Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([C:30](=O)[CH2:31][CH2:32][CH3:33])[C:25](OCC)=[O:26])=[CH:19][CH:18]=1)#[N:10].[Cl-].[NH4+]>CO.C(OCC)(=O)C>[CH3:3][C:2]1[NH:4][C:25](=[O:26])[C:24]([CH2:23][C:20]2[CH:21]=[CH:22][C:17]([C:12]3[C:11]([C:9]#[N:10])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:18][CH:19]=2)=[C:30]([CH2:31][CH2:32][CH3:33])[N:5]=1
Reactant: CC(=N)N
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
To a suspension of acetamidine hydrochloride (70 g) in methanol (500 ml) was added sodium methoxide (28% in methanol, 214 g) dropwise, followed by addition of a solution of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (129 g) in methanol (500 ml) at room temperature. After being stirred at room temperature for 15 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was collected and washed with diisopropyl ether to give the title compound as a white solid (104 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[F:7][C:8]([F:12])([F:11])[CH2:9]I.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:8]([F:12])([F:11])[F:7])[CH:6]=1
Reactant: FC(F)(F)CI
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-1-H-pyrazole (9.4 mmol, 1.38 g), 1,1,1-trifluoro-2-iodo-ethane (28.2 mmol, 2.75 mL), and cesium carbonate (14.1 mmol, 4.58 g) were combined in DMF (10 mL) and stirred at room temperature for overnight. The resulting mixture was subjected to standard aqueous workup to afford the title compound which was used crude in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[C:25]([F:27])([F:26])[F:28])[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccc(C(F)(F)F)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](Cc3ccc(C(F)(F)F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
(2S,4R)-Methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (589 mg, 1.46 mmol) (from example 140, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 10 mL, 57.10 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (329 mg, 65%). 1H NMR (600 MHz, cd3od) δ 1.66 (q, 1H), 1.81 (dq, 1H), 2.17-2.25 (m, 2H), 3.00-3.15 (m, 4H), 3.47-3.52 (m, 1H), 3.56-3.62 (m, 1H), 5.76 (s, 1H), 7.28 (dd, 2H), 7.67 (t, 1H). HRMS Calculated for [C16H16F4N2O2+H]+: 345.1226. Found: 345.1225
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[C:10]([CH2:11][N:12]2[CH:16]=[C:15]([C:17]([NH:19][NH2:20])=[O:18])[CH:14]=[N:13]2)=[C:9]([CH3:21])[O:8][N:7]=1>C(O)(=O)C>[CH3:5][C:6]1[C:10]([CH2:11][N:12]2[CH:16]=[C:15]([C:17]([N:19]=[N+:20]=[N-:1])=[O:18])[CH:14]=[N:13]2)=[C:9]([CH3:21])[O:8][N:7]=1
Reactant: O=N[O-]
Reactant: Cc1noc(C)c1Cn1cc(C(=O)NN)cn1
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1noc(C)c1Cn1cc(C(=O)N=[N+]=[N-])cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
Sodium nitrite (450 mg, 6.5 mmol, in H2O) (10 mL) was added dropwise, over 10 minutes, to a suspension of 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbohydrazide (example 10-1b) (1 g, 4.3 mmol) in 10% aqueous acetic acid (50 mL) and cooled to 0° C. via an ice water bath. The reaction was stirred for an additional 15 minutes then extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were washed with aqueous saturated sodium carbonate (100 mL) followed by H2O (100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The solid product was triturated with ethyl acetate/hexanes (1/9) and dried en vacuo to afford 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbonyl azide (1 g, 93%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ2.20 (s, 3H), 2.44 (s, 3H), 5.07 (s, 2H), 7.81 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:25])([F:24])[C:14]([NH:16][CH:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15]>>[CH2:7]([N:6]1[C:2]([N:20]2[CH2:21][CH2:22][CH2:23][CH:17]([NH:16][C:14](=[O:15])[C:13]([F:24])([F:12])[F:25])[CH2:18][CH2:19]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=[N:5]1)[CH3:8]
Reactant: O=C(NC1CCCNCC1)C(F)(F)F
Reactant: CCn1ncc([N+](=O)[O-])c1Cl
Product: CCn1ncc([N+](=O)[O-])c1N1CCCC(NC(=O)C(F)(F)F)CC1
Yield: 55 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-ethyl-4-nitro-1H-pyrazole and 2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.136 g, 55%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 6.39-6.37 (m, 1H), 4.22-4.19 (m, 1H), 4.12 (q, J=7 Hz, 2H), 3.42-3.35 (m, 1H), 3.27-3.18 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H), 1.47 (t, J=7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[OH:19]O.[OH-].[Na+].Cl>C(O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:12])=[O:19])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (2.7 g, 8.82 mmol), in ethanol (20 mL), was added 20 mL of a 30% commercial solution of hydrogen peroxide and 2.8 mL of 6.0 N aqueous NaOH solution. The reaction mixture was stirred at room temperature. After 3 hours, the reaction mixture was acidified with 6.0 N HCl aqueous solution. Water was added to aid precipitation. The solid was collected by filtration and was washed with small portions of water. The solid was dried under vacuum (2.77 g, 97% yield): ES-MS (m/z) 325 [M+H]+.
Reaction SMILES: Cl[N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:4]=[CH:3]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH2:11]([NH:18][C:6]1[C:5]2[N:4]=[CH:3][NH:2][C:10]=2[CH:9]=[CH:8][N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: Cln1cnc2cnccc21
Solvent: O
Product: c1ccc(CNc2nccc3[nH]cnc23)cc1
Yield: 31.5 %

