Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](O)(=[O:18])[C:16]#[CH:17].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])[C:16]#[CH:17]
Reactant: C#CC(=O)O
Reactant: OCCCCCCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C#CC(=O)OCCCCCCCc1ccccc1
Yield: 57.9 %

Procedure:
A mixture of 0.5 g of 7-phenylheptanol, 0.27 g of propiolic acid, 0.005 g of p-toluenesulfonic acid and 25 ml of benzene was refluxed with stirring for six hours while water formed was removed by a Dean-Stark water separator. After the reaction was completed, the reaction solution was washed successively with a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 0.368 g of 7-phenylheptyl propiolate (compound 3).
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:68])[CH:10]([NH:25][C:26]([NH:28][CH:29]([C:56]([O:58]CC2C=CC(OC)=CC=2)=[O:57])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([Sn](CCCC)(CCCC)CCCC)[CH:42]=2)=[O:36])=[O:27])[CH2:11][CH2:12][C:13]([O:15]CC2C=CC(OC)=CC=2)=[O:14])=CC=1.C(O)(=O)C.[I-:75].[Na+].ClN1C(=O)CCC1=O>CO>[C:56]([CH:29]([NH:28][C:26](=[O:27])[NH:25][CH:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:8])=[O:68])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([C:37]1[CH:38]=[N:39][CH:40]=[C:41]([I:75])[CH:42]=1)=[O:36])([OH:58])=[O:57]
Reactant: [I-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(C(=O)NCCCCC(NC(=O)NC(CCC(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)c1
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)CCC(NC(=O)NC(CCCCNC(=O)c1cncc(I)c1)C(=O)O)C(=O)O
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
To a solution of 7 (0.025 g, 0.023 mmol) in 2 mL methanol was added 0.020 mL acetic acid and sodium iodide (0.017 g, 0.113 mmol), followed by N-chlorosuccinimide (0.025 g, 0.187 mmol). After 20 min at room temperature, the solvent was removed under a stream of nitrogen. A solution of TFA in CH2Cl2 (1:1, 2 mL) was then added to the residue. After 1 h at room temperature, 8 (0.008 g, 62%) was isolated by HPLC (Econosphere C18 10μ., 250×10 mm, H2O/CH3CN/TFA (85/15/0.1), 4 mL/min, product peak eluting at 10 min). 1H NMR (400 MHz, D2O) δ 9.00-9.15 (m, 3H), 4.18-4.24 (m, 2H), 3.40-3.41 (m, 2H), 2.45-2.49 (m, 2H), 2.12-2.13 (m, 1H), 1.85-1.97 (m, 2H), 1.64-1.73 (m, 3H), 1.44 (m, 2H). ESI-Mass calcd for C18H24IN4O8 [M+H]+ 551.1, found 551.0. FAB-HRMS calcd for C18H24IN4O8 [M+H]+ 551.0639, found 551.0607.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl.O>O1CCCC1>[Cl:26][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Cl)cnc21
Reaction time: 1 h
Yield: 114.3 %

Procedure:
To 5-bromo-1-triisopropylsilyl-7-azaindole (2, 1.60 g, 4.53 mmol, prepared as described in Example 4) in tetrahydrofuran (50.0 mL), under an atmosphere of nitrogen at −78° C., was added tert-butyllithium (1.70 M in hexane, 6.12 mL). The reaction was stirred for 1 hour, followed by addition of hexachloroethane (1.29 g, 5.43 mmol). The reaction was stirred for 3 hours, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude compound (5, 1.60 g). MS (ESI)[M+H+]+=309.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:3]1=2.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[O:34][CH3:35])[C:18]([Cl:36])=[CH:17][N:16]=1.ClC1N=C(Cl)C(Cl)=CN=1.COC1C=C(N2CCOCC2)C=CC=1N>CO.C(Cl)Cl>[Cl:36][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:24][C:23]=2[O:34][CH3:35])=[N:20][C:15]([NH:13][C:10]2[CH:11]=[CH:12][C:3]3[N:2]([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH:9]=2)=[N:16][CH:17]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCCCc2cc(N)ccc21
Agent: COc1cc(N2CCOCC2)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCCCN3C)ncc1Cl

