Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH3:12])([CH3:3])[CH3:2].[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:13][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9]=1[CH3:10]
Reactant: COc1cccc(C)c1C(C)C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COc1ccc(Br)c(C)c1C(C)C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 2-iso-propyl-3-methylanisole (0.44 g, 2.7 mmol) in CH2Cl2 at room temperature was added a solution of tetrabutylammonium tribromide (1.42 g, 2.94 mmol) in CH2Cl2. The reaction mixture was stirred for 2 h and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexanes to afford 4-bromo-2-iso-propyl-3-methylanisole as yellowish oil (0.60 g, 92%): 1H NMR (300 MHz, DMSO-d6): δ 7.37 (d, J=13.2 Hz, 1H), 6.78 (d, J=13.2 Hz, 1H), 3.74 (s, 3H), 3.38 (m, 1H), 2.38 (s, 3H), 1.25 (d, J=10.8 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (5:95); Rf=0.80.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].P(Br)(Br)[Br:12].CO.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: COc1ccccc1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccccc1CBr
Reaction time: 1.5 h
Yield: 137.2 %

Procedure:
To a solution of 1-hydroxymethyl-2-methoxybenzene (28.7 gram, 0.207 mol) in CH2Cl2 (574 ml) at 0° C. under nitrogen was added slowly PBr3 (13.66 ml, 0.145 mol). After stirring for an additional 1.5 hours, MeOH (13.66 ml) was added and stirred for 5 minutes. To this mixture was added dropwise 10% Na2CO3 (2 ml) solution and stirred for 5 minutes. The mixture was then washed with 10% Na2 CO3 (50 ml, 2×) and brine (100 ml). It was dried over MgSO4, and filtered. The filtrate was removed under vacuum to give an oil (40 gram) of 1-bromomethyl-2-methoxy-benzene. This material was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14](Cl)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:17][NH2:18]>>[CH3:17][NH:18][C:14](=[O:15])[CH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1
Reactant: COc1cc(CC(=O)Cl)cc(OC)c1OC
Reactant: CN
Product: CNC(=O)Cc1cc(OC)c(OC)c(OC)c1

Procedure:
In a manner similar to Preparation 16, react 3,4,5-trimethoxybenzeneacetyl chloride with methylamine to obtain the title compound.
Reaction SMILES: C(N(CC)CC)C.Br.[CH3:9][N:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C:11]1=[NH:16].[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[CH3:9][N:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C:11]1=[N:16][C:24]([NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[S:25]
Reactant: S=C=Nc1ccccc1
Reactant: CN1CCN(C)C1=N
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CCN(C)C1=NC(=S)Nc1ccccc1

Procedure:
30.4 g (0.3 mol) of triethylamine are added to a suspension of 58.2 g (0.3 mol) of 1,3-dimethyl-2-imino-imidazolidine hydrobromide in 470 ml of chloroform, at 5°, with stirring. A solution of 40.6 g (0.3 mol) of phenyl isothiocyanate in 235 ml of chloroform is then added dropwise and the reaction mixture is refluxed for 15 hours. After cooling, it is washed with water, dried over sodium sulfate and evaporated in vacuo. Crude N-(1,3-dimethyl-2-imidazolidinylidene)-N'-phenyl-thiourea is obtained and after recrystallisation from ethanol this melts at 195°-196°.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:12]([N:15]1[C@H:20]([CH3:21])[CH2:19][N:18]([C@H:22]([C:37]2[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=2)[C:40](Cl)=[O:41])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][Si](C(C)(C)C)(C)C)[CH:24]=2)[C@@H:17]([CH3:46])[CH2:16]1)[CH:13]=[CH2:14]>>[CH2:12]([N:15]1[C@H:20]([CH3:21])[CH2:19][N:18]([C@H:22]([C:37]2[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=2)[C:40]([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:41])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[C@@H:17]([CH3:46])[CH2:16]1)[CH:13]=[CH2:14]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Reactant: c1ccc(NCC2CC2)cc1
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(CC3CC3)c3ccccc3)c2)C[C@H]1C

