Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14](Cl)(Cl)=[O:15].C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([N:6]=[C:14]=[O:15])=[C:4]([F:13])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(N=C=O)c(F)cc1Cl

Procedure:
A solution of 4-chloro-2-fluoro-5-isopropoxyaniline (30 g) in toluene (100 ml) was aded to a 1 mol/l phosgene/toluene solution (500 ml) at room temperature (ca. 20° C.), followed by heating under reflux for 2 hours. The mixture was concentrated under reduced pressure and the residue was distilled to give 26 g of 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate as pale yellow crystals. M.P., 36°-37° C. B.P., 90°-91° C./3 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:30][C@H:31]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:32][C:33](O)=[O:34])(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(Cl)CCl.CI>>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:33](=[O:34])[CH2:32][C@H:31]([O:30][C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Solvent: CI
Solvent: ClCCCl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Yield: 94.1 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (0.212 g, 1.08 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (0.541 g, 1.19 mmol) in the presence of EDC·MeI (0.353 g, 1.19 mmol) to give 0.642 g (94%) of N-[(R)-3-tetradecanoyloxytetradecanoyl]-L-serine benzyl ester as a waxy solid: mp 56-61° C.; 1H NMR (CDCl3) δ 0.88 (t, 6H, J=˜7 Hz), 1.1-1.7 (m, 42H), 2.29 (t, 2H, J=7.5 Hz), 2.50 (m, 2H), 3.87 (br t, 1H), 3.95 (m, 2H), 4.65 (m, 1H), 5.1-5.25 (m, 3H), 6.69 (d, 1H, J=7 Hz), 7.34 (br s, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].I[CH3:20].O>CN(C)C=O>[F:17][C:14]([F:15])([F:16])[C:13]([NH:12][CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][CH3:20])[CH:3]=1)=[O:18]
Reactant: CI
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(CCNC(=O)C(F)(F)F)ccc1OC
Yield: 11 %

Procedure:
N-[2-(3-Amino-4-methoxyphenyl)ethyl]-2,2,2-trifluoro acetamide (26.2 g., 0.2 mole) and iodomethane (14.0 g., 6.2 ml., 0.2 mole) in dry dimethylformamide (500 ml) were stirred under nitrogen for 3 hr. The solution was poured into water and the suspension extracted with ethyl acetate. Evaporation of the extracts afforded an oil which was separated by high pressure liquid chromatography on silica using 1% methanol in dichloromethane as eluant. Evaporation of the fractions containing the major bond afforded the sub-title compound (6.1 g) as a white solid mp 65°-67°. The hydrochloride, prepared in the usual way, had mp 153°-155°.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.C(Cl)Cl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:2][C@@H:3]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:26])=[CH:28][CH:29]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)C[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Prepared using General Procedure 7. A solution of (S)-methyl 3-amino-4-(4-hydroxyphenyl)butanoate hydrochloride (2.1 g, 8.7 mmol), 4-(tert-butyl)benzoic acid (1.6 g, 9.0 mmol) and DIEA (3.5 ml, 18.8 mmol) in DMF (20 mL) and DCM (20 mL) was treated with HATU (3.3 g, 8.5 mmol). After 1 h, the mixture was poured onto 1M HCl (100 mL) and extracted with EA (3×50 mL). The combined organic extracts were washed successively with 1M HCl (50 mL), water (50 mL) and brine (20 mL), then dried over MgSO4 and concentrated. The resulting residue was purified by chromatography (EA/hexane) to provide 2.3 g (72%) of (S)-methyl 3-(4-(tert-butyl)benzamido)-4-(4-hydroxyphenyl)butanoate as white needles. LCMS-ESI (m/z) calculated for C22H27NO: 369.4. found 370.0 [M+H]+, tR=2.52 min (Method 6).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.CO>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccc(CBr)cc1Br
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(CBr)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
The compound of Step 1 (23.8 g, 81 mmol, 1 eq) was dissolved in THF under nitrogen at 0° C. A 1M borane solution in THF (242 ml, 242 mmol, 3 eq) was then added dropwise and the mixture was stirred at RT for 1 hour under nitrogen. The solution was cooled in an ice bath and 125 ml of methanol was then added slowly. The solvent was removed and the mixture partitioned between 400 ml of water and 400 ml of 20% THF/EtOAc. The aqueous layer was washed 3 times with 400 ml of 20% THF/EtOAc and the combined organic layers were dried with sodium sulfate. The solvent was removed and 19.7 g (87%) of the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1.[NH:21]([C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[S:24])[NH2:22].CN(C)C=O>Cl.O>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:22][NH:21][C:23]([NH:25][C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[S:24])[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 89.3 %

