Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2nsc3ccccc23)CC1
Yield: 38.7 %

Procedure:
A mixture of 3-(1-piperazinyl)-I,2-benzisothiazole (4.0 g, 18.2 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20.0 mmol), K2 CO3 (3.0 g, 21.8 mmol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 5 hours. Most of the solvent was removed in vacuo and the resultant gummy residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried with MgSO4, and concentrated to yield 7.8 g. Purification by preparative HPLC (Waters Associates Prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent) afforded 6.5 g of a damp, off-white solid. The product was recrystallized twice from toluene to provide 3.1 g (39%) of 1-[4-[4-[4-(1,2-benzisothiazol-3yl)-1-piperazinyl]butoxy]-3-methoxy-phenyl]ethanone as a white solid, m.p.=114°-116° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][S:7]1)=[O:5])[CH3:2].[CH:13]([O-])([O-])[O:14]C.O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:3][C:4]([CH:6]1[C:11]([O:14][CH3:13])([O:12][CH3:19])[CH2:10][CH2:9][CH2:8][S:7]1)=[O:5])[CH3:2]
Reactant: COC([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)C1SCCCC1=O
Solvent: CO
Solvent: O
Product: CCOC(=O)C1SCCCC1(OC)OC

Procedure:
To a mixture of 3-oxothiane-2-carboxylic acid ethyl ester (2.0 g), methanol (8 ml), and methyl orthoformate (20 ml) is added p-toluenesulfonic acid monohydrate (120 mg). After refluxing overnight, the mixture is concentrated, diluted with ethyl acetate, washed with water, dried, and concentrated to give 3,3-dimethoxythiane-2-carboxylic acid ethyl ester (1.32 g).
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.F[C:26]1[C:35]([O:36][CH3:37])=[C:34]2[C:29]([C:30](=[O:45])[C:31]([C:42]([OH:44])=[O:43])=[CH:32][N:33]2[C@@H:38]2[CH2:40][C@@H:39]2[F:41])=[CH:28][CH:27]=1>CS(C)=O>[F:41][C@H:39]1[CH2:40][C@H:38]1[N:33]1[C:34]2[C:29](=[CH:28][CH:27]=[C:26]([N:15]3[CH2:16][CH2:17][C@@H:13]([C:10]4([NH:8][CH3:9])[CH2:11][CH2:12]4)[CH2:14]3)[C:35]=2[O:36][CH3:37])[C:30](=[O:45])[C:31]([C:42]([OH:44])=[O:43])=[CH:32]1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3OC)C2)CC1
Temperature: 100 °C
Yield: 49.7 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (102 mg, 379 μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (1 ml, 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (112 mg, 379 μmol) was added thereto and stirred while heating in an oil bath of 100° C. for 15 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (2 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (2 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×4), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by a preparative chromatography (developed into the lower layer of a 7:3:1 mixture of chloroform:methanol:water), purified further by recrystallization from ethanol, and then dried under a reduced pressure. 78.3 mg (50%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]([OH:21])[CH2:19][N:20]=2)=[CH:11][CH:10]=1)[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCCl>[CH3:1][N:2]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][CH:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]([O:21][C:35](=[O:36])[NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:19][N:20]=2)=[CH:13][CH:14]=1)[C:3](=[O:8])[C:4]([F:5])([F:7])[F:6]
Reactant: CN(C(=O)C(F)(F)F)c1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: CN(C(=O)C(F)(F)F)c1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Yield: 38 %

Procedure:
A mixture of (5RS, 6SR)-2-[4-(N-methyltrifluoroacetamido)phenyl]-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.54 g) and phenyl isocyanate (0.6 g) in 1,2-dichloroethane (25 cc) is heated to reflux for 18 hours. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization of the residue thereby obtained in isopropyl ether, (5RS, 6SR)-2-[4-(N-methyltrifluoroacetamido)phenyl]-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.77 g), m.p. 160° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH3:43][C:44]1[S:48][C:47]([CH:49]([NH2:51])[CH3:50])=[N:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:51][CH:49]([C:47]2[S:48][C:44]([CH3:43])=[CH:45][N:46]=2)[CH3:50])=[O:41])=[C:18]([CH3:23])[CH:17]=1
Reactant: Cc1cnc(C(C)N)s1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ncc(C)s4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(5-methyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (14 mg, yield 31%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[NH:22][CH2:21]1)[C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][N:9]=1.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[N:22]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)[CH2:21]1)[C:8]1[N:9]=[CH:10][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:12][N:13]=1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1ccc(C(F)(F)F)cn1
Temperature: 120 °C
Yield: 65.6 %