Procedure:
Following the procedure of Example 101b, 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (33 mgs, 0.19 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (1.2 eq) [prepared using a procedure analogous to Example 1d using 2,4,5-trichloropyrimidine and 2-Methoxy-4-morpholin-4-yl-phenylamine] were reacted except that the ISCO chromatography gradient was 0% to 5% MeOH/CH2Cl2 to give 5-Chloro-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-N*2*-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-pyrimidine-2,4-diamine (46.96 mgs) as an off-white/grey solid. MP=206-207° C. 1H-NMR (CDCl3) δ 8.27 (d, J=8.9 Hz, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 7.36 (s, 1H), 7.28-7.24 (m, 1H), 6.91 (d, J=9.1 Hz, 1H), 6.79 (s, 1H), 6.55 (s, 1H), 6.50 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 3.91-3.89 (m, 4H), 3.17-3.15 (m, 4H), 2.91-2.85 (m, 4H), 2.82-2.77 (m, 4H), 1.89-1.78 (m, 2H), 1.71-1.58 (m, 2H); LC/MS (ESI+): 495.29 (M+H).
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:29][CH:28]([CH2:30]OS(C)(=O)=O)[O:27][C:26]2=[O:36])[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:12]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:29][CH:28]([CH2:30][N:4]3[CH2:5][CH2:6][N:1]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3]3)[O:27][C:26]2=[O:36])[CH2:23][CH2:24]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: COC(=O)CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(COS(C)(=O)=O)OC2=O)CC1
Product: COC(=O)CN1CCN(CC2CN(C3CCN(C(=O)OC(C)(C)C)CC3)C(=O)O2)CC1

Procedure:
Analogously to Example 1, starting from methyl 2-piperazinoacetate [obtainable by reaction of methyl α-chloroacetate with piperazine] by reaction with 3-(1-BOC-4-piperidyl)-5-methanesulfonyloxymethyloxazolidin-2-one, 3-(1-BOC-4-piperidyl)-5-[4-(methoxycarbonylmethyl)piperazino]methyloxazolidin-2-one is obtained after customary working up.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
450 g (3 mol) of 4-methylphenyl-acetic acid (Aldrich), 1.13 l (12 mol) of tert-butanol and 90 g (0.74 mol) of 4(N,N dimethylamino)pyridine are dissolved in 2 l of dichloromethane. After addition of 680 g (3.3 mol of dicyclohexylcarbodiimide, dissolved in 400 ml of dichloromethane, the mixture is stirred at 25° C. for 20 h, the precipitated urea is filtered off with suction and washed with 200 ml of dichioromethane, and the organic phase is washed twice each with 500 ml of 2 M hydrochloric acid and water. The organic phase is concentrated and distilled.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([O:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(O)n(C)n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)n(C)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (10.0 g, 64.0 mmol), benzyl bromide (12.0 g, 70 mmol) and potassium carbonate (13.8 g, 100 mmol) in N,N-dimethylformamide (150 mL) was stirred at 50° C. for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 90:10 to 50:50). Solvent was removed to obtain a solid (15.8 g, quant.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].Br[CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>O1CCCC1.[Cl-].[Na+].O>[CH2:18]([O:17][C:15](=[O:16])[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:19]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CCOC1CCCCO1)(NC(=O)OC(C)(C)C)C(=O)OCC
Yield: 65.2 %