Procedure:
N-(Cyclopropyl)methylaniline was coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(cyclopropyl)methyl-N-phenylbenzamide as an off-white powder. NMR (200 MHz, DMSO-d6): δ 0.09 (m, 2H); 0.39 (m, 2H); 0.92 (d, J=6.3 Hz, 3H); 0.96 (d, J=6.2 Hz, 3H); 1.28 (m, 1H); 1.69 (dd, J1 =7.4 Hz, J2 =11.5 Hz, 1H); 2.04 (dd, J1 =6.6 Hz, J2 =11.0 Hz, 1H); 2.30 (br d, J=12.1 Hz, 1H); 2.40-2.54 (m, 2H); 2.67 (br d, J=9.8 Hz, 1H); 2.85 (dd, J1 =7.4 Hz, J2 =13.7 Hz, 1H); 3.16 (dd, J1 =4.5 Hz, J2 =14.7 Hz, 1H); 3.72 (d, J=7.0 Hz, 2H); 4.77 (s, 1H); 5.12 (d, J=10.0 Hz, 1H); 5.18 (d, J=15.6 Hz, 1H); 5.70-5.85 (m, 1H); 6.44 (d, J=7.3 Hz, 1H); 6.57 (s, 1H); 6.65 (d, J=8.0 Hz, 1H); 7.02-7.33 (m, 10H); 9.33 (s, 1H). Mass spectrum (CI--CH4) m/e: 510 (M+1, 61%), 356 (42%), 153 (100%). [α]D20 =+8.9° (abs. ethanol, c=1.1). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.75 followed by precipitation with diethyl ether from dichloromethane to give the monohydrochloride salt as a hygroscopic off-white powder. Calc. for C33H39N3O2 HCl 1.25 H2O: C, 69.70; H, 7.53; N, 7.39; Cl, 6.23. Found: C, 69.82; H, 7.52; N, 7.36; Cl, 6.28.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:35]2[C:36]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:37][CH:38]=[CH:39][C:34]=2[CH3:33]
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3Br)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 572.0 (M+H)+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8][CH2:9][CH3:10])=[CH2:7])CCC.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([CH:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH3:28])[N:21]=1.[F-].[K+]>CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:20]1[N:25]=[C:24]([C:6]([O:8][CH2:9][CH3:10])=[CH2:7])[CH:23]=[C:22]([CH:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH3:28])[N:21]=1
Reactant: CC(OCC(F)(F)F)c1cc(Cl)nc(Cl)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(C(C)OCC(F)(F)F)nc(Cl)n1
Temperature: 80 °C

Procedure:
Tributyl(1-ethoxyvinyl)stannane (0.466 mL, 1.38 mmol) was added to a degased solution of 2,4-dichloro-6-(1-(2,2,2-trifluoroethoxy)ethyl)pyrimidine (0.379 g, 1.38 mmol) and bis(triphenylphosphine)palladium chloride (0.019 g, 0.03 mmol) in dimethylformamide (8 mL) under nitrogen. The mixture was heated at 80° C. for 1.5 h, then cooled and poured into solution of potassium fluoride (2 g) in water (40 mL). The mixture was extracted with MTBE (2×50 mL), the organic phase was washed with water (30 mL), dried over sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica eluting with dichloromethane to yield the title product, 350 mg (82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OCC)=O)[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC(N2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)CC1
Agent: Br
Product: Fc1ccc(Cn2c(NC3CCN(C4CCNCC4)CC3)nc3ccccc32)cc1
Yield: 50 %

Procedure:
A mixture of 21 parts of ethyl 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino][1,4'-bipiperidine]-1'-carboxylate and 450 parts of hydrobromic acid solution 48% was stirred and refluxed for 16 hours. The reaction mixture was evaporated. From the residue the free base was liberated in the conventional manner with sodium hydroxide in water and extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 8 parts (50%) of N-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2yl][1,4'-bipiperidine]-4-amine as a residue (intermediate 71).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:35]1[C:43]2[C:38](=[C:39](B3OC(C)(C)C(C)(C)O3)[C:40]([F:44])=[CH:41][CH:42]=2)[CH:37]=[CH:36]1)(C(C)(C)C)(C)C>>[F:44][C:40]1[C:39]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:38]2[C:43](=[CH:42][CH:41]=1)[NH:35][CH:36]=[CH:37]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(=O)N1CCC(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
1-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)ethanone (30 mg) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 13.7 mg of 148 following reverse phase HPLC purification. MS (Q1) 489.2 (M)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH2:9][CH2:10][CH2:11]1
Reactant: Oc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Agent: [Pd]
Solvent: CO
Product: Oc1ccc2c(c1)C(C1(c3ccccn3)CCC1)NCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-[1-(6-Chloropyridin-2-yl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (1.93 g, 6.17 mmol) were dissolved in methanol (100 ml) under an atmosphere of nitrogen. 10% Pd/C (0.19 g) were added and the reaction mixture stirred at room temperature under an atmosphere of hydrogen for 48 hours. The catalyst was removed by filtration and the solvent was evaporated in vacuo. The crude product was used without further purification for the next step. Yield: 1.75 g (5.52 mmol, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([CH2:20][NH2:21])=[CH:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([CH2:20][NH:21][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chloro-5-fluorophenyl)-quinolin-3-yl)methanamine (0.050 g, 0.156 mmol), 6-chloropurine (0.027 g, 0.17 mmol, 1.2 eq) and DIEA (0.70 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-(2-chloro-5-fluorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=71 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.30 (s, 1H), 8.20 (s, 1H), 7.80 (dd, J=7.58, 0.49 Hz, 2H), 7.69-7.75 (m, 1H), 7.42-7.47 (m, 1H), 7.31-7.37 (m, 1H), 7.11-7.16 (m, 1H), 6.99-7.06 (m, 1H), 4.90-497. (m, 2H), Mass Spectrum (ESI) m/e=440 (M+1)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH:22]3[CH2:23][CH2:24][CH:18]2[CH2:19][O:20][CH2:21]3)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH2:31][CH2:32][O:33][CH2:34][CH:35]=1)CCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:33]1[CH2:32][CH:31]=[C:30]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[N:5]=[C:4]([N:17]3[CH:18]4[CH2:24][CH2:23][CH:22]3[CH2:21][O:20][CH2:19]4)[CH:3]=2)[CH2:35][CH2:34]1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3C4CCC3COC4)n2)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nc(C3=CCOCC3)cc(N3C4CCC3COC4)n2)cc1
Temperature: 150 °C
Yield: 65.6 %

