Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16]>>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:28]([NH:27][C:19]1[C:18]([CH:15]([CH3:16])[CH3:17])=[CH:23][CH:22]=[CH:21][C:20]=1[CH:24]([CH3:26])[CH3:25])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: c1ccc(CNc2ccccc2)cc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccccc1)c1ccccc1

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzylphenylamine (1.3 g) and 2,6-diisopropylphenyl isocyanate (1.7 mL) as starting materials, N-benzyl-N′-(2,6-diisopropylphenyl)-N-phenylurea (1.8 g) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.BrCC1CCCCO1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]1([C:34]3=[CH:35][C:36]4[O:40][CH2:39][O:38][C:37]=4[CH:41]=[C:33]3[O:32][CH2:31]1)[C:24](=[O:30])[NH:25]2>>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]1([C:34]3=[CH:35][C:36]4[O:40][CH2:39][O:38][C:37]=4[CH:41]=[C:33]3[O:32][CH2:31]1)[C:24](=[O:30])[N:25]2[CH2:2][C:3]1[O:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Cl)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-bromomethyl-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-chloro-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (43%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.36 (dd, J=8.0, 8.0 Hz, 1H), 7.20-7.18 (m, 2H), 7.08 (dd, J=0.7 Hz, 8.0 Hz, 1H), 6.77 (d, J=3.4 Hz, 1H), 6.66 (s, 1H), 6.12 (s, 1H), 5.94 (s, 2H), 5.09 (ABq, 2H), 4.92 (d, J=9.8 Hz, 1H), 4.75 (d, J=9.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 176.1, 156.1, 152.7, 148.6, 143.4, 141.5, 139.5 (q, 2JCF=42 Hz), 130.5, 129.7, 127.9, 123.6, 118.8 (q, 1JCF=267 Hz), 116.6, 114.0 (d, 3JCF=3 Hz), 109.9, 108.2, 102.2, 101.4, 92.9, 76.9, 57.9, 36.7; MS (ES+) m/z 464.3 (M+1), 466.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=O)[CH:11]=[N:12][CH:13]=2)[CH2:4][CH2:3]1.C(C1NC=CN=1)(C1[NH:21]C=CN=1)=O.[NH4+].[OH-]>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([NH2:21])=[O:17])[CH:11]=[N:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CN1CCN(c2cncc(CC(=O)O)c2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN1CCN(c2cncc(CC(N)=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[5-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-acetic acid (1.57 g, 5.78 mmol) and carbonyl diimidazole (1.03 g, 6.36 mmol) are dissolved under an atmosphere of argon in DMF (16 ml). After stirring at RT for 1 h, aqueous NH4OH (25%, 16 ml) is added, and stirring at RT is continued for 15 minutes. TLC analysis indicated complete consumption of starting material. The aqueous layer is saturated with NaCl and extracted repeatedly with CH2Cl2. The organic layers are dried over Na2SO4 and concentrated. Purification by FCC (CH2Cl2:MeOH 95:5 to 90:10 to 80:20 to 70:30 to 50:50 to 25:75 to 0:100) yields the title compound. 1H NMR (d6-DMSO 400 MHz): δ 2.76 (s, 3H), 3.12-3.42 (m, 8H), 3.34 (s, 2H), 6.86-6.96 (br s, 1H), 7.26 (s, 1H), 7.93 (s, 1H), 8.21 (s, 1H). ES+−MS: 235.4 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([NH:19]C(=O)OC(C)(C)C)=[C:12]3[C:16]=2[CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:3]1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[NH2:19][C:11]1[CH:10]=[CH:9][C:8]([CH:4]2[CH2:3][CH:2]([OH:1])[CH:6]([OH:7])[CH2:5]2)=[C:16]2[C:12]=1[C:13](=[O:18])[N:14]([CH3:17])[CH2:15]2
Reactant: CN1Cc2c(C3CC(O)C(O)C3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1Cc2c(C3CC(O)C(O)C3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [7-(3,4-dihydroxycyclopentyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]carbamate (Compound 243B, 36 mg, 0.099 mmol) in DCM (2 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 30 min, then evaporated under reduced pressure to give the desired product. This TFA salt was directly used in next step. MS (ES+): m/z=263.09 [MH+]. HPLC: tR=0.78 min (ZQ3, polar—5 min).
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])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Br.Br[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.O.C(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])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: BrCc1ccncc1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3ccncc3)c2cc1OC
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (197 mg, 899 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (1.20 mL, 2.40 mmol) at RT followed by 4-(bromomethyl)pyridine hydrobromide (250 mg, 988 μmol) and the mixture was stirred at 110° C. for 15 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (5 mL) before extraction with CH2Cl2 (50 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 90:10) gave 70 mg of 6,7-dimethoxy-1-methyl-4-(pyridin-4-ylmethyl)isoquinolin-3-ol as a yellow solid. This free base was dissolved in MeOH (5 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.15 M HCl solution in MeOH (7 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(pyridin-4-ylmethyl)isoquinolin-3-ol hydrochloride 11 as a yellow solid (78 mg, 25% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([C:13]([NH2:15])=[O:14])[CH2:9]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:16][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([C:13]([NH2:15])=[O:14])[CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)C1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cncc(Cl)c2N2CCC(C(N)=O)C2)cc1