Procedure:
A mixture of [3,5-bis(trifluoromethyl)benzyl]-((3S,5R)-5-ethyl-pyrrolidin-3-yl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]amine (45 mg, 0.09 mmol), 2-chloro-5-trifluoromethyl-pyridine (50 mg, 0.27 mmol) and iPr2EtN (45 uL 0.27 mmol) in THF (1.5 mL) is stirred at 120° C. under microwave irradiation. The mixture is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: hexane/EtOAc) to give (3,5-Bis-trifluoromethyl-benzyl)-[(3S,5R)-5-ethyl-1-(5-trifluoromethyl-pyridin-2-yl)-pyrrolidin-3-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine as a colorless oil (38 mg, 66%). ESI-MS m/z: 643 [M+1]+, Retention time 2.45 min (condition A).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH:10]1([CH:15]([N:19]2[CH:23]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=[N:20]2)[CH2:16][C:17]#[N:18])[CH2:14][CH2:13][CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOC[CH2:42]1>O.CCOC(C)=O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:22]2[CH:21]=[N:20][N:19]([CH:15]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:16][C:17]#[N:18])[CH:23]=2)[C:5]([CH2:9][CH3:42])=[CH:4][N:3]=1
Reactant: C1COCCO1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CCCC2)c1
Temperature: 100 °C
Yield: 78 %

Procedure:
A mixture of 2,4-dichloro-5-methylpyrimidine (0.62 g, 3.8 mmol), 3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (1.0 g, 3.17 mmol), tetrakis(triphenylphosphine)palladium (200 mg, 0.2 mmol), and potassium phosphate (2.0 g, 9.6 mmol) in 1,4-dioxane (9 mL) and water (0.9 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, concentrated. The residue was purified on silica gel, eluting with 0 to 80% EtOAc-hexanes, to give the desired product (780 mg, 78%). LCMS (M+H) 316.0.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][O:12][C:13](=[O:17])[CH2:14][CH2:15][SH:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:11][O:12][C:13](=[O:17])[CH2:14][CH2:15][S:16][CH2:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)CCS
Reactant: O=C(CCl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCSCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
15.5 parts of chloroacetophenone are added to a solution, cooled to 0° C., of 12 parts of 3-mercapto-propionic acid methyl ester and 15.3 parts by volume of triethylamine in 100 parts by volume of chloroform. The mixture is stirred for 2 hours at 0° C. and is washed with water, and the organic phase is separated off, dried and concentrated. 21 parts (90% of theory) of 3-(benzoylmethylthio)-propionic acid methyl ester of boiling point 156°-160° C./0.3 mbar are obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1cc2[nH]ccc2cc1O
Yield: 7.9 %

