Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([CH3:12])=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:8][C:7]=2[C:6]([O:18][CH3:19])=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:22])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH2:16]([O:15][C:13]([C:9]1[O:8][C:7]2[C:6]([O:18][CH3:19])=[CH:5][CH:4]=[C:3]([C:1]([OH:22])=[O:2])[C:11]=2[C:10]=1[CH3:12])=[O:14])[CH3:17]
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)c1oc2c(OC)ccc(C=O)c2c1C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1oc2c(OC)ccc(C(=O)O)c2c1C

Procedure:
The solution of ethyl 4-formyl-7-methoxy-3-methylbenzo[b]furan-2-carboxylate (3.0 g, 11.4 mmol) in acetone (30 ml) was cooled to 10-20° C. Sulfamic acid (1.55 g, 17.1 mmol) was added at once to the reaction mixture at 10-20° C. Then solution of sodium chlorite (1.6 g, 17.1 mmol) in water (10 ml) was added dropwise at the same temp. Water (100 ml) was added to reaction mixture. Acetone was distilled off under vacuum. The solid obtained was filtered and suck dried. Yellow coloured solid (3.0 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16](I)[N:15]=2)=[N:6]1.CO.[C:32](=O)([O-])[O-:33].[Cs+].[Cs+].CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C>[Cu]I.CN1CCCC1=O>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16]([O:33][CH3:32])[N:15]=2)=[N:6]1
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: [Cs+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(C)c12
Temperature: 180 °C
Yield: 10.5 %

Procedure:
200 mg (0.399 mmol) of the compound obtained in example 107 were admixed in a microwavable flask with methanol (3 ml), N-methylpyrrolidone (1 ml), 260 mg (0.798 mmol) of cesium carbonate, 8 mg (0.04 mmol) of copper(I) iodide and 19 mg (0.08 mmol) of 3,4,7,8-tetramethyl-1,10-phenanthroline. The flask was purged with argon while being treated with ultrasound for 5 min, and then closed with an appropriate septum. Then it was heated in a microwave at 180° C. for 8 h. After cooling, the reaction mixture was filtered and concentrated, and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 17 mg of the title compound were obtained (10% of theory).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[OH:6][C:7]1[C:15]2[N:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]([CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1>CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][O:6][C:7]1[C:15]2[N:14]=[C:13]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:12]([CH2:25][CH2:26][CH2:27][CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: BrCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCBr)cccc32)CC1
Yield: 80 %

Procedure:
A solution of 1,3-dibromopropane (41.3 mg, 0.3 mmol, 1.5 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with a solution of 4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (100 mg, 0.2 mmol, 1 eq) in anhydrous N,N-dimethylformamide (1 ml). The resulting mixture was stirred for twelve hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was subjected to column chromatography to yield the desired title product as a white crystalline product.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[N+:13]([C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1)([O-])=O.C(=O)([O-])O.[K+]>CCCCC(=O)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:25]1[CH2:24][CH2:23][N:22]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[NH2:13])[CH2:27][CH2:26]1
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: ClCC1COc2ccccc2O1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCCCC(C)=O
Product: Nc1cccc(N2CCN(CC3COc4ccccc4O3)CC2)c1

Procedure:
A solution of 54.2 mmol (10 g) of 2-chloromethyl-2,3-dihydro-1,4-benzodioxin, 54.2 mmol (9.2 g) of 3-nitrophenylpiperazine and 6 g of potassium hydrogen carbonate in 100 ml of methyl-4-pentanone is heated at reflux for 72 hours. After cooling, the reaction mixture is concentrated. The residue is taken up in 200 ml of water and extracted with 200 ml of dichloromethane. The organic phase is dried over magnesium sulphate, concentrated and purified by chromatography on silica gel, using as eluant a 99/1/0.1 dichloromethane/methanol/ammonium hydroxide mixture, to yield the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C1C(=O)N([Br:17])C(=O)C1>CN(C=O)C.CCOCC>[Br:17][C:8]1[C:2]([F:1])=[CH:3][C:4]([NH2:5])=[CH:6][C:7]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)cc(F)c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1cc(F)c(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-Difluoroaniline (10.0 g, 77.5 mmol) is dissolved in DMF (100 mL). NBS (13.9 g, 78.0 mmol) is added portionwise at room temperature. After stirring overnight at room temperature, the reaction mixture is diluted with Et2O and washed with brine. The separated organic phase is dried (Na2SO4) and concentrated to give an oil which is purified by column chromatography (methylene chloride/hexanes) to give 4-bromo-3,5-difluoroaniline.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3][CH2:4][OH:5].[Na].Cl[C:14]1[NH:19][C:18](=[O:20])[C:17]([F:21])=[CH:16][N:15]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3][CH2:4][O:5][C:14]1[NH:19][C:18](=[O:20])[C:17]([F:21])=[CH:16][N:15]=1
Reactant: O=c1[nH]c(Cl)ncc1F
Reactant: CC(C)=CCCC(C)=CCO
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC(C)=CCCC(C)=CCOc1ncc(F)c(=O)[nH]1
Yield: 61 %