Procedure:
Diethyl (t-butyloxycarbonyl)aminomalonate (52.3 g) was dissolved in tetrahydrofuran (400 ml), sodium t-butoxide (19.2 g) was added thereto, a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (40.4 g) in tetrahydrofuran (100 ml) was added to the reaction mixture at 70° C., and the mixture was stirred with heating for 10 hr. After cooling, the reaction mixture was poured into saturated brine. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the object product (50.0 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH:22]([NH:35][C:36](=[O:39])[CH2:37]Br)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH2:37][C:36](=[O:39])[NH:35][CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(CBr)NC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(CC(=O)NC(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of 60.1 mg (0.23 mmol) of the compound from example 1g in 1 ml of absolute DMF was mixed with 11 mg (0.23 mmol) of sodium hydride (50%) and stirred at RT for 1 h. Then 70.3 mg (0.23 mmol) of the compound from example 10a were added, and the mixture was stirred at RT for 1 h. The reaction solution was mixed with 1 ml of water and extracted several times with EA. The combined EA extracts were dried over Na2SO4, filtered and concentrated. Purification of the resulting residue by chromatography on silica gel with CH2Cl2/methanol (9:1) as mobile phase afforded 71.4 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.ClC[C:33]([N:35]=C=O)=[O:34].C(=O)(O)[O-].[Na+]>O1CCCC1.CO.[Zn]>[C:33]([O:1][CH2:2][C:3]1[N:4]([CH2:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1)(=[O:34])[NH2:35]
Reactant: CC(C)c1nc(CO)n(Cc2cnc3ccccc3c2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nc(COC(N)=O)n(Cc2cnc3ccccc3c2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 77.8 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 223 mg (0.50 mmol)of 2-hydroxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (109), followed by dropwise addition of 72 mg (0.60 mmol)of chloroacetylisocyanate with stirring at 0° C., and the mixture was stirred at room temperature for 30 minutes. After the reaction completion, the mixture was worked up. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, extracted with methylene chloride, the extract was washed with water and dried. The-solvent was distilled off under reduced pressure, and 2-chloroacetyl-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (110)suited to the next step of the reaction was obtained. mp 167-170° C. The crystals were dissolved in 20 ml of aqueous methanol, 40 mg of Zn powder was added, and the mixture was stirred at room temperature for 5 hours. After the reaction completion, the mixture was worked up. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the insoluble material was removed by filtration under reduced pressure through Celite. The filtrate was concentrated, extracted with methylene chloride, the extract was washed with water and dried, and the solvent was distilled off. The residual crystals were washed with ethyl acetate and ether to give 195 mg of Compound I-128 (yield 78%). mp 214-216° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:8]=1
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Reactant: C1CNCCN1
Product: O=C(CCN1CCNCC1)c1ccc(Cl)cc1

Procedure:
4′-Chloro-3-(piperazin-1-yl)propiophenone was prepared from commercially available 3,4′-dichloropropiophenone (Aldrich, 14,159-3) and piperazine according to the general methodology described at step A of example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([S:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:3]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.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>[CH3:30][O:29][C:25](=[O:28])[CH:26]=[CH:27][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:18])=[O:17]
Reactant: O=S(=O)(c1cc(F)ccc1OS(=O)(=O)C(F)(F)F)N1CCOCC1
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Temperature: 120 °C
Yield: 43 %

Procedure:
To a solution of the product of example 85 (100 mg 0.254 mmol) in dry DMF (3 ml) was added methyl acrylate (0.09 ml, 1.02 mmol), Pd(PPh3)2Cl2(17.83 mg, 0.0254 mmol), DPPP (10.5 mg, 0.0254 mmol) and DIPEA (0.2 ml, 1.02 mmol) successively at room temperature in sealed tube. The mixture was heated at 120° C. for about 24 h. After cooling to room temperature, the mixture was poured into ice water and extracted with EA three times. The combined extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=5/1) to give the desire product (36 mg, yield 43%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:16]=2[N:17]=1.O1CCCC1>C(N(CC)CC)C>[F:25][C:22]([F:23])([F:24])[C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([NH:12][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])[S:14][C:15]=2[CH:21]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccc(C(F)(F)F)cc2s1)c1c(F)cccc1F
Temperature: 35 °C
Reaction time: 5 h
Yield: 78.2 %

Procedure:
At 0 to 5° C., 2,6-difluorobenzoyl chloride (1.77 g) was added dropwise to a solution composed of 2-amino-6-trifluoromethylbenzothiazole (2.18 g), tetrahydrofuran (30 ml) and triethylamine (1.1 g). The reaction mixture was stirred at 30 to 40° C. for 5 hours, and then tetrahydrofuran was evaporated. The solid residue was washed with water and recrystallized from ethanol to give the desired N-(6-trifluoromethylbenzothiazol-2-yl)-2,6-difluorobenzamide (2.8 g).
Reaction SMILES: [OH:1][P:2]([CH2:23][CH:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25](O)=[O:26])([CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:33][C@H:34]([C:42]([O:44][CH3:45])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[OH:3][P:2]([CH2:23][CH:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]([NH:33][C@H:34]([C:42]([O:44][CH3:45])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:26])([CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: CC(C)CC(CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C(CC(C)C)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 65 %

