOc1cc(OCCCCCC)c(C23CC4CC(CC(C4)C2)C3)cc1C#Cc1ccc(C(=O)OC)cc1

Procedure:
1.8 g (4.1 mmol) of 2,4-dihexyloxy-5-(1-adamantyl)phenylacetylene, 1.2 g (4.5 mmol) of methyl 4-iodobenzoate and 15 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 15 min, 100 mg of copper iodide and 260 mg (0.37 mmol) of bis(triphenylphosphine)-palladium(II) chloride were added and stirring was carried out at room temperature for twelve hours. The reaction mixture was evaporated to dryness, the residue was taken up in water and ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([NH:27][CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][NH:27][C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:34][CH:35]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (88 mg, 0.29 mmol) and (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (86 mg, 0.29 mmol) in DCM (10 mL) and Diisopropylethylamine (0.22 mL, 1.3 mmol) was added HBTU (110 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL), washed with water (6×50 ml). The organic phase was dried and concentrated to give tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (116 mg, 78%). 1H NMR (CDCl3, 400 MHz) δ 8.51 (s, 1H), 7.34-7.20 (m, 4H), 5.15-5.09 (m, 2H), 4.15-4.05 (m, 1H), 3.87-3.85 (m, 2H), 3.78-3.38 (m, 7H), 3.22-3.19 (m, 1H), 2.20-2.10 (m, 2H), 1.48 (s, 9H), 1.41 (s, 9H), 1.14-1.12 (d, J=7.2 Hz, 3H). MS (APCI+) [M+H] +516.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[C:16]([OH:18])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[N:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:1][C:2]1[N:17]=[C:16]([O:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(O)c2c(n1)-c1ccccc1CCCC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCCc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 20B (950 mg, 2.4 mmol) in CH2Cl2 (30 mL) was added para-toluenesulfonyl chloride (1.09 g, 5.7 mmol), 4-dimethylaminopyridine (50 mg, 0.41 mmol) and triethylamine (1.1 mL. 7.9 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2 (100 mL), washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with EtOAc:hexanes (25:75) to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[O:17][CH2:18][CH:19]2[CH2:21][O:20]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][N:2]([CH2:21][CH:19]([OH:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: c1ccc(CCCCCc2ccccc2OCC2CO2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
0.7 ml of 50% by volume aqueous dimethylamine was added to a solution of 0.208 g of 2-[2-(5-phenylpentyl)phenoxymethyl]oxirane [prepared as described in step (a) above] in 9 ml of tetrahydrofuran, and the mixture was stirred at room temperature for one day. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.230 g (yield 96%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].C[Si](Cl)(C)C.CC1(C)[O:21][C:20](=O)[CH2:19][C:18](=[O:23])[O:17]1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:20](=[O:21])[CH2:19][C:18]([OH:23])=[O:17]
Reactant: COc1ccccc1N
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1NC(=O)CC(=O)O
Yield: 30 %

Procedure:
To a solution of 2-methoxybenzeneamine (1.1 g, 8.93 mmol) in DCM (90 mL) was added TMSCl (1.1 mL, 8.93 mmol) at room temperature [Rigo, B.; Fasseur, D.; Cauliez, P. and Couturier, D. Tetrahedron Lett.; 30; 23; 1989; 3073-3076.]. The reaction mixture was stirred for 30 mins before the addition of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.29 g, 8.93 mmol) and then stirring was continued mixture for additional 2 hours. Water (1 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 solution, and extracted with EtOAc. The aqueous phase was collected, acidified with conc. HCl to pH-4, extracted with EtOAc, the extract was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (eluent CHCl3/MeOH/AcOH 9:1:0.1) to afford the compound 27 (0.56 g, 30% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 12.62 (bs, 1H), 9.52 (s, 1H), 8.02 (dd, 1H), 7.03 (m, 2H), 6.88 (m, 1H), 3.82 (s, 3H), 3.46 (s, 2H). MS (m/z): 210.1 (M+H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1Br.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)#[CH:33]>ClCCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1[C:33]#[C:32][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)n1nc(-c2nc(C#Cc3ccccc3)c(N)nc2-c2ccccc2)ccc1=O

Procedure:
In the presence of copper(I) iodide (5 mg) and dichlorobis(triphenylphosphine)palladium(II) (18 mg), triethylamine (0.0794 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (200 mg) and ethynylbenzene (0.0626 ml) in 1,2-dichloroethane (2 ml) at 60° C. The mixture was refluxed for 2 hours. The mixture was cooled to give a precipitate. The precipitate was collected by filtration and suspended in MeOH to give 6-[5-amino-3-phenyl-6-(phenylethynyl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (104 mg).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[C:21]([NH:27][CH3:28])[N:20]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[O-:36][C:37]#[N:38].[K+]>CO>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:37]([NH2:38])=[O:36])[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[N:20][C:21]([NH:27][CH3:28])=[N:22][C:23]=1[Cl:26]
Reactant: N#C[O-]
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](NC(N)=O)CC3)CC2)n1

