Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](Cl)(Cl)(Cl)Cl.[C:20](#[N:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>ClCCCl.O.CO>[CH3:14][N:11]1[CH2:12][CH2:13][CH:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:20](=[NH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][CH2:10]1
Reactant: CN1CCC(Nc2ccccc2)CC1
Reactant: N#Cc1ccccc1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCCl
Solvent: O
Product: CN1CCC(Nc2ccccc2C(=N)c2ccccc2)CC1
Yield: 70.6 %

Procedure:
To a solution of 0.38 g (2 mmol) of 4-anilino-1-methyl-piperidine 1 dissolved in 10 ml of 1.2-dichloroethane are added 0.3 ml (2×1.2 mmol) of boron trifluoride ether adduct, 0.28 ml (2×1.2 mmol) of silicon tetrachloride, and 0.41 ml (2×2 mmol) of benzonitrile at room temperature with stirring, and the mixture is heated under reflux with stirring for 20 hours. The reaction mixture is cooled and a solution of 2.5 g of sodium hydroxide dissolved in 10 ml of water and 4 ml of methanol are added thereto with stirring under ice-cooling. The mixture is stirred at room temperature for 1 hour and extracted with dichloromethane; the organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue is recrystallized from ether-petroleum ether to give 414 mg of crystalline 2-(1-methyl-4-piperidinyl)aminobenzophenone imine 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[CH2:19][CH:18]=[C:17](B(O)O)[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=3)=[CH:9][N:8]([CH3:12])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1cc(I)c2cc(Br)cnc21
Reactant: CN1CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CC=C(c2cn(C)c3ncc(Br)cc23)CC1
Temperature: 40 °C

Procedure:
To a solution of 5-bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (180 mg, 0.534 mmol) and 1-methyl-1,2,3,6-tetrahydropyridin-4-boronic acid (155 mg, 0.694 mmol) in dioxane (5.4 mL, degassed) was added tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.064 mmol), K2CO3 (369 mg, 2.67 mmol) and water (1.8 mL, degassed). The reaction mixture was heated at 40° C. for 15 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C14H16BrN3: 306.2 (M+H+); Found: 306.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[O-]S([O-])(=O)=O.[Mg+2].[CH:14]1[C:19]([CH:20]=O)=[CH:18][C:17]2[O:22][CH2:23][O:24][C:16]=2[CH:15]=1>C(Cl)(Cl)Cl.O>[CH2:23]1[O:24][C:16]2[CH:15]=[CH:14][C:19]([CH:20]=[N:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[CH:18][C:17]=2[O:22]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(CN)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(CN=Cc1ccc2c(c1)OCO2)OC
Temperature: 25 °C
Yield: 100 %

Procedure:
Aminoacetaldehyde dimethylacetal (7.10 g, 0.0666 mol) was dissolved in chloroform (50 mL) and MgSO4 (12 g) was added. Then piperonal (10b, 10.10 g, 0.0666 mol) was added and the mixture was stirred at room temperature. After 24 h there still was unreacted piperonal in the reaction mixture and more amine (6.00 g) was added. The reaction mixture was stirred again at room temperature for 24 h and since there still was some piperonal present more amine (6.00 g) was added again. After stirring the reaction mixture for another 24 h at room temperature the imine was isolated. The reaction mixture was diluted with water (300 mL) and the organic layer was washed with water 200 mL×2, brine (200 mL) dried Na2SO4 and concentrated to provide the pure imine as a yellow oil (15.80 g, 100%). 1H NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), 7.33 (s, 1H), 7.07 (d, J=8.10 Hz, 1H), 6.78 (d, J=8.10 Hz, 1H), 5.96 (s, 2H), 4.62 (t, J=5.4 Hz, 1H), 3.70 (d, J=4.2, 2H), 3.83 (s, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:14][C:15]([CH:3]2[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1CCOCC1
Product: O=C1CCOCC1C(=O)Cc1ccccc1
Yield: 49.4 %