Procedure:
In a 20 mL microwave vial was placed 8-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (36, 500 mg, 1.442 mmol) in toluene (15 ml) to give a yellow suspension. The mixture was degassed with a stream of nitrogen and tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (646 mg, 1.730 mmol) and Pd(PPH3)4 (167 mg, 0.144 mmol) were added. The reaction mixture was heated under microwave irradiation at 150° C. for 1 hour. The mixture was concentrated and the crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (25-70%). Collected fractions were concentrated to give 373 mg of a yellow solid. HRMS: 395.1707 [M+H]+. For [M+H]+ mass error=−0.6 mDa or −1.51 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[F:20][C:21]([F:25])([F:24])[S:22]Cl.FC(F)(F)S(O)(=O)=O.ClCCCl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([S:22][C:21]([F:25])([F:24])[F:20])=[CH:11][C:12]=2[S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])=[CH:6][CH:7]=1
Reactant: FC(F)(F)SCl
Reactant: O=S(=O)(c1cc[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: O=S(=O)(c1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 70 °C
Yield: 72 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]pyrrole (2.47 g, 0.0080 mol), trifluoromethylsulfenyl chloride (2.18 g, 0.016 mol), trifluoromethanesulfonic acid (0.12 g, 0.0008 mol) and 1,2-dichloroethane (15 mL) is placed in a pressure tube, heated at 70° C. for five days, diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an amber syrup. Flash chromatography of the syrup using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as an off-white solid (2.36 g, mp 118°-122° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: Cl.Cl[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH3:10])[CH2:4]1.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:19]=1[CH2:20][N:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24](=[O:32])(=[O:31])[N:23](CCC2C(C)=NOC=2C)[C:22]1=[O:42]>CN(C=O)C>[F:17][C:18]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:19]=1[CH2:20][N:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24](=[O:32])(=[O:31])[N:23]([CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH3:10])[CH2:4]2)[C:22]1=[O:42]
Reactant: Cc1noc(C)c1CCN1C(=O)N(Cc2c(F)cccc2F)c2ccccc2S1(=O)=O
Reactant: CCN1CCCC(Cl)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC(N2C(=O)N(Cc3c(F)cccc3F)c3ccccc3S2(=O)=O)C1

Procedure:
The title compound (42 mg, 0.09 mmol) was prepared from (IntE3) (100 mg, 0.31 mmol), 3-chloro-1-ethylpiperidine hydrochloride (142 mg, 0.77 mmol), KI (10.2 mg, 0.06 mmol) and K2CO3 (107 mg, 0.77 mmol) in DMF (5 mL) in a CEM Discover microwave reactor (100° C., 1 h) using the methods of (120).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].N1C=CN=C1.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.O>[Si:11]([O:5][CH2:4][CH2:3][NH:2][CH3:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of N-methylethanolamine (600 mg), in N,N-dimethylformamide were added imidazole (1.13 g) and tert-butyldiphenylsilyl chloride (2.20 g) at ambient temperature with stirring. After 8 hours, the mixture was diluted with water (60 ml) and was extracted with ethyl acetate (20 ml) twice. The organic layer was washed with water three times and brine, dried over magnesium sulfate. The solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane-methanol to give N-(2-tert-butyldiphenylsilyloxyethyl)-N-methylamine (780 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[CH3:11][C:12](=O)[CH2:13][CH2:14][C:15](=O)[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:9][C:5]1[C:4]([CH3:10])=[N:3][C:2]([N:1]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:11])=[N:7][C:6]=1[CH3:8]
Reactant: Cc1nc(N)nc(C)c1Br
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(-n2c(C)ccc2C)nc(C)c1Br