Procedure:
1-[5-(4-trifluoromethylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.1694 mmol, HPLC purity 80%, 60.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.1694 mmol, 35.8 mg) were stirred with dimethylformamide (3 mL) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. Chloroform/n-hexane was added to the resulting solid, and the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (72.2 mg, yield 89%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][C:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:33][C:28]4([CH2:27][O:26][CH3:25])[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCC1(N)CCCC1
Product: COCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CCCC1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(methoxymethyl)cyclopentanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.74 (m, 6H) 1.94-2.08 (m, 2 H) 2.37 (s, 3 H) 3.20 (s, 3 H) 3.54 (s, 2 H) 7.59 (dd, J=7.96, 1.39 Hz, 1H) 7.66 (s, 1 H) 7.70 (br. s., 1 H) 8.04 (s, 1 H) 8.06-8.18 (m, 1 H) 8.33 (d, J=6.57 Hz, 2 H) 8.75-8.86 (m, 1 H) 12.59-13.45 (m, 1 H). MS m/z [M+H]+ 432.2
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N.CO>[N:21]1([CH2:20][CH2:19][O:15][C:12]2[CH:11]=[CH:10][C:9]([B:4]([OH:3])[OH:5])=[CH:14][CH:13]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: ClCCN1CCCCC1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CO
Product: OB(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 180 °C
Yield: 96.3 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.120 g, 0.55 mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.100 g, 0.54 mmol), potassium carbonate (0.226 g, 1.64 mmol) and 18-crown-6 (0.072 g, 0.27 mmol) in MeCN (3 mL) was heated in the microwave at 180° C. for 10 minutes. The mixture was diluted with MeOH and a small amount of water and purified by SPE using a MP-TsOH resin (1000 mg) cartridge. The solvent was removed in vacuo to afford 4-(2-(piperidin-1-yl)ethoxy)phenylboronic acid (0.129 g, 0.52 mmol, 95%) which was used without further purification. LCMS (1) Rt: 1.55; m/z (ES+) 250.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[Cl:18][C:19]1[C:26]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:36][CH:35]=2)=[CH:25][CH:24]=[C:23]([Cl:47])[C:20]=1[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:18][C:19]1[C:26]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]2[CH:35]=[CH:36][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:38][CH:39]=2)=[CH:25][CH:24]=[C:23]([Cl:47])[C:20]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: Cc1cc(-n2ccnc2)c2cccc(O)c2n1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(-n5ccnc5)cc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
A suspension of 8-hydroxy-4-(imidazol-1-yl)-2-methylquinoline (23 mg), 2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyl bromide (52.4 mg) and potassium carbonate (42.3 mg) in N,N-dimethylformamide (0.5 ml) was stirred for 3 hours at ambient temperature. Water was added thereto, and the resulting precipitate was collected by filtration. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (60 mg) as colorless amorphous.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:16][C:17]1[CH:22]=[C:21]([CH2:23][CH2:24][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:20]=[N:19][CH:18]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cncc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cncc(F)c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 3-fluoro-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:21][CH2:22][C:23]23[CH2:32][CH:27]4[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]4)[CH2:24]2)[CH2:30]3)=[CH:6][C:7]([F:20])=[C:8]([CH:19]=1)[C:9]([NH:11][S:12]([N:15]1[CH2:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])=[O:10])(=[O:3])[CH3:2].[CH3:33][Mg]Br.Cl>O1CCCC1.C(OCC)(=O)C>[C:23]12([CH2:22][O:21][C:5]3[C:4]([C:1]([OH:3])([CH3:33])[CH3:2])=[CH:19][C:8]([C:9]([NH:11][S:12]([N:15]4[CH2:18][CH2:17][CH2:16]4)(=[O:14])=[O:13])=[O:10])=[C:7]([F:20])[CH:6]=3)[CH2:24][CH:25]3[CH2:26][CH:27]([CH2:28][CH:29]([CH2:31]3)[CH2:30]1)[CH2:32]2
Reactant: C[Mg]Br
Reactant: CC(=O)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a solution of 5-acetyl-4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluorobenzamide (0.200 g, 0.43 mmol) in anhydrous tetrahydrofuran (4 mL) was added methylmagnesium bromide (3.0 M solution in diethyl ether, 0.29 mL, 0.86 mmol) at −78° C. After 1 hour at −78° C., additional methylmagnesium bromide (3.0 M solution in diethyl ether, 0.29 mL, 0.86 mmol) was added; the reaction mixture was allowed to warm to ambient temperature, and stirred for 1 hour. After addition of 1 N hydrochloride acid (5 mL) and diluting the mixture with ethyl acetate (100 mL), the organic phase was washed with brine (5 mL) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave a residue which was purified by reverse-phase preparative HPLC to give the title compound as a colorless solid (0.101 g, 49%): 1H NMR (300 MHz, DMSO-d6) δ 11.63 (br s, 1H), 7.93 (d, J=9.0 Hz, 1H), 6.96 (d, J=13.0 Hz, 1H), 5.25 (s, 1H), 4.04 (t, J=7.6 Hz, 4H), 3.65 (s, 2H), 2.22-2.10 (m, 2H), 2.01 (br s, 3H), 1.79-1.61 (m, 12H), 1.51 (s, 6H); 19F NMR (282 MHz, DMSO-d6) δ −111.6 (s, 1F); MS (ES−) m/z 479.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].[CH2:9](O)[CH:10]=[CH2:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][CH2:11][CH:10]=[CH2:9]
Reactant: C=CCO
Reactant: Oc1cnccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOc1cnccc1Cl
Temperature: 0 °C
Yield: 32.6 %

