Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:26]([O-])([OH:28])=[O:27].N([O-])=O.[Na+].O>C(O)(=O)C>[C:7]1([C:6]2[C:5]3[CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:4]=3[O:3][C:2]=2[N+:26]([O-:28])=[O:27])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c(Br)oc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
A solution of 6 g. (0.018 mole) of the product of step E in hot acetic acid is treated with 6 ml. of 70 percent nitric acid while the solution is maintained at about 80° C. Sodium nitrite (2.7 g., 2 equivalents) is added gradually, and the mixture is heated on a steam bath for 45 minutes. The mixture is then poured into 500 ml. of water. The solid is filtered, recrystallized twice from acetone,, then from an ethyl acetate-hexane mixture to provide yellow crystals of 3,5-diphenyl-2-nitrobenzofuran-7-carboxylic acid, m.p. 207°-209° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH:13]12[CH2:19][CH:16]([CH:17]=[CH:18]1)[CH2:15][CH:14]2[CH2:20][OH:21].[I:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[I:22][C:23]1[CH:28]=[CH:27][C:26]([O:21][CH2:20][CH:14]2[CH2:15][CH:16]3[CH2:19][CH:13]2[CH:18]=[CH:17]3)=[CH:25][CH:24]=1
Reactant: Oc1ccc(I)cc1
Reactant: OCC1CC2C=CC1C2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1ccc(OCC2CC3C=CC2C3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
Diethylazodicarboxylate (8.7 g) was added dropwise to a solution of 5-norbornene-2-methanol (6.2 g, 0.05 mol), 4-iodophenol (11.0 g, 0.05 mol) and triphenylphosphine (13.1 g, 0.05 mol) in 100 mL of anhydrous tetrahydrofuran. After completion of the addition, the resulting solution was stirred for 18 h at room temperature. The solvent was removed under reduced pressure and the oily residue was extracted three times with hot hexane. Combined hexane extracts were evaporated under reduced pressure to give 8 (15.0 g, 97%) as a colorless oil.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][N:6]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[O:9])[CH2:5]1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH:17]1([N:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([N:6]3[CH2:5][CH:4]([NH2:1])[CH2:7]3)=[O:9])[CH2:11][CH2:12]2)[CH2:20][CH2:19][CH2:18]1
Reactant: [N-]=[N+]=NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Reaction time: 16 h
Yield: 40.4 %

Procedure:
1-[(3-azidoazetidin-1-yl)carbonyl]-4-cyclobutyl-1,4-diazepane (140 mg, 0.50 mmol), was dissolved in THF (5 ml) and water (0.28 ml, 5 mmol) was added. PPh3 was then added as a solid and the reaction was stirred for 16 hours giving a clear solution. The reaction was concentrated in vacuo and purified by FCC (DCM/MeOH/MH3 gradient, 95:5:1 to 70:30:1) to provide the title compound as pale yellow solid (51 mg, 40%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:23])/[CH:20]=[CH:21]/[CH3:22])=[CH:12][CH:11]=1.CC(C)([O-])C.[K+].O1CCCC1>C(O)(C)(C)C.Cl>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][N:18]2[C:19](=[O:23])[CH2:20][C@@H:21]([CH3:22])[C@H:3]([C:1]#[N:2])[C:4]2=[O:6])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC#N
Reactant: C/C=C/C(=O)NCCc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C[C@@H]1CC(=O)N(CCc2ccc(F)cc2)C(=O)[C@H]1C#N
Temperature: 80 °C
Yield: 93.5 %

Procedure:
A solution of ethyl cyanoacetate (4.26 mL, 40 mmol) and trans-2-butenoic acid [2-(4-fluoro-phenyl)ethyl]amide (4.15 g, 20 mmol) in tert-butanol (60 mL) was treated with a solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 40 mL, 40 mmol) and the mixture was heated at 80° C. The mixture was cooled to room temperature after 16.5 hours and diluted with 1.0 N aqueous hydrochloric acid. The mixture was concentrated under vacuum to remove the organic solvents, providing a suspension of solid in the aqueous residue. This was collected by filtration, dried, and purified by recrystallization from 95% ethanol to provide a white solid (5.13 g, 93%). 1H NMR (300 MHz, CDCl3) δ7.19 (m, 2H), 7.00 (t, J=9 Hz, 2H), 4.02 (m, 2H), 3.41 (d, J=11 Hz, 1H), 2.91 (m, 1H), 2.83 (t, J=8 Hz, 2H), 2.5-2.3 (m, 2H), 1.31 (d, J=6 Hz, 3H). Mass spec (CI) m/z 275.0 (M+H+, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]2[N:7]3[CH:25]=[CH:24][CH:23]=[C:8]3[C:9]3([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[O:10][C:5]=2[CH:4]=1)#[N:2].O1CCOCC1>Cl>[NH:13]1[CH2:14][CH2:15][C:9]2([O:10][C:5]3[CH:4]=[C:3]([C:1]#[N:2])[CH:27]=[CH:26][C:6]=3[N:7]3[CH:25]=[CH:24][CH:23]=[C:8]23)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C#N)ccc1-n1cccc12
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Yield: 107 %