Procedure:
To a stirred solution containing 2.00 g (9.89 mmol) of 2-amino-5-bromo-4,6-dimethylpyrimidine in 16 mL of anhydrous toluene was added 1.36 mL (11.5 mmol) of 2,5-hexanedione followed by 96 mg (0.50 mmol) of p-toluenesulfonic acid. The reaction mixture was heated and stirred at reflux for 12 h. The reaction mixture was poured into 150 mL of water and then extracted with 200 mL of ethyl acetate. The organic solution was washed with 150 mL of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 5:1 hexanes-ethyl acetate afforded the expected product as light yellow crystals: yield 2.23 g (81%); mp 64-65° C.; silica gel TLC Rf 0.65 (6:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 2.34 (s, 6H), 2.67 (s, 6H) and 5.89 (s, 2H); 13C NMR (CDCl3) δ 14.5, 14.5, 24.9, 24.9, 108.7, 108.7, 118.6, 129.5, 129.5, 155.3, 155.3 and 166.9; mass spectrum (APCI), m/z 280.0458 (M+H)+ (C12H15N3Br requires 280.0449).
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[C:5](=[O:17])[O:6][C:7]12[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:18]1([C:24]2[CH:25]=[N:26][C:27]([NH:30][C:31](=O)[O:32]C3C=CC=CC=3)=[N:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[C:5](=[O:17])[O:6][C:7]12[CH2:12][CH2:11][N:10]([C:31]([NH:30][C:27]2[N:26]=[CH:25][C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:29][N:28]=2)=[O:32])[CH2:9][CH2:8]1
Reactant: O=C1OC2(CCNCC2)c2cccc(F)c21
Reactant: O=C(Nc1ncc(-c2ccccc2)cn1)Oc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1OC2(CCN(C(=O)Nc3ncc(-c4ccccc4)cn3)CC2)c2cccc(F)c21
Temperature: 60 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A mixture of 4-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (150 mg), phenyl N-(5-phenyl-2-pyrimidinyl)carbamate (170 mg) and triethylamine (0.24 mL) in chloroform (2 mL) was stirred at 60° C. for 3 hours. The concentration of the reaction mixture left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate/methanol=1/1/0˜8/8/1˜6/6/1) followed by recrystallization from ethyl acetate-hexane to give the subject compound(190 mg)as colorless crystals (melting point 247-249° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:14])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][O:16][CH2:17][CH:18]([NH2:20])[CH3:19]>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:20][CH:18]([CH3:19])[CH2:17][O:16][CH3:15])[N:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: COCC(C)N
Reactant: Clc1cc(-c2ccnc(Cl)n2)ccn1
Product: COCC(C)Nc1nccc(-c2ccnc(Cl)c2)n1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-(2-chloro-4-pyridinyl)pyrimidine (i.e., the product of Step A) (1.6 g, 7.0 mmol) in 1-methoxy-2-propylamine (5 mL) was stirred at reflux for 45 minutes. After cooling to room temperature, the mixture was purified using column chromatography on silica gel eluted with 40% ethyl acetate in hexanes to give 1.4 g of the title compound as a white 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.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: BrCc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3)C2=O)cn1
Yield: 40 %

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 benzyl bromide. Yield: 40%. 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H), 2.42 (s, 3H), 3.84 (s, 2H), 4.61 (s, 2H), 5.06 (s, 2H), 7.40-7.27 (m, 5H), 7.92 (s, 1H), 8.08 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.09 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1)=O>C(#N)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Temperature: 100 °C
Yield: 106.7 %

Procedure:
A stirred mixture of 2-amino-5-bromopyridine (0.259 g, 1.5 mmol) and 2-bromo-1-[3-nitro-4-(trifluoromethyl)phenyl]ethanone (0.468 g, 1.5 mmol) in acetonitrile (3 mL) is heated at 100° C. for 18 hr. The mixture is concentrated to give the title compound (618 mg), which is used without further purification. LCMS m/z=388.3 [M+H]+, tR=2.94 min.