Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[C:10]([C:14]1[CH:15]=[C:16]([CH:44]=[C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:46]=1[OH:47])[CH2:17][C:18]1[C:19]([CH3:43])=[C:20]([OH:42])[C:21]([CH3:41])=[C:22]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:29]([OH:36])=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:27]=2)[C:23]=1[CH3:24])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:32]([C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:29]=1[OH:36])[CH2:25][C:22]1[C:21]([CH3:41])=[C:20]([C:19]([CH3:43])=[C:18]([CH2:17][C:16]2[CH:15]=[C:14]([C:10]([CH3:11])([CH3:12])[CH3:13])[C:46]([OH:47])=[C:45]([C:48]([CH3:50])([CH3:49])[CH3:51])[CH:44]=2)[C:23]=1[CH3:24])[O:42][P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1)([CH3:33])([CH3:34])[CH3:35]
Reactant: Cc1c(O)c(C)c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c1Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)COP(Cl)OC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c(OP2OCC(C)(C)CO2)c(C)c1Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 8.45 g of 2-chloro-5,5-dimethyl[1,3,2]dioxaphosphinane in 50 ml of toluene is added dropwise, in the course of 15 minutes and at a temperature between 20° and 30° C., to a solution of 28.65 g of 3,5-bis-[3',5'-ditert.-butyl-4'-hydroxybenzyl]-2,4,6-trimethylphenol and 25.3 g of triethylamine in 150 ml of toluene. The reaction mixture is heated under reflux for 24 hours. After cooling to room temperature, the residue is filtered off and the filtrate is evaporated to dryness. This gives 35 g of a colourless product having a melting point of 190° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][C:22]=4[C:29]([F:32])([F:31])[F:30])[N:17]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1>C(Cl)Cl>[O:41]1[CH2:28][CH:27]1[C:24]1[CH:25]=[CH:26][C:21]([C:18]2[N:17]=[C:16]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]=3[C:12]([F:13])([F:14])[F:15])[O:20][N:19]=2)=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:23]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)c(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)c1cc(C2CO2)ccc1-c1noc(-c2onc(-c3ccccc3)c2C(F)(F)F)n1
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a mixture of 5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-3-(2-(trifluoromethyl)-4-vinylphenyl)-1,2,4-oxadiazole (56 mg, 0.124 mmol) in DCM (5 mL) was added mCPBA (64.2 mg, 0.372 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane and washed with 1N NaOH. The organic layer was dried with MgSO4, filtered, and concentrated to yield 50 mg of 3-(4-(oxiran-2-yl)-2-(trifluoromethyl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole. MS (m+1)=468. HPLC Peak RT=2.12 minutes (Analytical Method B).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[CH3:26][C:27]1[C:31]([C:32](Cl)=[O:33])=[C:30]([CH3:35])[O:29][N:28]=1.C(O)C(N)(CO)CO>ClCCCl>[CH3:1][C:2]1[C:7]([NH:8][C:32]([C:31]2[C:27]([CH3:26])=[N:28][O:29][C:30]=2[CH3:35])=[O:33])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: Cc1noc(C)c1C(=O)Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1c(C)noc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.9 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of 3,5-dimethyl-isoxazole-4-carbonyl chloride (43 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 12.4 mg of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH2:17]=O>C(O)C>[N:11]1([CH2:2][C:1]([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)([CH3:17])[CH3:3])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=O
Reactant: CC(C)c1ccncc1
Reactant: C1CCNCC1
Agent: Cl
Solvent: CCO
Product: CC(C)(CN1CCCCC1)c1ccncc1
Yield: 17 %

Procedure:
A suspension of 70 g (0.58 M) of 4-isopropylpyridine, 250 g (2 M) of piperidine hydrochloride and 85 g of paraformaldehyde in 600 ml of 95% ethanol is held under reflux for 48 hours. The reaction mixture is then concentrated under reduced pressure and the residue is taken up with 650 ml of 3N sodium hydroxide and extracted with thrice 250 ml of ethyl acetate. The combined organic phases are washed with a solution of sodium chloride, dried and concentrated under reduced pressure. The crude product is distilled under a vacuum of 1 mm Hg and the fraction collected between 80 and 125° C. is purified by silica gel chromatography in eluting with the aid of a toluene/isopropanol mixture (9/1; v/v). 