Procedure:
5-Benzyloxy-6-methoxyindole (253 mg, 11.0 mmol) was hydrogenated at 1 atmosphere pressure in methanol (10 ml) with 10% palladium on carbon (50 mg) for 2 hours at 25° C. The catalyst was filtered off and the filtrate evaporated to give 5-hydroxy-6-methoxylindole (141 mg, 87%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1Cl
Reactant: c1nc[nH]n1
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,5-dichloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][CH:2]([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]([CH3:16])[C:14]([CH2:17][CH2:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24](C3CCCCO3)[N:23]=[CH:22]4)=[N:13][N:12]=2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([CH2:18][CH2:17][C:14]3[N:15]([CH3:16])[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:34])=[CH:5][CH:6]=4)=[N:12][N:13]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: Cn1c(CCc2ccc3c(cnn3C3CCCCO3)c2)nnc1Nc1ccc(OC(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(CCc2ccc3[nH]ncc3c2)nnc1Nc1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(4-(difluoromethoxy)phenyl)-4-methyl-5-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)-4H-1,2,4-triazol-3-amine (131 mg, 0.280 mmol) in DCM (2 mL), was added TFA (0.646 mL, 8.39 mmol) and the reaction was stirred at room temperature overnight. Solvents were concentrated and the crude product was purified by preparative HPLC on a Sunfire C18 column (150×19×5.0 m) using a gradient of ACN in 10 mM ammonium acetate (0-100%) to give 5-(2-(1H-indazol-5-yl)ethyl)-N-(4-(difluoromethoxy)phenyl)-4-methyl-4H-1,2,4-triazol-3-amine as off white solid (0.026 g, 23%). 1HNMR: 400 MHz, DMSO-d6: δ 2.96-2.98 (m, 2H), 3.08-3.10 (m, 2H), 3.34 (s, 3H), 7.07-7.09 (m, 3H), 7.27-7.28 (m, 1H), 7.47-7.49 (m, 3H), 7.63 (s, 1H), 8.00 (s, 1H), 8.57 (s, 1H), 12.98 (s, 1H). LCMS: RT 1.322 min; LCMS (ES-API), m/z 385 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][N:13]3[C:14](=[O:21])[C:15]([C:18](O)=[O:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][CH2:25][N:26](CC)CC.ClC(OCC)=O.C(N)C>C(Cl)(Cl)Cl>[CH2:25]([NH:26][C:18]([C:15]1[C:14](=[O:21])[N:13]2[CH:22]=[CH:23][C:10]([C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:11][C:12]2=[N:17][CH:16]=1)=[O:19])[CH3:24]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCNC(=O)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Reaction time: 0.17 h

Procedure:
To a solution of 8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (50 mg, 0.62 mmol, 1 equiv) and Et3N (0.5 mL) in CHCl3 (20 mL) at 0° C. was added ethyl chloroformate (0.4 mL) dropwise. After the reaction mixture was stirred for 10 min, aq. ethanamine (3 mL) was added. Then the mixture was stirred for 10 min and extracted with CHCl3 (3×30 mL), dried over Na2SO4 and concentrated to give the desired product (30 mg). MS (ESI): 336 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.37 (s, 1H), 9.17-9.14 (d, J=7.32 Hz, 1H), 8.96-8.95 (m, 1H), 7.91 (s, 1H), 7.44-7.40 (m, 2H), 7.37-7.31 (m, 2H), 7.23-7.18 (m, 1H), 3.60-3.50 (m, 2H), 1.32-1.27 (t, J=7.2 Hz, 3H). mGluR5 PAM EC50: ++++.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[O:6][N:5]=1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=7[F:25])=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[O:6][N:5]=[C:4]([CH2:2][CH3:3])[N:8]=6)[C:11]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4F)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6F)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(2-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (272 mg; compound B88) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (237 mg; compound C10) and HBTU (249 mg) in DCM (7 ml) in the presence of DIPEA (0.42 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: DCM/MeOH, 1/0 to 1/1 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:12])[N:3]=1.[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][OH:33])[CH:28]=[CH:29][C:30]=1[F:31]>CN(C)C=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:7]2[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:12])[N:3]=[C:2]([O:33][CH2:32][C:27]4[CH:28]=[CH:29][C:30]([F:31])=[C:25]([F:24])[CH:26]=4)[CH:11]=[C:6]23)=[CH:18][CH:19]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1nc(Cl)cc2n1CCCN2
Reactant: OCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1nc(OCc2ccc(F)c(F)c2)cc2n1CCCN2Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
To a solution of 8-chloro-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (50 mg, 0.27 mmol) and sodium hydride (23.70 mg, 0.59 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added a solution of 1-(bromomethyl)-4-chlorobenzene (66.4 mg, 0.32 mmol) in anhydrous N,N-dimethylformamide (1 ml) at r.t, and then stirred for 1 h at 50° C. Then, a solution of (3,4-difluorophenyl) methanol (46.6 mg, 0.32 mmol) in N, N-dimethylformamide (1 ml) was added and stirred for 1 h at r.t. The reaction mixture was quenched by water. Purification via reverse phase column using acetonitrile/water as eluent afforded the title compound (13 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].Cl.[NH2:16][CH:17]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:18]1=[O:19].C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:10]=[C:8]1[C:7]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=2)[C:11](=[O:12])[N:16]1[CH:17]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:18]1=[O:19]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NC1CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C(=O)N1
Yield: 54.3 %