Procedure:
3-(2-Phenylacetyl)dihydro-2H-pyran-4(3H)-one (0.538 g, 49.4%) was synthesised from tetrahydro-4H-pyran-4-one (0.923 mL, 9.99 mmol) and phenylacetyl chloride (0.660 mL, 4.99 mmol) by the general procedure for the preparation of ketones.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:3]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=3)[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[N:3]=2)=[CH:27][CH:26]=1
Reactant: COc1cccc(-c2cc3ccc(N(C)C)cc3c(Cl)n2)c1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(-c3cccc(OC)c3)cc3ccc(N(C)C)cc23)cc1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A mixture of 1-chloroimine isoquinoline II (500 mg, 1.6 mmol), 4-methoxy benzylamine (877 mg, 6.4 mmol), and potassium carbonate (2 g, 15 mmol) in DMF was refluxed overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel with n-hexane-ethyl acetate (3:1) to afford compound III (310 mg, 47%). 1H NMR (300 MHz, CDCl3) δ: 7.74-7.62 (m, 3H), 7.45-7.33 (m, 4H), 7.22 (m, 1H), 6.92 (m, 3H), 6.66 (m, 1H), 5.24 (s, 1H), 4.91 (d, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.09 (s, 6H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-:8].[K+].[C:10](#[N:12])[CH3:11]>>[F:8][C:3]1[C:2]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:1]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:6]([F:8])=[C:11]([C:10]#[N:12])[C:11]=1[C:10]#[N:12]
Reactant: Sc1ccccc1
Reactant: [F-]
Reactant: CC#N
Agent: [K+]
Product: N#Cc1c(F)c(Sc2ccccc2)c(Sc2ccccc2)c(F)c1C#N
Temperature: 50 °C
Reaction time: 12 h

Procedure:
19.6 g (98 mmol) of tetraphthalonitrile, 21.6 g (196 mmol) of thiophenol, 17.1 g (294 mmol) of potassium fluoride and 100 ml of acetonitrile were fed into a 200 ml four-necked flask and the mixture was stirred at 50° C. for 12 hours. The temperature was then returned to room temperature, and the resulting yellow solid was filtrated. The resulting cake was washed with methanol and then with hot water to give 34.55 g of 3,6-difluoro-4,5-bisphenylthiophthalonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[OH:26][C:27]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH2:30][CH2:29]1>ClCCl>[OH:26][C:27]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:9](=[O:11])[CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:32][CH2:33]1
Reactant: O=C(O)COc1cccnc1
Reactant: NCCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(COc1cccnc1)NCCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.8 g (11.6 mmol) (pyridin-3-yloxy)-acetic acid and 1.7 ml (12.2 mmol) TEA are suspended in 80 ml absolute dichlormethane and cooled to ca. 0° C. under moisture exclusion. 2.1 g (13.7 mmol) 88% HOBT and 2.7 g (14.1 mmol) EDC are added and the mixture is stirred for 30 min under ice-cooling. 4,. g (13.0 mmol) 4-[4-(hydroxy-diphenylmehyl)-piperidin-1-yl]-butylamine are added and the mixture is stirred overnight without cooling. Subsequently, the batch is washed with 50 ml 1M sodium hydroxide solution and twice each with 30 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH/NH4OH (90/10/0 to 90/10/1): Yield 2.0 g (34%) of a colorless resin.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:10]=2)[CH2:5][CH2:4]1.[O-:28][C:29]#[N:30].[K+]>CC#N.O>[F:15][C:14]1[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:29]([NH2:30])=[O:28])[CH2:4][CH2:5]2)=[N:10][C:11]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[N:12][CH:13]=1
Reactant: N#C[O-]
Reactant: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 27.6 %

Procedure:
To a suspension of 6-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one (26 mg, 0.070 mmol) in CH3CN (1 mL), an aqueous solution of potassium cyanate (34 mg, 0.42 mmol) in H2O (1 mL) was added. The mixture was stirred at 70° C. for 1 h. Solvents were removed in vacuo. The residue was purified by HPLC to give the titled compound (8 mg). MS 414.3 (M+H);); UV 205.8, 276.8 nm
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1)[CH:9]=[CH:8]2)[CH:2]=[CH2:3].[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21].C1C[O:28]CC1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1)[CH:9]=[C:8]2[C:19](=[O:23])[C:20]([OH:28])=[O:21])[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOc1ccc2c(ccn2CC2CCC2)c1
Reactant: C1CCOC1
Product: C=CCOc1ccc2c(c1)c(C(=O)C(=O)O)cn2CC1CCC1

Procedure:
The crude 5-allyloxy-1-cyclobutylmethyl-1H-indole from Step 3 was dissolved in 0.5 mL anhydrous THF and 0.22 mL (2.5 mmol) oxalyl chloride was added. The reaction was mixed overnight on an orbital shaker. The reaction was concentrated and the crude product was redissolved in a minimum volume of dichloromethane. 0.8 mL 1N aqueous NaOH was added and the reaction was capped and shaken. The solution was acidified by the dropwise addition of 2N aqueous HCl and extracted with 1.6 mL dichloromethane. LC/MS (see Note 2) indicated that the reaction was not complete. The crude material was redissolved in 0.5 mL anhydrous THF, 0.16 mL
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:24]([CH3:35])[C:25](=[O:34])[C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)[CH2:21][CH2:22][CH3:23].[Br:36]C(Br)(Br)Br>C(Cl)Cl>[Br:36][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:25]([N:24]([CH2:20][CH2:21][CH2:22][CH3:23])[CH3:35])=[O:34]
Reactant: CCCCN(C)C(=O)C#CCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)C#CCCCCCBr
Temperature: -10 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
1.205 g of triphenyl phosphine were added to a solution of 855 mg of the product of Step D in 4 ml of methylene chloride and the mixture was cooled to −10° C. 1.522 g of tetrabromomethane were added, and after stirring for one hour at −5° C., the reaction mixture was chromatographed on silica (eluant: cyclohexane-ethyl acetate 35-65) to obtain 0.98 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:9]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cn1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cn1