Procedure:
A solution of diazenedicarboxylic acid diethyl ester (0.1572 mol) in THF (163 ml) was added dropwise to a mixture of 4-chloro-3-pyridinol (0.1429 mol), 2-propen-1-ol (0.1572 mol) and triphenyl-phosphine (0.1572 mol) in THF (276 ml), that was cooled with an ice-water bath and under nitrogen flow. The formed mixture was stirred on the ice-water bath for 15 minutes and at room temperature overnight. The mixture was concentrated under vacuum and the residue was washed with a saturated Na2CO3− solution. The mixture was extracted with DCM and the separated organic layer was dried, filtered and the solvent was evaporated until dry. The residue was treated with DIPE and the formed solid was filtered off and discarded. The filtrate was evaporated until dry and the residue was treated with diethyl ether and the formed solid was filtered off and discarded again. The filtrate was evaporated until dry and the residue was purified by open column chromatography over silica gel (eluent: DCM/2-propanone 99/1;98/2). The product fractions were collected and the solvent was evaporated, yielding 7.9 g of 4-chloro-3-(2-propenyloxy)-pyridine (intermediate (44).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:33])[CH:9]([NH:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:34](Cl)(=[O:36])[CH3:35].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:33])[CH:9]([N:21]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:34](=[O:36])[CH3:35])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)C(Cc1ccc(C(F)(F)F)cc1)NCc1cccc2ccccc12
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N(Cc1cccc2ccccc12)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-2-((1-naphthalenylmethyl)amino)-3-(4-(trifluoromethyl)phenyl)-1-propanol (100 mg, 0.22 mmol) in ethyl acetate (5 ml) were added acetyl chloride (225 ml, 3.3 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (45 mg, 41%).
Reaction SMILES: C1C=NC2N(O)N=NC=2C=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:13]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)CCl>C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][NH:18][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCCc1ccc(F)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCCc1ccc(F)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
1.5 g (10.8 mmol) of HOAt were added to a solution of 15.0 g (108.0 mmol) of 4-fluorophenethylamine and 13.2 g (108.0 mmol) of benzoic acid in DCM and the mixture was then cooled to 0° C. 22.8 g (119.0 mmol) of EDC were then added at this temperature and the mixture was then stirred for 16 h at RT. The reaction solution was then washed successively with a 1M aqueous hydrochloric acid (2×300 ml), a 2M aqueous NaOH solution (300 ml) and brine (200 ml). The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. 20.5 g (84.2 mmol, 78%) of N-(4-fluorophenethyl)benzamide were obtained as the residue.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[NH2:3].[C:12](OC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[Na].CO.C[O-].[Na+]>CO>[C:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N:2]1[C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[NH:3]1)#[N:7]
Reactant: N#Cc1ccccc1NN
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(=O)n(-c2ccccc2C#N)[nH]1
Yield: 70.3 %

