Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][N:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:26])[CH:16]=1)[CH2:10][C:11](OC)=[O:12])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-].CO.CC(C)=O>C1COCC1.C1CCCCC1.[OH-].[Na+]>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][N:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[C:17]([Cl:26])[CH:16]=1)[CH2:10][CH2:11][OH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(CCC(=O)OC(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CCN(CCO)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
A solution of 3.00 g (7.3 mmol) of 3-[(3-chloro-4-trifluoromethoxy-phenyl)-methoxycarbonylmethyl-amino]-propionic acid tert-butyl ester in 20 ml of THF was treated with 4.44 ml (8.9 mmol) of LiBH4 (2 M in THF) and 0.59 ml (14.6 mmol) of MeOH (with cooling bath at RT). The reaction was stirred for 2 h at RT, cooled to 0° C. and stopped with 2 ml of acetone. The reaction was diluted with 4.5 ml of cyclohexane, 18 ml of aqueous 2 N NaOH were added and after 30 min extracted with EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give after flash silica gel column (EtOAc:n-heptane 1:4 to 1:1) 2.21 g (78%) of the titled compound as light yellow oil. MS: 384.12 (MH+, Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.C1C(=O)N([I:19])C(=O)C1>CC#N>[Cl:1][C:2]1[C:7]([I:19])=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: COc1cc(Cl)nc(SC)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1nc(SC)nc(Cl)c1I
Temperature: 25 °C

Procedure:
Compound 2 (10 g, 52.5 mmol) was dissolved in MeCN (150 mL) and NIS (14.2 g, 62.9 mmol) was added. The solution was heated to reflux for 5 h and cooled to room temperature. The solvent was evaporated and the residue was dissolved in EtOAc. The organics were washed with sat. NaHCO3 and sat. NaS2O3, dried (MgSO4), filtered and concentrated to give the title compound as a white solid. 1H NMR (CDCl3) δ 4.04 (s, 3H), 2.54 (s, 3H); LCMS 2.64 min, 317 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH:20]([C:24]1[S:28][C:27]([SH:29])=[N:26][CH:25]=1)([CH2:22][CH3:23])[CH3:21].C([O-])([O-])=O.[K+].[K+]>>[CH:20]([C:24]1[S:28][C:27]([S:29][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[CH:7][C:8](=[O:12])[O:9]3)=[CH:4][CH:3]=2)=[N:26][CH:25]=1)([CH2:22][CH3:23])[CH3:21]
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccc(Br)cc2o1
Reactant: CCC(C)c1cnc(S)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(C)c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1