Procedure:
A mixture of 10.5 g (0.046 mole) 1-(5-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone, prepared above, and 8.37 g (0.047 mole) N-bromosuccinimide (NBS) in 300 ml. carbon tetrachloride, with stirring, was irradiated and heated with a sunlamp until all of the NBS was consumed (about 45 min.). The reaction mixture was cooled, filtered, and the filtrate washed with aqueous sodium bisulfite and dried. After removal of the solvent, there was obtained a quantitative yield of 1-bromo-1-(5-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone, a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.Cl[Si](CC)(CC)CC.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:23])=[CH:18][CH:17]=1>CCCCCC.C1COCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[OH:23])=[CH:20][CH:21]=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[OH:23])=[CH:20][CH:21]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1ccnc1C(O)(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 26.6 %
Yield: 20 %

Procedure:
n-Buthyl-lithium in hexane (1.6M; 71.6 ml) was added dropwise at −70° C. under N2 flow to a mixture of 1-methylimidazole (0.1146 mol) in THF (195 ml). The mixture was stirred at −70° C. for 30 minutes. Chlorotrietylsilane (0.1146 mol) was added. The mixture was brought slowly to 10° C. and cooled again to −70° C. n-Buthyl-lithium in hexane (1.6M; 71.6 ml) was added dropwise. The mixture was stirred at −70° C. for 1 hour, brought to −15° C. and cooled again to −70° C. A mixture of 4-chlorophenyl-4-nitrophenyl-methanone (0.095 mol) in THF (150 ml) was added dropwise. The mixture was stirred at −70° C. for 30 minutes, hydrolized and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1). The desired fractions were collected and their solvents were evaporated, yielding 6.5 g (20%) of (±)-α-(4-chlorophenyl)-1-methyl-α-(4-nitrophenyl)-1H-imidazole-2-methanol (interm 12), 8.7 g (26.6%) of (±)-α-(4-chlorophenyl)-1-methyl-α-(4-nitrophenyl)-1H-imidazole-5-methanol (interm 13) and 18 g (53%) of the mixture of intermediate 12 and 13.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[NH:34][S:35](C1C=CC(C2C=C3N=C(CCC4CCCCC(=S)N4)NC3=NC=2)=CC=1)(=[O:37])=[O:36].N>CO>[NH2:25][C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][C:14]2[NH:13][C:10]3=[N:11][CH:12]=[C:7]([C:1]4[CH:2]=[CH:3][C:4]([S:35]([NH:34][C:28]5[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=5[F:26])(=[O:36])=[O:37])=[CH:5][CH:6]=4)[CH:8]=[C:9]3[N:15]=2)[N:24]=1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=S)N5)nc4c3)cc2)c(F)c1
Agent: N
Solvent: CO
Product: Cc1ccc(NS(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(N)=N5)nc4c3)cc2)c(F)c1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 100 mg of N-(2-fluoro-4-methyl-phenyl)-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide (compound A8) and 4.30 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 90 hours. Subsequently, the mixture is filtered with suction. The residue is washed with 20 ml of methanol and dried under high vacuum to afford 61 mg of the pure title compound as an amorphous, colorless solid of m.p. 265° C. ESI-MS: 521.2 (MH+), TLC: Rf=0.28 (HPTLC RP-C18; acetonitrile/water 2:1 parts by volume).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]([NH2:23])[CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=1.[O:24]([CH2:28][CH:29]=O)[CH2:25][CH:26]=O.O.[BH3-]C#N.[Na+].Cl>CC#N>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]([N:23]2[CH2:29][CH2:28][O:24][CH2:25][CH2:26]2)[CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=CCOCC=O
Reactant: COc1cccc(C(N)C(c2cccnc2)c2cccnc2)n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(C(C(c2cccnc2)c2cccnc2)N2CCOCC2)n1