Procedure:
The process is performed according to the procedure described in 1.8., starting with 250 mg (0.58 mol) of 2-[[hydroxy[2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]methyl]-4-methylpentanoic acid and 124.5 mg (0.58 mmol) of methyl phenylalaninate hydrochloride. 228 mg of product are recovered (yield=65%).
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])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=1>>[CH3:30][N:29]1[C:25]([CH2:24][N:15]2[C:16]([CH3:19])([CH3:20])[C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:22])[CH:12]=3)[C:14]2=[O:21])=[CH:26][C:27]([CH3:31])=[N:28]1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: Cc1cc(CCl)n(C)n1
Product: Cc1cc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)n(C)n1

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole. MS 412 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.23 μM.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([OH:45])[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[N:46]1([C:50]([C:52]2[CH:57]=[CH:56][C:55](F)=[CH:54][C:53]=2[F:59])=[O:51])[CH2:49][CH2:48][CH2:47]1>>[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([O:45][C:55]2[CH:56]=[CH:57][C:52]([C:50]([N:46]3[CH2:49][CH2:48][CH2:47]3)=[O:51])=[C:53]([F:59])[CH:54]=2)[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Reactant: O=C(c1ccc(F)cc1F)N1CCC1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)c2c(c1)OC(C)(CO)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 7.48-7.56 (m, 1 H) 7.24 (s, 1 H) 7.20 (d, J=1.26 Hz, 1 H) 6.77 (dd, J=8.59, 2.53 Hz, 1 H) 6.66 (dd, J=11.24, 2.40 Hz, 1 H) 4.21 (t, J=7.83 Hz, 2 H) 4.11-4.17 (m, 2 H) 3.65-3.74 (m, 1 H) 3.55-3.63 (m, 1 H) 3.13 (d, J=16.67 Hz, 1 H) 2.76 (d, J=16.67 Hz, 1 H) 2.34 (dt, J=15.60, 7.74 Hz, 2 H) 1.89-1.97 (m, 1 H) 1.56 (s, 9 H) 1.44 (s, 3 H); LCMS for C25H28FNO6 m/z 458.20 (M+H)+.
Reaction SMILES: N[C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[BrH:13].N([O-])=O.[Na+]>O>[Br:13][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: Br
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)[C@H](Br)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
(S)-methyl 2-amino-2-phenylacetate (5 g, 24.8 mmol, 1 equiv) was dissolved in a mixture of 48% hydrogen bromide (13 ml, 198 mmol, 8 equiv) and water (19 ml). An aqueous solution of sodium nitrite (5.48 g, 79.36 mmol, 3.2 equiv) was added slowly and the mixture stirred at 0° C. for 1.5 h. The reaction was degassed in vacuo and extracted with ether. The organic layer was further washed with water and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, gradient—1%-10% ethyl acetate/hexanes) to afford the (R)-methyl 2-bromo-2-phenylacetate as a light yellow oil (2.3 g, 40% yield).). 1H NMR (400 MHz, DMSO-d6): δ 3.72 (s, 3H); 5.95 (s, 1H); 7.36-7.42 (m, 3H); 7.54 (d, 2H, J=1.6 Hz); 7.56 (d, 1H, J=2 Hz). MS for C9H9BrO2 m/z 229.98 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]1=2.O[C:22]1[CH:36]=[CH:35][C:25]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCOCC>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:22]3[CH:36]=[CH:35][C:25]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])=[O:27])=[CH:24][CH:23]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CC=C(c2cccs2)c2cc(C(=O)O)ccc21
Reactant: C[Si](C)(C)CCOC(=O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)CC=C(c2cccs2)c2cc(C(=O)Oc3ccc(C(=O)OCC[Si](C)(C)C)cc3)ccc21

Procedure:
A solution of 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid (Compound E6, 79.0 mg, 0.280 mmol), 2-trimethylsilylethyl 4-hydroxybenzoate (73.3 mg, 0.308 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.0 mg, 0.364 mmol), and 4-N,N-dimethylaminopyridine (44.5 mg, 0.364 mmol) in 2.0 mL DMF was stirred overnight at room temperature. Et2O (100 mL) was added and the solution washed with H2O, 5% HCl, saturated aqueous NaCO3, and saturated aqueous NaCl before being dried over MgSO4. Removal of the sovents under reduced pressure and column chromatography (10% EtOAc-hexanes) of the residual oil afforded the title compound as a colorless solid.