Procedure:
Employing the procedure described in Example 1, Step 3, but using 7-bromo-4-(4-fluorophenyl)-2H-chromen-2-one, 5-sec-butyl-1,3-thiazole-2-thiol and K2CO3, the title compound was obtained. 1H NMR (400 MHz, acetone-d6): δ 7.58-7.67 (m, 3H), 7.52 (d, 1H), 7.46 (d, 1H), 7.32-7.42 (m, 3H), 6.38 (s, 1H), 3.08 (sextet, 1H), 1.83-1.67 (m, 2H), 1.32 (d, 3H), 0.89 (t, 3H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:23]=[CH:24][C:25]=3[O:26][CH:27]([CH3:29])[CH3:28])[CH2:14][CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:30]I>C1COCC1>[C:1]12([C:11]3[CH:12]=[C:13]([CH:23]=[CH:24][C:25]=3[O:26][CH:27]([CH3:29])[CH3:28])[CH2:14][CH2:15][N:16]([CH3:30])[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(C)Oc1ccc(CCNC(=O)C(F)(F)F)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CI
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(CCN(C)C(=O)C(F)(F)F)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of the product of Step D (0.25 g, 0.61 mmol) in anhydrous THF (5 ml) 60% NaH in mineral oil (0.03 g, 0.75 mmol) was added at 0° C. and the mixture was stirred for 2 h. To it MeI (0.23 ml) was added and the resulting mixture was stirred for additional 3 h. The mixture was passed trough Celite bead and washed with CH2Cl2 (10 ml). The combined filtrates were evaporated to dryness to give the title product (0.22 g; 85.3%). 1H-NMR (CDCl3) 1.36 (d, 6H, J=6 Hz); 1.75 (s, 6H); 2.04 (s, 3H); 2.09 (s, 6H); 2.8 (tr, 2H, J=7.7 Hz); 2.96 (s, 3H); 3.59 (tr, 2H, J=6.02 Hz); 4.58-4.63 (m, 1H); 6.76 (d, 1H, J=8.32 Hz); 6.91-7.01 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][CH:30]([F:40])[O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[O:31][CH:30]([F:29])[F:40])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccccc1OC(F)F
Product: FC(F)Oc1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-difluoromethoxy-benzaldehyde. MS (ESI) m/z 535.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:55]([Si:59]([CH2:72][O:73][C:74]1([CH2:77]O)[CH2:76][CH2:75]1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([CH3:58])([CH3:57])[CH3:56]>O1CCCC1>[Si:59]([CH2:72][O:73][C:74]1([CH2:77][O:1][C:2]2[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=2[C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH2:76][CH2:75]1)([C:55]([CH3:58])([CH3:56])[CH3:57])([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: CC(C)(C)[Si](COC1(CO)CC1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(OC[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-(2-hydroxy-3,4-dimethoxy-phenyl)-indan-1-one (Compound 303) (5 g, 17.60 mmol) in tetrahydrofuran (50 mL), were added triphenylphosphine (9.2 g, 35.21 mmol) and diisopropylazodicarboxylate (7.11 g, 35.21 mmol) and {1-[(tert-Butyl-diphenyl-silanyl)-methoxy]-cyclopropyl}-methanol (7.18 g, 21.12 mmol) and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded 4-(2-((1-((tert-butyldiphenylsilyl)methoxy)cyclopropyl)methoxy)-3,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one as a liquid.
Reaction SMILES: FC(F)(F)C([O-])=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][CH2:20]/[C:19](=[CH:23]\[C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[C:33]([CH3:35])[N+:32]([CH2:36][O:37][P:38]([OH:41])([OH:40])=[O:39])=[CH:31]4)=[C:26]([O:42][CH3:43])[CH:25]=3)/[C:18]2=[O:44])[CH3:16])=[CH:11][CH:10]=1.O>C(#N)C>[P:38]([O-:40])([O:37][CH2:36][N+:32]1[C:33]([CH3:35])=[CH:34][N:30]([C:27]2[CH:28]=[CH:29][C:24](/[CH:23]=[C:19]3/[C:18](=[O:44])[N:17]([C@H:15]([C:12]4[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=4)[CH3:16])[CH2:22][CH2:21][CH2:20]/3)=[CH:25][C:26]=2[O:42][CH3:43])[CH:31]=1)([OH:41])=[O:39]
Reactant: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cc(C)[n+](COP(=O)(O)O)c1
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cc(C)[n+](COP(=O)([O-])O)c1
Yield: 90.7 %

Procedure:
An aqueous solution (4 mL) of 3-{4-{1-[(S)-1-(4-fluorophenyl)ethyl]-2-oxopiperidin-(3E)-ylidenemethyl}-2-methoxyphenyl}-5-methyl-1-(phosphonooxymethyl)-3H-imidazol-1-ium trifluoroacetate (150 mg) obtained in Example 1 was subjected to reversed phase C18 silica gel column chromatography (developing solvent: 100% water to 35% acetonitrile aqueous solution). The objective fraction was concentrated and then lyophilized to give 112 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH2:16][CH2:15][CH:14]([CH2:17]O)[CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:17][CH:14]2[CH2:15][CH2:16][O:12][CH2:13]2)=[C:4]([Cl:11])[N:3]=1
Reactant: OCC1CCOC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(CC3CCOC3)c2n1
Yield: 142.6 %

Procedure:
2,6-Dichloropurine (21 g, 113 mmol) and (tetrahydrofuran-3-yl)methanol (11.5 g, 113 mmol) were dissolved in tetrahydrofuran (250 ml) followed by the dropwise addition of triphenylphosphine (33 g, 125 mmol) and a diisopropyl azodicarboxylate (24.5 ml, 125 mmol)-tetrahydrofuran (50 ml) solution with ice cooling and the resulting mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure and then the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1 to 1:1 to 0:1) to give the title compound (44 g) as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[N:4][C:3]1=2.[CH3:16][N:17]([CH3:22])[CH2:18][CH:19](O)[CH3:20]>>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15][CH:19]([CH3:20])[CH2:18][N:17]([CH3:22])[CH3:16])=[O:14])[CH:5]=[N:4][C:3]1=2
Reactant: O=C(O)CCn1cnc2c(=O)[nH]cnc21
Reactant: CC(O)CN(C)C
Product: CC(CN(C)C)OC(=O)CCn1cnc2c(=O)[nH]cnc21

Procedure:
3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, compd with 1-(dimethylamino)-2-propanol (1:1)
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:31]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1)C1C=CC=CC=1>[Pd]>[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:31]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1
Reactant: Cn1c(=O)c2c(nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n2Cc2ccccc2)c2ccccc21
Agent: [Pd]
Product: Cn1c(=O)c2c(nc(C3CCCC(N)C3)n2Cc2ccccc2)c2ccccc21
Yield: 86.2 %