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)pyrrolidine-3-carboxamide E21 (23 mg, 0.088 mmol), 4-methoxybenzene boronic acid (13 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to give impure title compound as a white solid (15 mg). Further purification by preparative hplc (H2O, MeCN, gradient 90:10 to 10:90 over 30 min) furnished the title compound as a white solid, LC-MS (ESI, 3.5 min) Rt 1.40 min, m/z 332 (100%, [M+H]+); m/z (ESI, 3.5 min) C17H18ClN3NaO2 requires 354.0980 found [M+Na]+ 354.0980
Reaction SMILES: [CH3:1][C:2]([N+:20]([O-:22])=[O:21])([CH3:19])[CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12](C=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)(Cl)Cl>[CH3:1][C:2]([N+:20]([O-:22])=[O:21])([CH3:19])[CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([OH:28])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(Cc1ccc(Oc2ccc(C=O)cc2)cc1)[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: CC(C)(Cc1ccc(Oc2ccc(O)cc2)cc1)[N+](=O)[O-]
Reaction time: 1 h

Procedure:
4-(4-(2-Methyl-2-nitropropyl)phenoxy)benzaldehyde (6.00 g, 20 mmol) was dissolved in chloroform (500 mL). m-Chloroperoxy-benzoic acid (10.0 g, 58 mmol) was added in small portions at RT. After stirring for 1 hour, the mixture was concentrated in vacuo and MeOH (300 mL) added followed by the dropwise addition of conc. HCl (5 mL). This mixture was stirred for 3 hours at RT and then concentrated in vacuo. Chromatography over silica gel (MeOH/CHCl3) allowed for the isolation of 3.20 g (55%) of the desired product. MS(FD+): 287.2
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:20][CH2:19][CH2:18][CH2:17][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCCCN1CCCC1
Product: Brc1cnc2ccc(NCCCN3CCCC3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-(pyrrolidin-1-yl)propan-1-amine according to general procedure 1 providing the intermediate (227 mg, 81%) as a clear oil; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J=9.6 Hz, 1H), 7.44 (s, 1H), 6.40 (brs, 1H), 6.35 (d, J=9.6 Hz, 1H), 3.52 (quart, J=5.2 Hz, 2H), 2.67 (t, J=6.2 Hz, 2H), 2.57-2.54 (m, 4H), 1.86 (quin, J=6.3 Hz, 2H), 1.84-1.78 (m, 4H); ES-MS: (M+H)=324, 326 m/z.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:9]\[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:33]=[C:32](OC/C=C(/C2C=CC(C#CCN3CCOCC3)=CC=2)\C2C=CC=CC=2)[CH:31]=[CH:30][C:24]=1[O:25][CH2:26][C:27]([OH:29])=[O:28].[C:59]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)=[CH:9]\[CH2:10][O:11][C:32]2[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([O:29][CH3:59])=[O:28])=[C:23]([CH3:22])[CH:33]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(OC/C=C(\c2ccccc2)c2ccc(C#CCN3CCOCC3)cc2)ccc1OCC(=O)O
Reactant: OC/C=C(\c1ccc(I)cc1)c1cccc(C(F)(F)F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
The above allyl alcohol (2.0 g, 4.94 mmol), methyl (4-hydroxy-2-methylphenoxy)-acetate (1.08 g, 5.54 mmol; example 2) and triphenylphosphine (1.50 g, 6.02 mmol) were dissolved in a mixture of anhydrous toluene (40 mL) and tetrahydrofuran (20 mL). The mixture was cooled to 0° C., kept under argon and a degassed solution of diisopropyl azodicarboxylate (1.15 mL, 5.82 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise during 10 min. The reaction mixture was allowed to warm up to ambient temperature with the bath and then was stirred for 20 h. The solvents were evaporated in vacuo and the residue was submitted to flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 9:1) affording methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methyl-phenoxy]acetate as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:18]([CH2:25][CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:32]1C=CC=CC=1>>[CH3:32][C:23]1[CH:24]=[C:19]([N:18]([CH2:16][CH3:17])[CH2:25][CH3:26])[CH:20]=[CH:21][C:22]=1[C:11]([C:6]1[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: CCN(CC)c1ccccc1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(C)c1
Temperature: 75 °C