Procedure:
23.1 g of 3,7-dimethyl-2,6-octadien-1-ol and 3.4 g of metal sodium are added to 200 ml of absolute toluene, and the mixture is stirred at 40° to 50° C until the metal sodium has been completely dissolved. Subsequently 7.4 g of 2-chloro-5-fluoropyrimidin-4-one is added to the solution, and the mixture is refluxed for 8 hours. The solvent is distilled off from the resulting reaction mixture, 30 ml of water is added to the residue and the pH of the mixture is adjusted to 4-5 with dilute hydrochloric acid. The resulting mixture is extracted with 200 ml of chloroform and the extract is concentrated. Purification of the residue by silica gel column chromatography gives 8.3 g of slightly yellow oily 2-(3,7-dimethyl-2,6-octadien-1-oxy)-5-fluoropyrimidin-4-one in a yield of 61.0 %.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1C(OC)=O.CN1CCNCC1.CN1C(=O)CCC1.C(O[CH:28]=[C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])C>CC#N>[S:4]1[CH:5]=[CH:6][C:2]([NH:1][CH:28]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:3]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COC(=O)c1sccc1N
Agent: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: CCOC(=O)C(=CNc1ccsc1)C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of methyl 3-aminothiophene-2-carboxylate 1 (5.0 g, 32 mmol, 1.0 eq), N-methyl piperazine (6.5 g, 64 mmol, 2.0 eq) and NMP (30 mL) was heated to reflux for 16 hours. After the decarboxylation was complete, the reaction mixture was allowed to cool to room temperature and diethyl 2-(ethoxymethylene)-malonate (7.0 g, 32 mmol, 2.0 eq) was added. The reaction mixture was heated to reflux for 4 h. The product was purified using SiO2 column chromatography (Hex/EtOAc; 100:0 to 80:20%) to obtain a light yellow powder, 5.0 g (31%). LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 270.2, retention time 1.52 minutes. 1H NMR (DMSO-d6) δ: 10.80 (d, 1.0 H, J=13.87 Hz, NH), 8.30 (d, 1.0 H, J=13.94 Hz), 7.60 (dd, 1.0H, J=3.0 Hz, J′=2.0 Hz), 7.40 (dd, 1.0 H, J=1.5 Hz, J′=3.13 Hz), 7.28 (dd, 1.0 H, J=1.5 Hz, J′=5.2 Hz), 4.20 (q, 2H, J=7.0 Hz), 4.10 (q, 2H, J=7.0 Hz), 1.30 (m, 6H).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:13]([NH:15][C@H:16]([C:23]([NH:25][C@H:26](C=NNC(N)=O)[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:17][C:18]2[N:22]=[CH:21][NH:20][CH:19]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.C=O.[C:50](=[O:53])(O)[O-].[Na+]>CO>[C:1]1([CH2:11][CH:12]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:13]([NH:15][C@H:16]([C:23]([NH:25][C@H:26]([CH:50]=[O:53])[CH2:27][CH:28]([CH3:29])[CH3:30])=[O:24])[CH2:17][C:18]2[N:22]=[CH:21][NH:20][CH:19]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CCCCc1ccccc1)Cc1cccc2ccccc12
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@@H](C=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CCCCc1ccccc1)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.82 g of N-[2-(1-naphthylmethyl)-6-phenylhexanoyl]-L-histidyl-L-leucinal semicarbazone in 80 ml of methanol were added 29 ml of 1N-hydrochloric acid and 7.6 ml of a 37 wt% formaldehyde solution while ice-cooling under an argon atmosphere. The mixture was stirred for 1.5 hours at room temperature, and then a 5% aqueous sodium bicarbonate solution was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.55 g of N-[2-(1-naphthylmethyl)-6-phenylhexanoyl]-L-histidyl-L-leucinal as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[O:52]=[C:53]1[C:62]2[CH2:61][CH2:60][NH:59][CH2:58][C:57]=2[NH:56][C:55]2[CH:63]=[CH:64][CH:65]=[C:66]([C:67]([O:69][CH3:70])=[O:68])[C:54]1=2>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([N:59]1[CH2:58][C:57]2[NH:56][C:55]3[CH:63]=[CH:64][CH:65]=[C:66]([C:67]([O:69][CH3:70])=[O:68])[C:54]=3[C:53](=[O:52])[C:62]=2[CH2:61][CH2:60]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCNC3
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C(C)(C)NC(=O)OCc1ccccc1)C3
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.9 %