Procedure:
As described in example 3F, [3-(3-benzyl-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (70 mg, 0.135 mmol) was hydrogenated over 10% Pd/C (70 mg, 0.066 mmol) to give 2-(3-amino-cyclohexyl)-3-benzyl-5-methyl-3,5-dihydro-imidazo[4,5-c]quinolin-4-one (45 mg, 87% yield). The HCl salt was prepared by treating the amine in EtOAc with ethereal HCl (0.3 mL). 1H-NMR (CD3OD): δ 8.53 (d, 1H,J=8.0 Hz), 7.78 (m, 2H), 7.53 (m, 1H), 7.36 (m, 5H), 6.38 (m, 1H), 6.13 (m, 1H), 3.84 (s, 3H), 3.53 (m, 1H), 3.34 (m, 1H), 2.17 (m, 2H), 1.94 (m, 2H), 1.79 (m, 2H), 1.58 (m, 2H). MS: calculated for C24H26N4O+H 387.2; found: 387.3.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]12[C:25]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:24]3[C:23](=[O:30])[O:22][C:20](=[O:21])[C:19]1=[CH:31][CH:32]=[CH:33][CH:34]=2>C1(C)C=CC=CC=1>[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:18]3[C:19]([C:20]([OH:22])=[O:21])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:30])[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1oc(=O)c2ccccc2c2ccccc12
Reactant: NCCCN1CCC(c2ccccc2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1-c1ccccc1C(=O)NCCCN1CCC(c2ccccc2)CC1
Reaction time: 8 h

Procedure:
4-Phenyl-1-piperidinepropanamine, hydrochloride (prepared in part A) (16.33 g, 53.5 mM) and diphenic anhydride (12.0 g, 53.5 mM) are refluxed in toluene for 2 hours. The mixture is allowed to stand overnight at room temperature during which time product crystallizes out. The crystals are filtered off, washed with toluene, recrystallized from ethanol, and dried at 80° to give the title compound.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9](O)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.S(Cl)([Cl:16])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([Cl:16])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCN(C2CCCCC2)C1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: ClC1CCN(C2CCCCC2)C1

Procedure:
To a stirred solution of 169 g. of N-cyclohexyl-3-pyrrolidinol in 600 ml. of chloroform, acidified with gaseous hydrogen chloride, is added 130 g. of thionyl chloride. This solution is refluxed for four hours, then poured onto ice water and made basic with sodium carbonate. The organic layer is dried over sodium sulfate, concentrated, and the residue distilled in vacuo to give N-cyclohexyl-3-chloropyrrolidine.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[N:16]=[C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:12][C:13]1[N:14]=[C:15]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:16]=[C:17]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=[C:3]2[S:2][CH3:1])[N:18]=1
Reactant: CSc1nc2ccccc2[nH]1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of 2-(methylsulfanyl)-1H-benzimidazole (1.64 g, 10 mmol), 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine (2.35 g, 10 mmol), and powdered K2CO3 (11 g, 80 mmol) in DMF (50 mL) was stirred at room temperature for 1 hr. The mixture was diluted with water and the resulting precipitate was collected, washed with water and then ethanol, and dried to give 3.56 g (98% yield) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(methylsulfanyl)-1H-benzimidazole: mp (CHCl3/EtOH) 260-261° C.; 1H NMR (CDCl3) δ 8.42 (br dd, J=7.0, 1.9 Hz, 1H), 7.65 (br dd, J=6.8, 1.9 Hz, 1H), 7.30 (m, 2H), 4.06 (m, 2H), 3.95 (m, 2H), 3.84 (m, 2H), 3.80 (m, 2H), 2.74 (s, 3H); Anal. Calcd. for C1sH15ClN6OS: C, 49.65; H, 4.2; N, 23.2. Found: C, 49.8; H, 4.1; N, 23.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]([O:37][CH3:38])[CH2:35][CH3:36])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([O:37][CH3:38])[CH2:35][CH3:36])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CCC(COS(=O)(=O)C(F)(F)F)OC
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: CCC(CC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O)OC

Procedure:
1.00 g (2.67 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 2.94 ml (2.94 mmol, 1.1 eq.) of bis(trimethylsilyl)lithium amide (1M in tetrahydrofuran) and 945 mg (4.00 mmol, 1.5 eq.) of 2-methoxybutyl trifluoromethanesulphonate (racemate) were reacted according to General Method 7B. Yield: 669 mg (54% of theory)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:17]([O:19]CC3C=CC([N+]([O-])=O)=CC=3)=[O:18])=[CH:14][CH2:15][S:16][C@H:11]12)=[O:8].CO.O1CCCC1.Cl>[Pd].O.C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Yield: 92.1 %