Procedure:
A mixture of tetrachlorophthalic anhydride (42.8 g.), N,N-diethylaniline (74 g.), aluminum chloride (60 g.) and chlorobenzene (180 ml.) was heated (to 75° C.) during one and one-half hours, then diluted with ice-water (500 ml.). The chlorobenzene layer was separated and steam distilled. Addition of sodium hydroxide solution (50%) to a solution of the residue in dilute sulfuric acid (50%, 250 ml.) afforded 2-(4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (IV: Y2 =H, Y'4 =(CH3CH2)2N, Z4 =Z"5 =Z"6 =Z7 =Cl) (59 g., m.p. 228°-233° C.).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11]>C1(C)C=CC=CC=1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:11]
Reactant: CCCCCCO
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCOCC(OCC)OCC
Temperature: 25 °C
Yield: 44.3 %

Procedure:
2--Hexyloxyacetaldehyde diethylacetal was prepared as follows: Hexanol (200 g, 1.96 mol) and toluene (600 ml) were added to a 3 liter flask fitted with a mechanical stirrer and a reflux condenser. Sodium hydride (51.6 g, 2.15 mol) was added slowly to the resulting mixture, and then bromoacetaldehyde diethylacetal (385.7 g, 1.96 mol) was added dropwise. The mixture was heated to reflux temperature and maintained at that temperature for 6 hours. The mixture was then cooled to ambient temperature and was filtered to remove the resulting solids. Toluene was removed from the filtrate under reduced pressure, and the resulting product was distilled (85-88° C.) to give 189.4 g of 2-hexyloxyacetaldehyde diethylacetal.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([N:16]([CH3:18])[CH3:17])([C:14]#N)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(Cl)(Cl)Cl.[NH4+].[Cl-].[CH2:27]1[CH2:31]OC[CH2:28]1>>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][CH2:28][CH2:27][CH3:31])([N:16]([CH3:17])[CH3:18])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CN(C)C1(C#N)CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCC1(N(C)C)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53 %

Procedure:
A little iodine was added to a mixture of 17.7 g (6 eq) magnesium and 50 ml dry ether, followed over a period of 1 h by 100 g (6 eq) bromobutane dissolved in 100 ml dry ether. This reaction mixture was stirred for 1 h at room temperature. The Grignard reagent produced in the preceding step was added over a period of 20 min to a solution of 30 g (1 eq) 1-benzyl-4-(dimethylamino)piperidine-4-carbonitrile dissolved in 210 ml dry THF and the reaction mixture obtained was then stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the reaction solution was cooled to 0° C., mixed with saturated NH4Cl solution, filtered over celite, extracted with ethyl acetate (3×200 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (aluminium oxide neutral; hexane). 18.2 g (53%) of product were obtained in the form of an oil.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[CH3:43][NH:44][C:45]([C:47]1[NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[CH:55][C:49]=2[N:48]=1)=[O:46]>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]3[C:27]=2[CH2:26][N:48]2[C:49]3[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=3[N:51]=[C:47]2[C:45]([NH:44][CH3:43])=[O:46])=[CH:37][CH:38]=1
Reactant: CNC(=O)c1nc2ccccc2[nH]1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: CNC(=O)c1nc2ccccc2n1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and N-methyl-1H-benzo[d]imidazole-2-carboxamide. M/e+ 416 for C23H19ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.40 (d, J=6.9 Hz, 1H), 7.90 (d, J=4.7 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.62 (dd, J=13.1, 8.0 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.18 (dd, J=8.4, 1.1 Hz, 2H), 6.98 (m, 1H), 6.73 (m, 1H), 6.67 (s, 2H) 3.12 (d, J=5.1 Hz, 3H) 1.83 (s, 1H) ppm.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:13][C:14]([NH2:16])=[S:15].CCCCCC>CN(C=O)C.C(OCC)(=O)C>[C:6]1([C:5]#[C:4][C:3]2[N:13]=[C:14]([NH2:16])[S:15][CH:2]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(C#Cc1ccccc1)CCl
Reactant: NC(N)=S
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc(C#Cc2ccccc2)cs1
Temperature: 25 °C
Reaction time: 120 h
Yield: 20.4 %