Procedure:
To a solution of 1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethanamine (75 mg, 0.25 mmole) in CH3CN (1 mL) was added a solution of 2,2′-oxydiacetaldehyde in H2O (1.47 mL, 0.5 M, 0.73 mmole). After 10 minutes NaBH3CN (92 mg, 1.47 mmole) was added. After 2 hr 1N HCl (2 mL) was added.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH:15]=[O:16])[N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1.C(C1N=C[N:27]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35]C=CC=2)[CH:28]=1)C1C=CC=CC=1.C[C:38]([C:46]1N=CNC=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:39]>>[CH3:46][C:38]([C:2]1[N:3]=[C:4]2[N:5]([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:15]2[O:16][CH:31]2[CH2:30][CH2:29][N:27]([CH3:28])[CH2:35][CH2:36]2)[CH:6]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH3:39]
Reactant: c1ccc(CCn2cnc(Cc3ccccc3)c2)cc1
Reactant: CC(C)(c1ccccc1)c1c[nH]cn1
Reactant: O=Cc1nc(I)cn1CCc1ccccc1
Product: CN1CCC(OC2c3ccccc3CCn3cc(C(C)(C)c4ccccc4)nc32)CC1

Procedure:
The compound is synthesized using the method described in example 2A, 2B and 110B starting from 4-(1-methyl-1-phenylethyl) imidazole (example 207B).
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:10]1[CH2:11][CH:1]2[CH2:13][CH2:12][CH:8]([C:7]3[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=3)[CH2:9]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(C)=O)C2)ncc1Cl

Procedure:
2-[2-(10-Acetyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide was prepared from 2-[2-(10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide and acetyl chloride in an analogous manner to Example 282. Product isolated as a yellow oil (25.3 mg, 77%). LCMS (m/e) 527 (M+1); 1H-NMR (CDCl3, 400 MHz,) major rotomer δ 9.09 (s, 1H), (d, 1H, J=9.5 Hz), 8.11 (s, 1H), 8.00-7.94 (m, 1H), 7.63-7.53 (s, 1H), 7.42-7.20 (m, 3H), 7.18-6.92 (m, 2H), 4.80-4.67 (m, 1H), 4.26-4.10 (m, 1H), 3.80-3.70 (m, 1H), 3.45-3.22 (m, 3H), 3.18-2.92 (m, 2H), 2.65 (d, 3H, J=2.3 Hz), 2.04 (s, 3H), 2.04-1.90 (m, 2H), 1.82-1.62 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]1=2.CCN=C=NCCCN(C)C.Cl.[CH3:33][C:34]1[S:38][C:37]([NH2:39])=[N:36][CH:35]=1.Cl>C(Cl)Cl>[CH3:33][C:34]1[S:38][C:37]([NH:39][C:12]([C:10]2[CH:9]=[CH:8][N:7]3[C:2](=[O:1])[C:3]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:4]=4[N:5]=[C:6]3[CH:11]=2)=[O:14])=[N:36][CH:35]=1
Reactant: O=C(O)c1ccn2c(=O)c3c(nc2c1)CCCCCC3
Reactant: Cc1cnc(N)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2ccn3c(=O)c4c(nc3c2)CCCCCC4)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the acid prepared from Example 28.1b and EDCI-HCl (80.2 mg, 0.42 mmol) in DCM (10 mL) was added 5-methylthiazol-2-amine (25.5 mg, 0.22 mmol). The mixture was stirred at room temperature for 10 min and then poured into 2 N HCl. The mixture was extracted with DCM (30 mL) and the organic layer was washed with aqueous NaHCO3, brine, dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by preparative HPLC to afford 5.5 mg of desired product. MS (ESI): 369 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.09-9.06 (d, J=7.38 Hz, 1H), 8.22 (s, 1H), 7.60-7.58 (d, J=6.57 Hz, 1H), 7.06 (t, J=5.4 Hz, 1H), 3.01-2.93 (m, 4H), 2.44 (s, 3H), 1.92-1.80 (m, 4H), 1.49 (broad, 4H). mGluR5 PAM EC50: +++++. Fold shift at 10 μM: +.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[CH:26][C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[CH:26][C:27]=6[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:40][CH:39]=2)[CH2:36][CH2:37]1
Reactant: Cn1ncc(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6c(Cl)cnn6C)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
A small screw cap test tube was charged with 4-Chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (50.53 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜1 mL of i-prOH yielding 32% (45 mg, 0.076 mmol) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3ccc(OC(F)(F)F)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and bromomethyl-4-trifluoromethoxy-benzene as described in Example 49 and isolated as a yellow solid (0.078 g, 52% yield) 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.41 (d, J=2 Hz, 1H), 7.26-7:31 (m, 3H), 7.17-7.23 (m, 2H), 6.86 (d, J=2 Hz, 1H), 6.10-6.16 (m, 1H), 5.35 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=474.1; Rt=1.38 min; HRMS (M+H)+=474.12.