Procedure:
A mixture of chloro-1H-imidazo(4,5-c)pyridine (2.0 g, 13 mmol), benzylamine (5 ml) and a few drops of water was heated at reflux for 4 days. The reaction mixture was poured onto ice and water and the cold mixture was extracted twice with diethyl ether. The ether was removed in vacuo and the residual oil was triturated twice with hexane. The oil was suspended in water and the aqueous phase was neutralised with glacial acetic acid. The aqueous phase was taken to dryness in vacuo and resuspended in water (15 ml) and applied to a column of Dowex 50 (H+) resin (10 g). The column was washed with water until the ultra violet absorbance of the eluant was zero. The column packing was removed from the column and heated with several portions of concentrated ammonium hydroxide solution (400 ml). The basic solution was filtered in vacuo, cooled and neutralized with glacial acetic acid. The yellow solid was collected and dried in vacuo at 40° C. to give 4-benzylamino-1H-imidazo(4,5-c)pyridine 0.94 g, m.p. 60°-64° C., 31.5%.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:50])([CH3:49])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][C:30]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:38][CH:37]=2)([OH:35])[C:31]([F:34])([F:33])[F:32])[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>CO>[CH3:2][C:3]([CH3:50])([CH3:49])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][C:30]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:38][CH:37]=2)([OH:35])[C:31]([F:34])([F:33])[F:32])[NH:8][CH:9]=1
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)(F)F)n1
Agent: Cl
Solvent: CO
Product: CC(C)(C)Cc1c[nH]c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (108 mL, 433 mmol) was added to an ambient temperature solution of 3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1,1-trifluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]propan-2-ol (5.75 g, 8.7 mmol) in methanol (30 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was partitioned between diethyl ether and 1N hydrochloric acid. The aqueous phase was washed with diethyl ether, basified with 2.5 N aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound. LCMS: 422 (M+H). High pressure liquid chromatography (Chiralcel AD-H column) eluting with 15% isopropanol/heptane afforded the two individual enantiomers (E1 and E2). 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 7.87 (d, J=7.3 Hz, 2H), 7.67-7.65 (m, 3H), 7.48-7.45 (m, 2H), 6.56 (s, 1H), 3.46 (dd, J=15.1, 51.1), 2.33 (s, 2H), 0.80 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]([NH:23][C:24](=[N:27][CH3:28])SC)#[N:22].O>CN(C)C=O>[C:21]([N:23]=[C:24]([N:27]([CH3:28])[C:24]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1)=[N:23][C:21]#[N:22])[NH:27][CH3:28])#[N:22]
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Reactant: CN=C(NC#N)SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=NC#N)N(C)C(=NC#N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Temperature: 100 °C
Reaction time: 12 h
Yield: 14.9 %