Procedure:
0.6 g (1.3 mmol) trans-(4-{4-[2-(4-amino-cyclohexyl)-ethyl]-piperazin-1-yl}-5,6-dichloro-pyrimidin-2-yl)-methyl-amine trihydrochlorid was suspended in methanol. Triethylamine (0.36 ml, 2.6 mmol) was added followed by the addition potassium cyanate (0.26 g, 3.12 mmol). The mixture was refluxed for 10 hours. The solvent was removed in vacuo. The residue was triturated with water, and the precipitate was filtered to give the title compound (0.42 g 75%) MS (EI): 431.2 (MH+). 1H NMR (300 MHz, DMSO-d6 (TMS)+1 drop of cc. DCl, (ppm)): 0.91-1.12 m (2H); 1.15-1.36 m (3H); 1.56-1.92 m (6H); 2.76 s (3H); 3.00-3.21 m (4H); 3.30-3.61 m (5H); 4.15-4.31 m (2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2>CCOC(C)=O.O=[Mn]=O>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([CH:2]=[O:1])=[CH:11]2
Reactant: COc1ccc2[nH]c(CO)cc2c1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(C=O)cc2c1
Yield: 76.5 %

Procedure:
Compound 425 (100 mg, 0.56 mmol) and MnO2 (490 mg, 5.6 mmol) in EtOAc (5 mL) were heated to reflux for 24 h. The mixture was filtered over Celite, and the filtrate was concentrated in vacuo and purified by chromatography (0% to 10% EtOAc/hexanes) to yield a pale-yellow powder (75 mg, 76%): mp 143-144° C. (lit.58 140-141° C.). TLC Rf 0.28 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 9.81 (s, 1H), 9.05 (s, 1H), 7.36-7.34 (d, 1H, J=12 Hz), 7.20-7.19 (m, 1H), 7.12-7.11 (d, 1H, J=6 Hz), 7.09-7.07 (dd, 1H, J1=9 Hz, J2=2.5 Hz), 3.86 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 181.8, 155.0, 136.3, 133.4, 127.7, 119.4, 114.15, 113.36, 102.8, 55.7. Elemental analysis calculated for C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.42; H, 5.34; N, 7.85.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4](=[O:11])[C:5]2[N:10]=[N:9][NH:8][C:6]=2[N:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=O.C(OC(=O)C)(=O)C>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4](=[O:11])[C:5]2[N:10]=[N:9][NH:8][C:6]=2[N:7]=1
Reactant: Cc1ccccc1-n1c(C)nc2[nH]nnc2c1=O
Reactant: O=Cc1ccccn1
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1-n1c(C=Cc2ccccn2)nc2[nH]nnc2c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 3.4 %

Procedure:
To a mixture of fused zinc chloride (0.551 g, 4.04 mmol) and dioxane (20 mL) was added 5-methyl-6-o-tolyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (0.488 g, 2.02 mmol), 2-pyridinecarboxaldehyde (0.58 mL, 6.06 mmol), and acetic anhydride (0.57 mL, 6.06 mmol). The mixture was heated to 70° C. for 6 hours, cooled, and quenched with saturated sodium bicarbonate. This mixture was stirred overnight at ambient temperature. The dioxane was removed at reduced pressure and the resulting black liquid was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, treated with activated carbon, filtered, and concentrated. The residue (1.5 g) was flash chromatographed on silica gel (50 g). Elution with 50% and 60% ethyl acetate/hexane gave 5-(2-pyridin-2-yl-vinyl)-6-o-tolyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (0.023 g, 3.5%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].Cl[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].C(N(C(C)C)CC)(C)C.O>C1COCC1>[CH2:13]([O:12][C:10]([NH:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)C[C@H](C)N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N[C@@H](C)CC(=O)OC
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of methyl (3S)-3-aminobutanoate (1.47 g, 12.5 mmol) in THF (30 ml) were added at 0° C. allyl chloroformate (1.60 ml, 15.1 mmol) and diisopropylethylamine (2.62 ml, 15.0 mmol), and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and extracted twice with ethylacetate. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel (25 g) chromatography to give methyl (3S)-3-{[(allyloxy)carbonyl]amino}butanoate (2.06 g, 81%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:46])[C:6]1[CH:11]=[C:10]([O: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][CH2:25][CH3:26])[CH:9]=[C:8]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:34][CH:33]=2)[CH:7]=1>>[C:40]1([CH2:39][O:38][C:35]2[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][CH2:28][O:27][C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([O: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][CH2:25][CH3:26])[CH:9]=3)[C:5]([OH:46])=[O:4])=[CH:37][CH:36]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)O)c1
Yield: 96 %