Procedure:
8.5 g (0.05 mol) of 2-hydrazino benzonitrile hydrochloride, 6 g (0.05 mol) of methyl acetoacetate and 100 ml of methanol were added into a 250 ml reaction flask, and then 50% methanol sodium solution (5.5 g (0.051 mol) sodium methoxide dissolved in 50 ml methanol) was added under stirring. After stirring for 10 min, the mixture was heated and refluxed for 6 h, and immediately filtered. The solid was washed with 20 ml of methanol. The methanol was recovered until the remained volume was 50 ml. 200 ml of ice water was poured with stirring to give the solid. The solid was filtered and washed with water to give 7 g of light yellow solid.
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.Br[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[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]([CH2:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccc(C#N)cc3)C2=O)cn1
Yield: 21 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-(bromomethyl)benzonitrile. Yield 21%. MS M+H calculated 391.1; found 391.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.05 uM.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C([Si]([O:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH:53]2[CH2:55][O:54]2)=[CH:47][CH:46]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:54][C@@H:53]([CH2:55][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][N:14]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1)[CH2:52][O:51][C:48]1[CH:49]=[CH:50][C:45]([OH:44])=[CH:46][CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 26.9 %

Procedure:
N-[4-(2-Aminoethyl)phenyl]-1-[(4-methylphenyl)sulfonyl]-4 piperidinamine (0.275 g, 0.65 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.251 g, 0.62 mmol) according to Procedure G to give the title compound (0.130 g, 0.167 mmol).
Reaction SMILES: [CH:1]([PH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].CN([CH2:11][C-:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17]N(C)C)C.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]>C(O)(=O)C>[CH:1]([P:4]([CH2:11][C-:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][P:4]([CH:25]([CH3:24])[CH3:21])[CH:1]([CH3:3])[CH3:2])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: CC(C)PC(C)C
Reactant: CN(C)Cc1ccc[c-]1CN(C)C
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: CC(C)P(Cc1ccc[c-]1CP(C(C)C)C(C)C)C(C)C

Procedure:
The title compound was prepared in accordance with the procedure of Example 10 employing di-iso-propylphosphine (Digital Speciality Chemicals 392 mg, 3.33 mmol), 1,2-bis(dimethylaminomethyl)ferrocene (0.5 g, 1.66 mmol) and anhydrous acetic acid (100 ml). Yield 0.262 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH2:11])=[CH:4][C:3]=1[S:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15][C:14]=1[Cl:32].Cl[Sn]Cl>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:11])=[CH:4][C:3]=1[S:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29](=[O:31])[CH3:30])[CH2:27][CH2:28]2)=[O:22])=[CH:15][C:14]=1[Cl:32]
Reactant: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3cc(N)c([N+](=O)[O-])cc3Cl)c(Cl)c2)CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3cc(N)c(N)cc3Cl)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
To a stirred solution of nitrobenzene from Example 144A (170 mg, 0.34 mmol) in 2 mL of EtOH was added SnCl2 (325 mg, 1.72 mmol). The mixture was then refluxed under nitrogen atmosphere for 2 h. The reaction was allowed to cool down to ambient temperature, quenched with sat. NaHCO3, extracted with EtOAc(2×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo. The residue was then purified on Gilson preparative HPLC as described in Example 38B to give the title compound (70 mg, 44% yield) as a light yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.42-3.80 (m, 8H), 4.84 (s, 2H), 5.32 (s, 2H), 6.51 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 2H), 7.26 (d, J=15.6 Hz, 1H), 7.41 (d, J=15.6 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H). MS (APCI+) (M+H)+ at m/z 465, 467, 469, 471.