21.4 g of the compound sought after are thus obtained as a clear yellow oil (yield=17%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH3:23][C:24]([O:27][C:28]([N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:31]1[NH:32][C:33]([C:37](O)=[O:38])=[C:34]([Cl:36])[N:35]=1)=[O:29])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:46][C:43]([O:42][C:40]([N:30]([C:31]1[NH:32][C:33]([C:37]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]3[CH:18]=[C:17]([CH:19]4[CH2:20][CH2:21]4)[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=3)[C:4]=2[F:22])=[O:38])=[C:34]([Cl:36])[N:35]=1)[C:28]([O:27][C:24]([CH3:23])([CH3:25])[CH3:26])=[O:29])=[O:41])([CH3:44])[CH3:45]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C2CC2)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)c(C(=O)O)[nH]1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C4CC4)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.6 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-cyclopropylbenzonitrile (95 mg, 0.299 mmol), 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-chloro-1H-imidazole-5-carboxylic acid (120 mg, 0.299 mmol) and HOBT (45.7 mg, 0.299 mmol) in DMF (3 ml) was added EDC (57.2 mg, 0.299 mmol) and the reaction mixture was stirred at RT for 45 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material bis(1,1-dimethylethyl)(4-chloro-5-{[({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (165 mg, 0.250 mmol, 84% yield) was used directly in the next step. LC-MS (ES+) m/z 660 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:42])[CH2:38][C:39](O)=[O:40])=[CH:32][CH:31]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:39](=[O:40])[CH2:38][C:37]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([S:29][CH3:28])=[CH:31][CH:32]=1)=[O:42]
Reactant: CSc1ccc(NC(=O)CC(=O)O)cc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(NC(=O)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (30 mg, 0.071 mmol), 3-(4-(methylthio)-phenylamino)-3-oxopropanoic acid (32.2 mg, 0.143 mmol), DMAP (13.08 mg, 0.107 mmol), and EDC (41.1 mg, 0.214 mmol) were dissolved in DMF (1.5 ml). The reaction was stirred at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with HCl 1N, Na2CO3 sat. sol. and brine, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative reverse-phase HPLC to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(4-(methylthio)-phenylamino)-3-oxopropanoyloxy)ethyl)pyridine 1-oxide (20 mg, 44.6% yield).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]([CH3:17])[C:15]#N)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-:23].[K+].[OH2:25]>>[O:1]([CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]([CH3:17])[C:15]([OH:25])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: CC(C#N)Oc1ccc(COc2ccccc2)cc1
Agent: [K+]
Solvent: CCO
Product: CC(Oc1ccc(COc2ccccc2)cc1)C(=O)O

Procedure:
One gram of 2-(4-phenoxymethylphenoxy)-propionitrile (obtainable from 4-phenoxymethylphenol and 2-bromopropionitrile) is refluxed in 15 ml. of ethanol and 2 ml. of water with 2 g. of KOH for 40 hours. The mixture is then evaporated and worked up as usual, yielding 2-(4-phenoxymethylphenoxy)-propionic acid.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C>O.CS(C)=O>[F:15][C:12]([F:13])([F:14])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[NH:5][CH2:2][C:3]#[N:4]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCNc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
Chloroacetonitrile (16 g), m-aminobenzotrifluoride (32.2 g), K2CO3 (39.2 g) and DMSO (40 ml) were heated with stirring in a round-bottomed three-necked flask at 70°-80° C. for 4.0 hours. Pouring the reaction mixture into approximately 1 liter of ice and water resulted in the formation of an oil. The mixture was extracted with CH2Cl2 and the extracts obtained treated with diatomaceous earth and activated charcoal, and then filtered. The filtrate was taken to dryness, which gave 29.5 g of m-trifluoromethylanilinoacetonitrile as a dark oil.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH3:14])[C:7]=1[NH:15][C:16]([C:18]1[S:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1)=[O:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO.O>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:27])=[O:4])=[C:7]([NH:15][C:16]([C:18]2[S:19][CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[N:22]=2)=[O:17])[C:8]=1[CH3:14]