Procedure:
A solution of tert-butyl 7′-cyanospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (1.1 g, 3.1 mmol) in HCl in dioxane (3.1 mL of 4.0 M, 12 mmol) was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness to yield spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carbonitrile (880 mg, 94%). ESI-MS m/z calc. 265.3. found 266.1 (M+1)+. Retention time: 0.92 minutes (3 min run).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22](O)=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O(CC)CC.O.[CH3:31][CH2:32][CH2:33][CH2:34]CC>>[C:1]1([NH:7][C:8]2([C:22](=[O:23])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CCCCC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
To a stirred and cooled (-5° C) suspension of 16.2 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid in 525 parts of dry 1,1'-oxybisethane, are added dropwise 228.5 parts of 1-lithiumbutane solution 20% in hexane at 0° C. Upon completion, stirring is continued for 3 hours at 0° C. The reaction mixture is decomposed by addition of 300 parts of water. The organic phase is separated, washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 2.5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oil residue is dissolved in 2,2'-oxybispropane and the solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from petroleum-ether, yielding 1-[4-(phenylamino)-1-(2-phenylethyl)-4-piperidinyl]-1-pentanone; mp. 71.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:8]=3[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:8]=3[CH:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)C(c1ccncc1)=Nc1cc(Cl)ccc1O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)C(c1ccncc1)Nc1cc(Cl)ccc1O2

Procedure:
A 5.0 g. portion of 8-Chloro-2-methoxy-11-(4-pyridyl)-dibenz[b,f][1,4]oxazepine (Example 1) is added to 2.5 g. of lithium aluminum hydride in 200 ml. of ether. The mixture is stirred and heated under reflux for 4 hours. Water is added dropwise to decompose the excess lithium aluminum hydride. The ether is decanted and the residue is extracted with methylene chloride which is then combined with the ether, dried and evaporated. The residue is crystallized from acetone-hexane giving 8-chloro-10,11-dihydro-2-methoxy-11-(4-pyridyl)-dibenz[b,f][1,4]oxazepine, m.p. 186°-188° C.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[N:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][C:8]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:9][CH:10]=3)[C:5]([CH3:35])([CH3:34])[C:4]=2[CH:3]=1.[CH2:36](O)[CH3:37].C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.CO>[C:8]1([C:37]2[CH:36]=[CH:33][CH:28]=[CH:29][CH:30]=2)[CH:9]=[CH:10][C:11]([N:12]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)[C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]4[N:12]([C:11]5[CH:10]=[CH:9][C:8]([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=6)=[CH:7][CH:6]=5)[C:13]5[C:4](=[CH:3][C:2]([C:15]6[CH:2]=[CH:3][CH:4]=[CH:13][CH:14]=6)=[CH:15][CH:14]=5)[C:5]([CH3:34])([CH3:35])[C:17]=4[CH:18]=3)=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC1(C)c2cc(Br)ccc2N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc21
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: CO
Solvent: Cc1ccccc1
Product: CC1(C)c2cc(-c3ccccc3)ccc2N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccc(N(c4ccc(-c5ccccc5)cc4)c4ccc(-c5ccccc5)cc4)cc3)cc21
Temperature: 72 °C
Reaction time: 8.5 h
Yield: 75 %