Procedure:
Sodium hydroxide hydrolysis of 3-[3-[4-(phenylmethoxy) phenoxy]propoxy]-5-(tetradecyloxy)benzoic acid methyl ester gave 3-[3-[4-(phenylmethoxy)phenoxy]propoxy]-5-(tetradecyloxy)benzoic acid (96% yield, mp 77°-79°).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:35]=2N=N1.CN1CCOCC1.[OH-].[Na+]>C(#N)C.CO>[CH3:35][O:14][C:13](=[O:15])[C@@H:12]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester (300 mg, 0.89 mmol) and methanol (4 mL) were added benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (390 mg, 0.89 mmol), N-methylmorpholine (98 μL, 0.89 mmol), and acetonitrile (1 mL) at 0° C., which was stirred overnight at room temperature. A 1N sodium hydroxide aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed first with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, so as to obtain the titled compound (380 mg, purity of 66%) in a crude form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(O)(c2ccc(F)cc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(4-fluoro-phenyl)-4-hydroxy-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: O[C:2]1([C:7]2[CH:8]=[C:9]([CH:32]=[CH:33][CH:34]=2)[O:10][C:11]2[C:16]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:6][CH:5]=[CH:4][CH2:3]1.OC(C1C=C(C=CC=1)OC1C(NC(NC2C=CC(OC(F)(F)F)=CC=2)=O)=CC=CN=1)(CC=C)CC=C>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.ClCCl>[CH:2]1([C:7]2[CH:8]=[C:9]([CH:32]=[CH:33][CH:34]=2)[O:10][C:11]2[C:16]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cccnc1Oc1cccc(C2(O)CC=CC2)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: C=CCC(O)(CC=C)c1cccc(Oc2ncccc2NC(=O)Nc2ccc(OC(F)(F)F)cc2)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cccnc1Oc1cccc(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-(2-(3-(1-hydroxycyclopent-3-enyl)phenoxy)pyridin-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea: A mixture of Example 640 (125 mg, 0.25 mmol) and Grubb's second generation catalyst (0.6 mg) in dichloromethane (70 mL) was stirred at rt for 16 h. An additional 1.0 mg of Grubb's second generation catalyst was added and the mixture was stirred at rt for an additional 17 h. Evaporation under reduced pressure afforded a residue which was filtered and purified using reverse-phase preparative HPLC. (M+H)+=472.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](Cl)=[O:4].[CH2:9]([NH:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28](=[O:35])[NH:27][C:26]3[CH:36]=[CH:37][CH:38]=[N:39][C:25]2=3)=[O:23])[CH2:17][CH2:16]1)[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3]([N:11]([CH2:9][CH3:10])[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28](=[O:35])[NH:27][C:26]3[CH:36]=[CH:37][CH:38]=[N:39][C:25]2=3)=[O:23])[CH2:17][CH2:16]1)=[O:4]
Reactant: CCNCCCC1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Reactant: CCC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CCCC1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1)C(=O)C(C)(C)CC
Temperature: 50 °C

Procedure:
1.48 g (0.01 mol) of 2,2-dimethylbutyric acid chloride dissolved in 20 ml of tetrahydrofuran are added dropwise, with stirring, at ambient temperature, to a solution of 4.2 g (0.01 mol) of 5,11-dihydro-11-[[4-[3-(ethylamino)propyl]-1-piperidinyl]acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one and 2 ml of triethylamine in 150 ml of tetrahydrofuran. In order to complete the reaction the solution is stirred for a further hour at 50° C. After cooling, the precipitated triethylamine hydrochloride is filtered off and the filtrate is evaporated to dryness using a rotary evaporator in a water jet vacuum. In order to purify it the residue is dissolved in ethyl acetate. The ethyl acetate solution is extracted twice with 10% hydrochloric acid, the organic phase is separated off and the aqueous phase is made alkaline by the addition of concentrated ammonia. Then the aqueous phase is extracted twice with ethyl acetate. The organic phase is dried over sodium sulphate and evaporated to dryness in vacuo. The residue obtained is crystallised by digesting it in ethyl acetate. Colourless crystals are obtained of m.p. 136°-138° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17]CCO)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C(CN)[OH:22]>>[Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][OH:22])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCNC1CCCN(c2cccc(Br)n2)CC1
Reactant: NCCO
Product: OCCNC1CCCN(c2cccc(Br)n2)CC1

Procedure:
The preparation is carried out analogously to 4-[1-(6-bromopyridin-2-yl)azepan-4-ylamino]butan-1-ol starting from 99 μl (1.65 mmol) of ethanolamine 85 mg, colourless oil, Rt.=1.55 min (method B), LCMS: 315 (M+H).
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][O:25][CH3:26]>>[I:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:23][CH2:24][O:25][CH3:26])[C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: COc1ccc(I)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)ccc(OC)c21

Procedure:
The title compound is prepared starting from 4-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1H-benzoimidazole and (2-bromoethyl)-methyl ether using the same reaction conditions as described in Example 1. The title compound is obtained as a colorless oil.