Reactant: COC(=O)c1ccc(OC)c(C)c1NC(=O)c1nc(C(F)(F)F)cs1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)O)c(NC(=O)c2nc(C(F)(F)F)cs2)c1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
LiOH (240 mg, 1.2 eq.) was added to a mixture of compound 204 (3 g, 1 eq.) in EtOH/H2O (20 mL/20 mL) at room temperature. The reaction mixture was stirred at 60° C. for 3 hrs and was allowed to cooled down to room temperature. A 5% aqueous solution of citric acid was added and the mixture was extracted with EtOAc. Organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to yield compound 205 as a white solid in 88% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.51 (s, 3H), 3.85 (s, 3H), 6.75 (d, J=8.75 Hz, 1H), 7.87 (d, J=8.75 Hz, 1H), 7.95 (s, 1H), 10.48 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2]C(C)=O.[OH-].[Ca+2].[OH-].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].N>C(Cl)Cl.C(C(C)=O)C>[C:12]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)CC(C)=O
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: COC(=O)CC(=O)C(C)C
Yield: 94.3 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 122.6 g (1.15 mol) of isobutyryl chloride. The pH in the subsequent reaction with ammonia was adjusted to 9.2. This gave 136 g (GC purity 79.8%) of methyl isobutyrylacetate (yield 75.4%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.[O:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C.O1CCCC1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:42][CH:39]2[CH2:40][CH2:41][O:36][CH2:37][CH2:38]2)[CH2:31][CH2:30]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: NC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](NC3CCOCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4′-{[5-Oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.0 g) and tetrahydro-2H-pyran-4-amine (0.43 g) were dissolved in acetic acid (20 mL) and tetrahydrofuran (8 mL), sodium triacetoxyborohydride (1.3 g) was gradually added at room temperature, and the mixture was stirred at room temperature for 24 hr. Water was added, and the solvent was evaporated under reduced pressure. The residue was gradually added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.77 g, 32%).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([NH:37][CH2:38][C:39](O)=[O:40])(OC(C)(C)C)=[O:31].CCN(CC)CC.CCN=C=NCCCN(C)C.Cl.CN([CH:64]=[O:65])C>O>[F:2][C:3]([F:29])([F:28])[C:64]([OH:65])=[O:31].[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:39](=[O:40])[CH2:38][NH2:37])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: NCC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (35 mg) obtained in Example 1, Boc-glycine (15 mg) and Et3N (22 μl) in DMF (2.0 ml), WSC.HCl (17 mg) and HoBt.H2O (13 mg) were added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC. To the obtained product, trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred for 1 hour, and then the solvent was evaporated to obtain the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][C:18]#[C:19][CH2:20]Br.O>C(O)C>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][C:18]#[C:19][CH2:20][O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: BrCC#CCOC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C(#CCOC1CCCCO1)COc1ccccc1

Procedure:
1.10 g of sodium hydroxide was added to a solution of 2.35 g of phenol in 20 ml of absolute ethanol. The mixture was refluxed until complete dissolution, then 2.92 g of 1-bromobut-2-yn-4-ol tetrahydropyranyl ether was added. The reflux was resumed for 2 additional hours. It was then cooled, poured into water and extracted with ether (3×50 ml). The organic extracts were washed with 20% aqueous sodium hydroxide solution and water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on 50 g of silica gel, using hexane:ethyl acetate (98:2) as eluant, to yield 4-phenoxy-but-2-yn-1-ol tetrahydropyranyl ether, as an oil.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[C:28]([F:42])[CH:27]=3)=[O:25])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]1[CH3:43])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:51][C:52]([CH3:57])([CH3:56])[CH2:53][CH:54]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:3]([N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][N:39]([CH2:54][CH2:53][C:52]([CH3:57])([CH3:56])[CH3:51])[CH2:38][CH2:37]4)=[C:28]([F:42])[CH:27]=3)=[O:25])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]1[CH3:43])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)CC=O