Procedure:
2-Bromo-10-(biphenyl-4-yl)-9,9-dimethyl-7-phenylacridan (2.5 g), bis(biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboran-2-yl)phenyl]amine (3.0 g), toluene (37 ml), ethanol (9.3 ml), and a 2M potassium carbonate aqueous solution (7.2 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (0.11 g) and stirred at 72° C. for 8.5 hours. The mixture was allowed to cool to a room temperature, and methanol (40 ml) was added. A precipitated solid was collected by filtration and washed with water to obtain an orange crude product. The crude product was dissolved by adding toluene (360 ml), purified by adsorption using silica gel (3.6 g), and crystallized with toluene/methanol three times. Further, methanol (60 ml) was added to the product, and the product was washed and purified by heating under reflux to obtain a white powder of bis(biphenyl-4-yl)-[4-{10-(biphenyl-4-yl)-9,9-dimethyl-7-phenylacridan-2-yl}phenyl]amine (3.04 g; yield 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@H:10]([CH2:48][O:49][CH2:50][C@H:51](O)[CH2:52][O:53]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>N1C=CC=CC=1.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:48][O:49][CH2:50][C@H:51]2[CH2:52][O:53]2)[C@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](COC[C@H](O)COS(=O)(=O)c3ccc(C)cc3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](COC[C@H]3CO3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1

Procedure:
In analogy to the procedure described in example 1) (h)-(I), (R)-3-[(3S,4R,5R)-4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol was treated with di-tert-butyl-dicarbonate in dioxane/water in the presence of sodium hydrogencarbonate to yield the (3S,4R,5R))-3-[(2R)-2,3-dihydroxy-propoxymethyl]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester. Subsequent mono-tosylation of the aforementioned diol by toluene-4-sulfochloride in pyridine led to the (3S,4R,5R)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonyloxy)-propoxymethyl]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester which after treatment with NaOH in DMSO yielded the (3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester. Further reaction of the epoxide with sodium methylate in a mixture of N,N-dimethylformamide and methanol gave the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxymethyl]-4-{4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl}-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester which was finally deprotected by treatment with hydrochloric acid in methanol to yield the (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propan-2-ol as a colorless foam; MS: 660 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CCN(CC)CC.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH2:26]([N:13]1[CH2:12][CH2:11][CH:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([Br:1])[CH:17]=[CH:16][C:5]=3[N:6]=2)[CH2:15][CH2:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc2nc(OC3CCN(Cc4ccccc4)CC3)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of Compound 1B (4.32 g, 13.79 mmol) in THF (100 mL) was added Et3N (3.84 mL, 27.6 mmol) followed by (bromomethyl)benzene (1.64 mL, 13.8 mmol). Upon completion of addition, the reaction mixture was stirred at rt overnight. After this time, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL), and then extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (40 mL) and dried (MgSO4). The solvent was removed and the resulting residue was recrystallized from MeOH to give Compound 14A as a white solid (2.12 g, 5.26 mmol, 38% yield). LC/MS (m/z)=404 (M+H)+.
Reaction SMILES: COC(=O)[CH2:4][N:5]([S:29]([C:32]1[CH:37]=[CH:36][C:35]([O:38]CC2C=CC=CC=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH:6]([C:20]12[O:27][CH2:26][C:23]([CH3:28])([CH2:24][O:25]1)[CH2:22][O:21]2)[CH:7]([NH:9][C:10]([O:12]CC1C=CC=CC=1)=O)[CH3:8].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[OH:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([N:5]2[CH:6]([C:20]34[O:27][CH2:26][C:23]([CH3:28])([CH2:22][O:21]3)[CH2:24][O:25]4)[CH:7]([CH3:8])[NH:9][C:10](=[O:12])[CH2:4]2)(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: [H][H]
Reactant: COC(=O)CN(C(C(C)NC(=O)OCc1ccccc1)C12OCC(C)(CO1)CO2)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1NC(=O)CN(S(=O)(=O)c2ccc(O)cc2)C1C12OCC(C)(CO1)CO2
Yield: 75.3 %