Procedure:
To a solution of 2-(((benzyloxy)carbonyl)amino)-2-methylpropanoic acid (385 mg, 1.62 mmol) in DMF (8.0 mL) were added HATU (1.1 g, 2.94 mmol), DIPEA (0.75 g, 5.87 mmol), and methyl 5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate hydrobromide (410 mg, 1.6 mmol). The mixture was then stirred at room temperature for 24 h. Then the reaction was quenched by water (20 mL). The mixture was extracted with THF/EtOAc (10 ml/60 ml) three times. The organic layers were combined, dried, concentrated, and chromatographed on silica gel using gradient eluant of 0-50% methanol in dichloromethane to give the desired compound as pale solid (114 mg, 14%). MS (ESI) m/e [M+1]+478.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)[C:2]#[CH:3].Br[C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1>C1COCC1.C(NC(C)C)(C)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:3]#[C:2][CH2:1][N:4]2[C:12]3[C:7](=[CH:8][C:9]([CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:10][CH:11]=3)[CH:6]=[CH:5]2)=[N:21][CH:22]=1
Reactant: C#CCn1ccc2cc(CN3CCCC3)ccc21
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Brc1ccc(C#CCn2ccc3cc(CN4CCCC4)ccc32)nc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Under an argon atmosphere 5 mg (0.03 mmol) CuI and 18 mg (0.03 mmol) Pd(PPh3)2Cl2 are added to a solution of 337 mg (1.41 mmol) 1-prop-2-ynyl-5-pyrrolidin-1-ylmethyl-1H-indole and 345 mg (1.41 mmol) 2,5-dibromo-pyridine in 50 mL THF and 0.4 mL diisopropylamine and the reaction mixture is stirred for 17 h at RT. The mixture is evaporated down i. vac., the residue is taken up in 30 mL EtOAc, the organic phase is washed with 30 mL water and 30 mL saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1.[CH3:15]I>CN(C=O)C>[Br:3][C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[N:11]([CH3:15])[C:6]=2[CH:5]=1
Reactant: CI
Reactant: O=C1COc2ccc(Br)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)COc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To sodium hydride (63 mg) in DMF (3 mL) under an atmosphere of nitrogen was added 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (0.3 g) and the mixture was stirred at room temperature for 1 h. Methyl iodide (0.123 mL) was added and the mixture was stirred overnight at room temperature. The mixture was poured onto ice/water and extracted into ethyl acetate (×2). The ethyl acetate was washed with water (×3), dried and the solvent was evaporated. The resulting material was purified by chromatography on silica eluting with 10% ethyl acetate/isohexane to afford the sub-titled compound (299 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[NH:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([C:20](O)=O)=[N:12]1.C(OCC)(=O)C>CCCCCC>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:20]([C:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[NH:11][N:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c1CCCC2
Reactant: Cc1cc(N)c(N)cc1C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2nc(-c3n[nH]c4c3CCCC4)[nH]c2cc1C
Reaction time: 0.03 h
Yield: 17 %

Procedure:
4,5-Dimethylbenzene-1,2-diamine (90 mg) and 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [110 mg, Reference Example 17(a)] were mixed in a glass vial then subjected to microwave radiation (900 W, domestic oven) twice for two minutes. The resulting solid was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (85:15, v/v) to give 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-indazole (30 mg) as a pale brown solid. LC-MS (METHOD B): RT=2.28 minutes; 267 (M+H)+. (b) 2-(5-Isopropyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16]>CN(C)C=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: ClCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a suspension of sodium hydride (50% in oil, 3.9 g, 82 mmol) in dimethylformamide (100 ml) was added p-hydroxybenzaldehyde (5.0 g, 41 mmol). The mixture was stirred at room temperature under an atmosphere of nitrogen for one hour, then treated dropwise with 1-bromo-3-chloropropane (8.1 ml, 82 mmol). The mixture was stirred at room temperature for 12 hours, quenched with methanol and filtered through Celite. The filtrate was dissolved in diethyl ether (500 ml), washed with water (3×200 ml) and dried over Na2SO4. The ether layer was concentrated to give 6.1 g (80% yield) of 4-chloropropoxybenzaldehyde as a yellow liquid. 1H NMR (CDCl3): δ 9.95 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.01 (d, J=8.1 Hz, 2H), 4.21 (t, J=5 Hz, 2H), 3.81 (t, J=5 Hz, 2H), 1.26 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH:21](=[C:16]1/[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14](=[O:19])[NH:15]/1)\[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N/C(=C\c3ccccc3)C2=O)cn1
Yield: 47.6 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (275 mg, 1 mmol), benzaldehyde (140 mg, 1.3 mmol), and sodium acetate (205 mg, 2.5 mmol), in glacial acetic acid (3 mL) were irradiated in the microwave reactor for 7 hours at 185° C. Upon cooling the mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3×, 50 mL). The combined organic extracts were washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate, filtered and concentrated. the solid product was triturated with ethyl acetate/hexanes (1/1) and dried under high vacuum to afford (Z)-5-benzylidene-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (173 mg, 48%) as a light yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ 2.14 (s, 3H), 2.40 (s, 3H), 6.59 (s, 1H), 5.20 (s, 2H), 7.33-7.40 (m, 3H), 7.66 (s, 2H), 7.81 (s, 1H), 8.21 (s, 1H), 11.01 (bs, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.34 μM.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.O.Cl>CS(C)=O>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC1
Yield: 49.2 %