Procedure:
To a suspension of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)-thiazole (308 mg) and potassium carbonate (207 mg) in N,N-dimethylformamide (5 ml) was added N-cyano-N′,S-dimethylisothiourea (194 mg), and the mixture was stirred at 100° C. for 12 hours. The mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (2:1, 150 ml×2). The organic layer was washed with brine and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 10 g, 0 to 2% methanol in dichloromethane) to give 2,4-dicyano-1,3-dimethyl-5-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)biguanide (41 mg) as a mixture of regioisomers.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)[CH2:2][CH2:3][CH3:4].[CH:28]1(O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:68]>C1COCC1.C(Cl)Cl.CCOCC>[ClH:68].[ClH:68].[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:20][CH:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:13]([O:18][CH3:19])[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(O)c(OC)c1
Reactant: OC1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(OC)c1

Procedure:
To a solution of 4-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-methoxy-phenol (1.0 mmol, 371 mg) in dry THF (3.0 mL) was added cyclohexanol (3.0 mmol, 317 μL) and triphenylphosphine (3.0 mmol, 787 mg). While sonicating, diisopropyl azodicarboxylate (3.0 mmol, 591 μL) was added. And the mixture was sonicated for another 1 hour then condensed. The residue was purified by silica gel chromatography (DCM to DCM+10% MeOH) to afford a colorless sticky solid, which was dissolved in DCM (5.0 mL), 2N HCl in ether (5.0 mL) was added, condensed, triturated with hexanes to provide the title compound (332 mg). LCMS: m/z 455 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.09 (1H, d), 6.98-7.03 (2H, m), 6.90-6.93 (1H, m), 5.45 (1H, bs), 4.30-4.38 (1H, m), 3.85 (3H, s), 3.10-3.37 (4H, m), 2.90-2.96 (2H, m), 2.79 (3H, s), 2.10-2.35 (4H, m), 1.96-2.03 (2H, m), 1.80-1.87 (2H, m), 1.31-1.63 (8H, m), 1.20-1.29 (2H, m), 0.80 (3H, t).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=2[C:8]#[N:9])[CH:5]=[N:4][N:3]=[N:2]1>N.[Ni].O>[N:1]1([C:6]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][C:7]=2[CH2:8][NH2:9])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: N#Cc1cc(C(F)(F)F)ccc1-n1cnnn1
Agent: [Ni]
Agent: N
Solvent: O
Product: NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Reaction time: 16 h

Procedure:
To a solution of 2-(1H-tetraazol-1-yl)-5-(trifluoromethyl)benzonitrile (166 mg, 0.69 mmol) in saturated ethanolic ammonia (12 mL) was added Raney nickel (50% slurry in water; the water was decanted and the catalyst rinsed with EtOH three times before use). The mixture was quickly degassed and purged with Ar, and was then placed under H2 atmosphere (balloon) and stirred for 16 h. The mixture was then filtered through Celite and the filter cake was rinsed thoroughly with EtOH. The filtrate was concentrated to a brown oil. Silica gel chromatography (70% EtOAc-hexanes then 5% MeOH-CHCl3) afforded the title compound as an orange-brown solid. 1H NMR (400 MHz, CDCl3): δ 9.41 (s, 1H), 7.93 (br s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 3.81 (s, 2H), 1.57 (br s, 2H). LCMS (M+H): 243.9.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][CH3:23])[N:21]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH3:23])[N:21]=2)=[O:12])[C:3]1=[O:15]
Reactant: CCc1csc(N)n1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: CCc1csc(NC(=O)c2c(O)cc(C)n(C)c2=O)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 56 %

Procedure:
210 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 117 mg of 2-amino-4-ethylthiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 5.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 150 mg of 1,6-dimethyl-N-(4-ethylthiazol-2-yl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 21) represented by the formula:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][N:3]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:29]3[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]3)=[N:3][CH:4]=2)=[N:12][N:11]=1
Reactant: OC1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCC(O)CC3)nc2)o1
Yield: 7 %