Procedure:
A solution of {(4-benzyloxy-benzenesulfonyl)-[2-benzyloxycarbonylamino-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-propyl]-amino}-acetic acid methyl ester (compound of formula LIII, 1.3 g, 2.0 mmol) in 75 ml of ethanol was treated with triethylamine (0.28 ml, 0.20 g, 2.0 mmol) and 0.2 g of 10% palladium on carbon. After stirring for about 2 hours under 1 atmosphere of hydrogen, the mixture was filtered through a pad of Celite® and concentrated in vacuo. The residue was dissolved in 10 ml of toluene, diluted with 3 ml of methanol and was refluxed for about 1.5 hours. Concentration of the mixture in vacuo afforded 0.6 g of 4-(4-hydroxy-benzenesulfonyl)-6-methyl-5-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazin-2-one (compound of formula LIV). A compound of the formula LI can be converted to a compound of the formula LIII by the method of Step 42 that, in turn, can be converted to a compound of Formula I according to the procedure of Step 43.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[C:12]([N:29]=[C:30]=[S:31])([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:5][C:4]1[S:31][C:30]([NH:29][C:12]([O:14][CH2:15][CH:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:13])=[N:2][C:3]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: N#CC(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1sc(NC(=O)OCC2c3ccccc3-c3ccccc32)nc1-c1ccccc1
Reaction time: 3 h
Yield: 48 %

Procedure:
A suspension of α-aminophenylacetonitrile hydrochloride (3.19 g, 18.9 mmol) and Fmoc-isothiocyanate (5.31 g, 18.9 mmol) in DCM was treated with ethyldiisopropylamine (3.62 ml, 20.8 mmol) at 0° C. for 1 hr and then at ambient temperature for 3 hr. The mixture was poured into saturated aqueous sodium bicarbonate and extracted three times into ethyl acetate. The combined organic phases were washed with water and brine, and dried over sodium sulfate and concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded 5-amino-2-(Fmoc-amino)-4-phenylthiazole (3.75 g, 48%).
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.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25]Br>>[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][N:15]([CH2:25][CH2:24][C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[F:21])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Fc1ccccc1CCBr
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccccc3F)C2=O)cn1
Yield: 24 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 2-fluorophenethyl bromide. Yield: 24%. MS M+H calculated 398.16. found 398.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH:17]([F:19])[F:18])[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:5]=[C:6]([N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=[C:9]3[CH:17]([F:18])[F:19])[N:7]=2)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNCC1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of 6-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-1,3,5-triazine (3.66 g, 10 mmol), 1-acetylpiperazine (1.40 g, 11 mmol), potassium carbonate (1.38 g, 10 mmol) and DMF (30 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by silica gel column to obtain 4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine (4.08 g, 9.0 mmol) in a yield of 90% as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:8](=[O:12])[N:7]=[CH:6][NH:5][C:4]=2[CH:3]=1.[CH3:13][O-:14].[Na+].CO.[Cl-].[NH4+]>>[CH3:13][O:14][C:2]1[CH:11]=[N:10][C:9]2[C:8](=[O:12])[N:7]=[CH:6][NH:5][C:4]=2[CH:3]=1
Reactant: C[O-]
Reactant: O=c1nc[nH]c2cc(Cl)cnc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2c(=O)nc[nH]c2c1

Procedure:
A microwave vial was charged with 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one (110 mg, 0.606 mmol), a 0.5 M solution of sodium methoxide in methanol (3.65 mL, 1.817 mmol) and sodium methoxide (327 mg, 6.06 mmol). The vial was capped and irradiated in a microwave reactor at 145° C. for 30 minutes. The reaction was neutralized with saturated aqueous ammonium chloride (3 mL), concentrated, and diluted with cold water. The resulting precipitate was collected by vacuum filtration and dried in vacuo to provide the title compound (107 mg, 0.604 mmol) as pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.95 (s, 3H) 7.49 (d, J=2.74 Hz, 1H) 8.11 (s, 1H) 8.47 (d, J=2.74 Hz, 1H). LC/MS (ESI+) m/z=178 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[S:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])C.[OH-].[K+]>CO>[CH2:11]([CH:5]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:4]([OH:3])=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=S)C(Cc1ccccc1)CC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CC(Cc1ccccc1)C(O)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
400 mg of 2-benzyl-3-tert.-butylthio-propionic acid ethyl ester was dissolved in 1.5 ml of methanol and then reacted with 5 ml of 2N potassium hydroxide solution. The mixture was stirred at room temperature overnight and concentrated by evaporation. The residue was diluted with water and washed with ether. The aqueous layer was acidified to pH 3 with 2N HCl, and then evaporated to give the title compound (280 mg, 78% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N2CCCCC2)ncn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 85 mg of piperidine was added therein, and the mixture was stirred for 5 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 178 mg of 4-(2-butynyloxy)-6-piperidinopyrimidine (hereinafter, referred to as Compound (16)).