Procedure:
To a mixture of p-nitrobenzyl 7-(2-thienyl)acetamido-3-cephem-4-carboxylate (2.0 g), methanol (40 ml), and tetrahydrofuran (40 ml) one adds 10% hydrochloric acid (1.4 ml) and 5% palladium on carbon (1.9 g), shakes the mixture under hydrogen atmosphere (1 atm.) at room temperature for 2.5 hours, pours into water, extracts with methylene chloride, washes with water, dries, concentrates, and crystallizes from ether to give 7-(2-thienyl)acetamido-3-cephem-4-carboxylic acid (1.30 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[F:15][C:16]([F:43])([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:15][C:16]([F:43])([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:41])([F:40])[F:42])=[CH:31][CH:30]=1)[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:8][CH2:7][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=2)=[O:26])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2.33 g (11.8 mmol) of 3,5-dinitrobenzylalcohol, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-dimethylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloro-methane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yields 6.9 g of 3,5-dinitrobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[N:10]=[CH:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](Cl)=[O:25])=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:24]([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)=[O:25])[N:10]=[CH:9]2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cnc(N)c1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1Cn1cnc(NC(=O)c2ccc3c(c2)OCO3)c1
Yield: 16.5 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-amine (example 10-40a) (110 mg, 0.57 mmol), benzo[d][1,3]dioxole-5-carbonyl chloride (105 mg, 0.57 mmol), and triethylamine (90 μL, 0.69 mmol) in dichloromethane was stirred for 16 hours. The reaction was diluted with dichloromethane (30 mL) and washed consecutively with brine and water. The organics were dried over sodium sulfate and concentrated by rotary evaporation. The crude product was purified by reverse phase HPLC (Solvent system: acetonitrile/water, 10% to 100% gradient, 25 minute run) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-yl)benzo[d][1,3]dioxole-5-carboxamide as a white crystalline solid (32 mg, 15% yield). MS M+H calculated 341.3, found 341.3. 1H NMR (400 MHz, DMSO-d6): δ 2.08 (s, 3H), 2.41 (s, 3H), 5.02 (s, 2H), 6.07 (s, 2H), 6.95 (d, J=8.4 Hz, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.54 (m, 3H), 10.6 (s, 1H). The compound had an IC50 on hT2R8 bitter receptor of 12.1 μM.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:3]=1.C(N(CC)CC)C.[CH:29]1([C:34]2[CH:35]=[C:36]3[N:41]([C:42]=2[C:43](=[O:47])[C:44](Cl)=[O:45])[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[CH:29]1([C:34]2[CH:35]=[C:36]3[N:41]([C:42]=2[C:43](=[O:47])[C:44]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]4[CH2:13][CH2:14][N:9]([C:4]5[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=2)=[O:45])[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Reactant: O=C(Cl)C(=O)c1c(C2CCCC2)cc2n1CCCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(N2CCN(c3ccc(NC(=O)C(=O)c4c(C5CCCC5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
A solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (prepared as described in Reference Example 94; 0.20 g, 0.71 mmol) and triethylamine (0.3 mL, 2.1 mmol) in THF (5 mL) was cooled to 0° C. A solution of (2-cyclopentyl-5,6,7,8-tetrahydro-indolizin-3-yl)-oxo-acetyl chloride (prepared as described in Reference Example 22, 0.24 g, 0.85 mmol) in THF (2 mL) was added and the mixture stirred under N2 atmosphere at 0° C. for 1 h and then at room temperature for 1 h. The mixture was quenched with sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (60-120 mesh) eluting with 12% ethyl acetate/chloroform to afford 2-(2-cyclopentyl-5,6,7,8-tetrahydro-indolizin-3-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide (0.17 g, 46%) as a solid.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[C:5]([NH2:8])[C:4](Cl)=[N:3][CH:2]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.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>[NH2:8][C:5]1[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][CH:2]=[CH:1][C:6]=1[Cl:7]
Reactant: OB(O)c1ccccc1
Reactant: Nc1c(Cl)ccnc1Cl
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+]
Product: Nc1c(Cl)ccnc1-c1ccccc1

Procedure:
3-Amino-2-4-dichloropyridine d (0.7047 g, 4.32 mmol), phenylboronic acid (0.5177 g, 4.24 mmol), K2CO3 (0.8023 g, 5.80 mmol), and Pd(PPh3)4 (0.0702 g, 0.0607 mmol) were combined. The sample was evacuated and purged with nitrogen three times. Dry DMF (2 mL) and deoxygenated H2O (0.4 mL) were added. The sample was microwaved at 130° C. for 40 minutes. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3×50 mL). The EtOAc extracts was dried over MgSO4 and filtered. The crude material was adsorbed onto silica gel and purified by flash chromatography (40 g SiO2, 0-30% EtOAc in hexanes) to give 3-amino-4-chloro-2-phenylpyridine e (0.435 g, 2.12 mmol, 49%).