Procedure:
As described for example 136b, 2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.59 mmol) was converted using 4-hydroxypiperidine instead of morpholine to the title compound (17 mg, 7%) which was obtained as a light yellow solid. MS: m/e=404.5 [M+H]+.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:28][C:29]1[CH:43]=[CH:42][C:32]([C:33]2[CH:38]=[C:37]([CH2:39][CH3:40])[C:36]([Pb+3])=[CH:35][CH:34]=2)=[CH:31][CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH:4]3[C:5](=[O:10])[C@H:6]4[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]4)[C:3]3=[O:11])=[C:37]([CH2:39][CH3:40])[CH:38]=2)=[CH:42][CH:43]=1
Reactant: CCc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 33.4 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.20 g, 1.30 mmol) and 4-dimethylaminopyridine (0.792 g, 6.49 mmol) are added to a mixture of chloroform (4 ml) and toluene (1 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4′-Chloro-3-ethylbiphen-4-yllead triacetate (0.856 g, 1.43 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×5 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4′-chloro-3-ethylbiphenyl-4-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (0.16 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cncnc3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-chloro-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M87) (0.42 g, 0.90 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light red solid (230 mg, 61%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[CH:18]1([C:24]2[N:32]3[C:27](C(=O)NC=N3)=[C:26]([I:34])[N:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[CH:18]1([C:24]2[N:32]3[C:27]([C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)=[C:26]([I:34])[N:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=c1[nH]cnn2c(C3CCCCC3)nc(I)c12
Reactant: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ncnn2c(C3CCCCC3)nc(I)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1H-1,2,4-triazole (1 g, 0.02 mol) in acetonitrile (23 mL) was added dropwise phosphoryl chloride (0.6 mL, 0.007 mol) and triethylamine (3 mL, 0.02 mol) at 0° C. To this mixture was added 7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4(3H)-one (77 mg, 0.224 mmol) and the resulting mixture refluxed overnight. The cooled mixture was then quenched with excess NH3 in iPrOH (pH 8) stirred at rt for 30 min. then filtered and the isolated solid washed with DCM. The filtrate was concentrated in vacuo and purified by chromatography over silica gel eluting with 2% MeOH in DCM to afford the 7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-amine. 1H NMR (400 MHz-DMSO-d6) δ 1.14-1.91 (m, 10H), 3.11-3.18 (m, 1H), 6.75 (br.s, 1H), 7.84 (s, 1H) 8.42 (bs, 1H); MS (ES+): m/z: 344.01 (100) [MH+]. HPLC: tR=3.10 min (OpenLynx: polar—5 min).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2([NH2:29])[CH2:28][CH2:27][CH2:26]2)[N:21]=1>>[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2([NH:29][C:15]([C:7]3[CH:6]=[N:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[C:9]([O:10][CH2:11][CH:12]4[CH2:13][CH2:14]4)[N:8]=3)=[O:17])[CH2:28][CH2:27][CH2:26]2)[N:21]=1
Reactant: Cc1nc(C2(N)CCC2)no1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: Cc1nc(C2(NC(=O)c3cnc(C4CC4)c(OCC4CC4)n3)CCC2)no1

Procedure:
The title compound was synthesized in analogy to Example 8e, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 1-(5-methyl-1,2,4-oxadiazol-3-yl)-cyclobutanamine (CAN 1170897-128-5, 98.07 mg, 0.64 mmol) as starting materials, and isolated (50 mg, 31.67%) as off white solid; LC-MS (UV peak area, ESI) 99.91%, 370.0 (M+H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[CH3:28])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[Cl:27][C:23]1[CH:24]=[C:25]([CH3:26])[C:20]([O:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10]([C:29]#[N:30])=[N:9][C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])=[C:17]3[OH:18])=[C:21]([CH3:28])[CH:22]=1
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cc(Cl)cc3C)cc2c1O
Reactant: NCC(=O)O
Product: Cc1cc(Cl)cc(C)c1Oc1ccc2c(C#N)nc(C(=O)NCC(=O)O)c(O)c2c1

Procedure:
The title compound was synthesized from 6-(4-Chloro-2,6-dimethyl-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=424.3.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)#[CH:14]>>[F:21][C:17]1[CH:16]=[C:15]([C:13]#[C:14][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Reactant: C#Cc1cccc(F)c1
Product: O=c1[nH]cnc2cc(C#Cc3cccc(F)c3)ccc12

Procedure:
The title compound was prepared from 7-bromoquinazolin-4(3H)-one and 1-ethynyl-3-fluorobenzene according to the experimental procedure as described in Example 1.1. MS (ESI): 265 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.14 (s, 2H), 7.83 (s, 1H), 7.68-7.64 (m, 1H), 7.53-7.49 (m, 3H), 7.36-7.33 (m, 1H). mGluR5 PAM EC50: +.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccncc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccncc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and isonicotinic acid as starting materials, MS (LC/MS): 408.0 (M+H).