Procedure:
1-Chloro-4-phenyl-3-butyn-2-one (245 mg, 1.37 mmol) was dissolved in DMF (1.0 mL), thiourea (126 mg, 1.66 mmol) was added, and the resulting pale brown solution was stirred at ambient temperature for 5 days. The reaction mixture was diluted with Ethyl acetate (50 mL), washed with saturated NaHCO3 solution (10 mL), water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The dark oil was dissolved in methanol, adsorbed onto silica gel and purified by column chromatography eluting with 4:1, 3:1, then 2:1 hexane:ethyl acetate to afford 4-(phenylethynyl)-1,3-thiazol-2-amine (56 mg, 20% yield) as an oil. 1H NMR (CDCl3, 300 MHz) δ 7.53–7.50 (m, 2H), 7.37–7.32 (m, 3H), 6.77 (s, 1H), 5.41 (br s, 2H). MS (EI ionization) 200 (M+).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13].O>C1(C)C=CC=CC=1>[CH:1](=[N:13]/[C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[O:10][CH3:9])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1N
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1/N=C/c1ccccc1
Yield: 99.8 %

Procedure:
To benzaldehyde (26.1 g, 25.0 mL, 0.246 mol, 1.21 equiv) in toluene (100 mL) was added 2-methoxyaniline (25.1 g, 23.0 mL, 0.204 mol, 1.00 equiv). The reaction mixture was heated to reflux with azeotropic removal of water with a Dean-Stark trap for 12 h. The reaction mixture was concentrated and dried under high vacuum to afford (E)-N-benzylidene-2-methoxyaniline as a yellow oil (43.0 g, >99% yield).
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.[CH2:21](Br)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[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]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[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: BrCCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccccc3)C2=O)cn1
Yield: 37 %

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 phenethylbromide. Yield: 37%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.83 (t, J=6.4 Hz, 2H), 3.55 (t, J=7.4 Hz, 2H), 4.03 (s, 2H), 5.17 (s, 2H), 7.18-7.30 (m, 5H), 7.73 (s, 1H), 8.13 (s, 1H). MS M+H calculated 380.2; found 380.1. Melting point: 95-96° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[N:8][C:7]([OH:10])=[N:6]1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:18]Cl>C(O)C>[CH2:1]([N:5]1[C:9]([Cl:18])=[N:8][C:7]([OH:10])=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: ClCl
Reactant: CC(C)Cn1cnc(O)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)Cn1nc(O)nc1Cl
Temperature: 25 °C

Procedure:
241 g of 1-isobutyl-3-hydroxy-1,2,4-triazole and 475 ml of triethylamine are dissolved in 2100 ml of absolute ethanol, and 182 g of chlorine are passed in while cooling at 20°-30°C. The solution is stirred for 1 1/4 hours at room temperature, after which the triethylamine hydrochloride is filtered off. The filtrate is concentrated in a rotary evaporator, the residue dissolved in 1000 ml of ether and 1000 ml of water are added. The phases are separated and the aqueous phase is extracted 3 times with 300 ml of ether each time. The ether phase is dried and concentrated. The residue is recrystallised from ligroin/xylene. Yield: 104.7 g (34 % of theory); m.p. 84°-86°C.
Reaction SMILES: [I:1][C:2](=[CH:4][CH2:5][C@@H:6]([O:16][Si](CC)(CC)CC)[C:7]([CH3:15])=[CH:8][C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[CH3:3]>C(O)(=O)C.C1COCC1.O>[OH:16][C@@H:6]([C:7]([CH3:15])=[CH:8][C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[CH2:5][CH:4]=[C:2]([I:1])[CH3:3]
Reactant: CC[Si](CC)(CC)O[C@H](CC=C(C)I)C(C)=Cc1csc(C)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(I)=CC[C@@H](O)C(C)=Cc1csc(C)n1

Procedure:
A solution of (5R)-2-iodo-6-methyl-7-(2-methylthiazol-4-yl)-5-(triethylsilyloxy)-2,6-heptadiene (2.28 g) in 50 mL of 3:1:1 acetic acid/THF/water is stirred at ambient temperature for 8 hoursours, then concentrated. The residue is dissolved in ethyl acetate, washed sequentially with sat. NaHCO3 and brine, then dried over MgSO4, filtered, and evaporated. The product is purified by SiO2 chromatography (30% ethyl acetate/hexanes).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].N1C=CC=CC=1.Cl[C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:22]>ClCCl>[OH:13][C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:10][CH:11]=[CH:12][C:2]=1[NH:1][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:22]
Reactant: O=C(Cl)C1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)c1cccc(N)c1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)C2CCCN2C(=O)OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a stirred solution of ethyl 3-amino-2-hydroxybenzoate (0.601 g, 3.6 mmol) and pyridine (0.633 g, 8 mmol) in anhydrous dichloromethane (20 mL) was added dropwise a solution of benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate (1.12 g, 4 mmol) in anhydrous dichloromethane (5 mL). After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water (30 mL×3), 1N hydrochloric acid (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give benzyl 2-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)pyrrolidine-1-carboxylate (1.43 g). LC-MS (ESI) m/z: 399 (M+1)+.