Procedure:
A suspension of 0.47 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 0.6 g of 1-methylpiperazine in 7 cm3 of dimethyl sulphoxide is heated at a temperature close to 80° C. for 15 minutes. The reaction mixture is poured into 25 cm3 of water and 9 cm3 of N hydrochloric acid are added. The solid obtained is drained and washed with 3 times 5 cm3 of water. After recrystallizing once from a mixture of 4.5 cm3 of ethanol and of 4.5 cm3 of dimethylformamide, 0.29 g of 1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 250° C..
Reaction SMILES: C([N:8]1[CH2:20][CH2:19][C:11]2([O:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]([CH3:18])[O:12]2)[C@H:10]([CH3:21])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH3:17][C@H:15]1[CH2:14][C@H:13]([CH3:18])[O:12][C:11]2([CH2:19][CH2:20][NH:8][CH2:9][C@H:10]2[CH3:21])[O:16]1
Reactant: C[C@@H]1CN(Cc2ccccc2)CCC12O[C@@H](C)C[C@H](C)O2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNCCC12O[C@@H](C)C[C@H](C)O2
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of (2S,4S,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane from Example 1A (20.30 g, 70.20 mmol) in methanol (300 mL) was added palladium hydroxide (0.986 g, 7.02 mmol) and the mixture stirred under 60 psi pressure of hydrogen. After 4 hours, the mixture was filtered and concentrated to provide 13.71 g (98%) of the title compound as an oil. 1H NMR (300 MHz, CDCl3) δ 4.06-3.97 (m, 2H), 2.94 (dd, 1H, J=12.7, 4.0 Hz), 2.87 (dd, 2H, J=5.2, 5.2 Hz), 2.66 (dd, 1H, J=12.7, 5.6 Hz), 1.92-1.85 (m, 1H), 1.82-1.73 (m, 1H), 1.63-1.53 (m, 4H), 1.20 (d, 3H, J=6.4 Hz), 1.19 (d, 3H, J=6.4 Hz), 0.96 (d, 3H, J=7.1 Hz); MS (DCI/NH3) m/e 200 (M+H)+.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH3:7][O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][C:19]2[CH:28]=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)[CH2:13][CH2:12]1)=[O:10].CI>CN(C)C=O>[CH3:7][O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([N:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)[CH3:1])[CH2:13][CH2:12]1)=[O:10]
Reactant: COC(=O)[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](N(C)Cc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium tert-butylate (35 mg, 0.31 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylic acid methyl ester (100 mg, 0.31 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by methyl iodide (10 μL, 0.16 mmol, 0.5 eq). After 15 hours stirring at room temperature methyl iodide (10 μL, 0.16 mmol, 0.5 eq) is added again. After 4 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×5 mL) and water (5 mL). The combined organic layers are washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated to afford trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-cyclohexanecarboxylic acid methyl ester as a brown oil (1.60 g, 98% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[O:10][C:9]=2[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]2[CH:45]=1>O>[N:38]1[C:37]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12](=[O:13])[C:11]([CH3:14])([CH3:15])[O:10][C:9]=3[C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)=[CH:6][CH:7]=2)=[CH:45][N:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(O)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(OCc3cn4ccccc4n3)cc2)C1=O
Temperature: 80 °C
Yield: 60.2 %

Procedure:
4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydro furan-2-yl)benzonitrile (3.15 g, 10.3 mmol) was added to a mixture of cesium carbonate (13.4 g, 41.3 mmol) and DMF (100 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)imidazo[1,2-a]pyridine (2.0 g, 12.3 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (2.7 g, 60%) as an off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.15 (s, 2H), 1.25 (s, 6H). MS: [M+H]+: m/z=436.2. HPLC: (97.3%, Condition-A).