Reactant: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCNCC3)c(F)c1)CC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCN(CCC(C)(C)C)CC3)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-[3-fluoro-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride from Example E69.2 (105 mg, 0.17 mmol) was dissolved in methanol (2.45 ml) and triethylamine (0.07 ml, 0.50 mmol). Acetic acid (0.05 ml) then 3,3-dimethylbutyraldehyde (0.032 ml, 0.25 mmol) were added and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (16 mg, 0.25 mmol) was added and the mixture was stirred for 3 h at room temperature then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (102 mg, 95%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:23](=[O:24])[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5]1.[H-].[Na+].Cl[C:28]1C=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1.C[N:39](C=O)C>>[F:21][C:19]([F:20])([F:22])[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:23](=[O:24])[N:4]([CH2:3][CH2:2][O:1][C:28]4[N:39]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=4)[N:5]=3)[CH:8]=2)=[CH:13][CH:14]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CN(C)C=O
Reactant: O=c1n(CCO)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Agent: [H-]
Agent: [Na+]
Product: O=c1n(CCOc2ncc(C(F)(F)F)cn2)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12

Procedure:
6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (825 mg) from Example 1 above was dissolved in DMA (10 mL), 2-bromoethanol (1.0 g) and potassium carbonate (235 mg) were added. Heated overnight at 110° C. Filtered, concentrated, and purified by chromatography (ethyl acetate/hexanes). 2-(2-hydroxyethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was obtained as white solid (830 mg). m/z (ESI)=340.0 (base peak, M+H+); 701.1 (2M+Na+). 2-(2-hydroxyethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg) was dissolved in dry DMF and the NaH suspension (12 mg, 60% in oil) was added, followed shortly by 2-chloro-5-trifluoromethylpyridine (54 mg). Concentrated and purified on silica using ethyl acetate/hexanes gradient to obtain compound 180 as a white solid (71 mg). m/z (ESI)=486.1 (base peak, M+H+); 508.1 (M+Na+); 993.2 (2M+Na+). 1H NMR (δ, CDCl3, 400 MHz) 8.75 (s, 2H); 7.98 (d, 1H); 7.53 (d, 2H); 7.40-7.30 (m, 3H); 7.18 (d, 1H); 4.90 (t, 2H); 4.49 (t, 2H). 19F NMR (δ, CDCl3, 376 MHz) −58.36 (s, 1F); −61.99 (s, 1F).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CNc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1ccc(C#N)cc1
Reaction time: 6 h
Yield: 96.5 %

Procedure:
The above general procedure was followed using 4-bromobenzonitrile (187 mg, 1.00 mmol) and N-methylaniline (107 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.0 mL of toluene. After 6 hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 10% ethyl acetate/hexanes to give 201 mg (97%) of N-(4-cyanophenyl)-N-methylaniline. 1H NMR (500 MHz, CDCl3) δ 7.45-7.42 (m, 4H), 7.27 (t, J=7.5 Hz, 1H), 7.21 (d, J=8.3 Hz, 2H), 6.73 (d, J=9.0 Hz, 2H), 3.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 152.0, 146.8, 133.1, 130.1, 126.4, 126.2, 120.2, 114.0, 99.4, 40.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1Br.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: O=C1CCCCC1
Reactant: COc1cc(OC)c(Br)c(OC)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c(C2=CCCCC2)c(OC)c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
2,4,6-Trimethoxybromobenzene (1 eqvt.) was taken in a flame dried 3-necked flask under nitrogen. Dry tetrahydrofuran (THF) (983 ml) was added and the reaction mixture was cooled to -30° C. n-BuLi (1.3 eqvt.) in hexane (commercial) was added dropwise and after the addition the reaction mixture was stirred for 30 min. Thin layer chromatographic examination at this stage indicated completion of metallation reaction. Cyclohexanone (1.1 eqvt.) diluted with equal volume of dry THF was added to the reaction mixture at -30° C. and the reaction mixture was stirred for another one hour at -30° C. and later allowed to come to room temperature. Water (150 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The residue was taken in dichloromethane and stirred for 30 min. with catalytic amount of p-toluenesulphonic acid (9 g). The dichloromethane layer was washed with sodium bicarbonate solution followed by water and dried. The residue was crystallized from Diisopropylether to give the title compound; m.p. 127° C., Yield: 64.7%.