Procedure:
A mixture of 4-nitrophthalic anhydride (1.7 g, 8.5 mmol), α-aminoglutarimide hydrochloride (1.4 g, 8.5 mmol) and sodium acetate (0.7 g, 8.6 mmol) in glacial acetic acid (30 mL) was heated under reflux for 17 hours. The mixture was concentrated in vacuo and the residue was stirred with methylene chloride (40 mL) and water (30 mL). The aqueous layer was separated, extracted with methylene chloride (2×40 mL). The combined methylene chloride solutions were dried over magnesium sulfate and concentrated in vacuo to give 1.4 g (54%) of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline as a light brown solid. An analytical sample was obtained by recrystallization from methanol: mp 228.5-229.5° C.; 1H NMR (DMSO-d6) δ 11.18(s, 1H), 8.69-8.65(d,d J=1.9 and 8.0 Hz, 1H), 8.56(d, J=1.9 Hz, 1H), 8.21(d, H=8.2 Hz, 1H), 5.28(d,d J=5.3 and 12.8 Hz, 1H), 2.93-2.07(m, 4H); 13C NMR (DMSO)-d6) δ 172.66, 169.47, 165.50, 165.23, 151.69, 135.70, 132.50, 130.05, 124.97, 118.34, 49.46, 30.85, 21.79; Anal. Calcd for C13H9N3O6: C, 51.49; H, 2.99; N, 13.86. Found: C, 51.59; H, 3.07; N, 13.73.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:17]([NH:21][NH2:22])([O:19][CH3:20])=[O:18].CC(O)=O>C(O)C.O>[C:17]([NH:21][N:22]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)([O:19][CH3:20])=[O:18]
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COC(=O)NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COC(=O)NN=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.8 %

Procedure:
To a solution of 4-(4-fluorophenoxy)benzaldehyde (277 mg, 1.28 mmol) in ethanol (10 mL) was added a solution of carbomethoxyhydrazine (180 mg, 2.0 mmol) in water (5 mL), followed by AcOH (0.1 mL) at room temperature. The mixture was stirred at room temperature for 17 h and water (20 mL) was added. The resulting solid was collected by filtration, washed with water and dried in vacuo to yield the title compound as a white solid (228 mg, 0.74 mmol, 58%),mp: 109-111° C. 1HNMR (DMSO-d6): δ 11.05 (s, 1H), 8.00 (s, 1H), 7.64 (d, J=8.7, 2H), 7.30-6.99 (m, 6H, 3.69 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.CN1CCOCC1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.CN(C)C=O>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:7](=[O:9])[C:6]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[NH2:11])=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
171 mg of 5-chloroanthranilic acid is introduced into 10 ml of dimethylformamide under argon and in a moisture-free environment and mixed in succession with 253 mg of N-methylmorpholine, 266 mg of 5-aminoindazole and 456 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and stirred for 4 hours at room temperature. After standing overnight, it is mixed with 50 ml of water and extracted with 30 ml of ethyl acetate. The organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate as an eluant. 266 mg of N-(indazol-5-yl)-5-chloroanthranilic acid amide is obtained.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH-:10].[Na+].O>CN1C(=O)CCC1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:10][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: BrCc1ccc(I)cc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Ic1ccc(COCc2ccc(I)cc2)cc1
Reaction time: 0.17 h

Procedure:
825 mg of PVA 13 kDa was dissolved in 55 ml of dry NMP under a nitrogen flow at 130° C. Then the temperature was decreased to 50° C. and 5 g of 4-monoiodobenzyl bromide was added. After 10 minutes, 1.35 g of dried sodium hydroxide was added. After 5 hours of reaction time, cold water was added and a paste material has appeared. The sticky paste could not be filtrated. Water was easily removed because the material was struck to the walls of the flask. After water was poured out, the pasty residue was washed with methanol and dried. After conventional steps of purification, MIB-PVA 13 kDa including residual NMP was obtained.