Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[CH2:17][CH2:16][NH:15][C:14]3=[O:18])[CH:10]=[N:9]2)=[C:5]([CH3:19])[O:4][N:3]=1.[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:15]1[CH2:16][CH2:17][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[CH3:19])[CH:12]=2)[C:14]1=[O:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2CCNC2=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2CCN(Cc3ccccc3)C2=O)cn1
Temperature: 0 °C
Yield: 31.5 %

Procedure:
1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidin-2-one (example 10-88a) (50 mg, 0.19 mmol) and 60% sodium hydride (8 mg, 0.21 mmol) in DMF (3 mL) were stirred at room temperature for 15 minutes then cooled to 0° C. Benzyl bromide (33 mg, 0.19 mmol) was added to the mixture and allowed to warm up at room temperature for 2 hours. The reaction was quenched with methanol and concentrated on the rotovap. The reaction was diluted with brine (50 mL) and extracted with dichloromethane (2×, 50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) to afford 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidin-2-one (21 mg, 31%) as a white solid. MS M+H calculated 352.17. Found 352.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.71 μM.
Reaction SMILES: [CH:1]1([CH2:8][O:9][C:10]2[N:15]=[C:14]([C:16]([O:18]C)=O)[CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]#[N:22]>>[CH:1]1([CH2:8][O:9][C:10]2[N:15]=[C:14]([C:16](=[O:18])[CH2:20][C:21]#[N:22])[CH:13]=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC#N
Reactant: COC(=O)c1cccc(OCC2CCCCCC2)n1
Product: N#CCC(=O)c1cccc(OCC2CCCCCC2)n1

Procedure:
CH3CN addition to methyl 6-(cycloheptylmethoxy)picolinate following the method used in Example 6 gave 3-(6-(cycloheptylmethoxy)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (2.12 g, quant.).
Reaction SMILES: ClC1SC2C=CC=CC=2N=1.N[C@H](C(O)=O)C.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][C@H:27]([C:29]([OH:31])=O)[CH3:28].Cl.[CH3:33][O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH2:39][CH2:40][CH3:41])[NH2:37].Cl>>[CH3:33][O:34][C:35](=[O:42])[C@@H:36]([NH:37][C:29](=[O:31])[C@H:27]([CH3:28])[NH:26][C:18]1[S:17][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1)[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: C[C@H](Nc1nc2ccccc2s1)C(=O)O
Reactant: CCCC[C@H](N)C(=O)OC
Agent: C[C@H](N)C(=O)O
Agent: Cl
Agent: Clc1nc2ccccc2s1
Product: CCCC[C@H](NC(=O)[C@H](C)Nc1nc2ccccc2s1)C(=O)OC

Procedure:
Following General Procedure B and using 2-chlorobenzothiazole (Aldrich) and L-alanine (Aldrich), N-(benzothiazol-2-yl)-L-alanine was prepared. This compound was then coupled to L-norleucine methyl ester hydrochloride (Sigma) using General Procedure D (without the 1N HCl wash) to provide for the title compound as a solid (mp=99-120° C.). The latter reaction was monitored by tlc (Rf=0.42 in 1:1 EtOAc:Hexanes) and the product was purified by preparative plate chromatography using 1:1 EtOAc:Hexanes and 5:95 MeOH:dichloromethane as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[Cl:20]N1C(=O)CCC1=O>ClCCl.CCOCC>[Cl:20][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CCN(C(=O)c2[nH]c3ccc(Cl)cc3c2Cl)CC1
Reaction time: 18 h
Yield: 50.3 %

Procedure:
(5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 1, 0.23 g) in dichloromethane (3 mL) at ambient temperature was treated with N-chlorosuccinimide (0.123 g) and stirred for 18 h. The reaction mixture was diluted with ether, washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane afforded the title compound (0.13 g). 1H NMR (400 MHz, CDCl3): δ 2.36 (3H), 2.53 (4H), 3.79 (4H), 7.22 (1H), 7.29 (1H), 7.58 (1H), 10.39 (1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH:10]([CH3:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1.[OH-:15].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[OH:15][C:10]([CH3:13])([CH2:11][CH3:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: [OH-]
Reactant: CCC(C)C(=O)c1ccc(SC)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)(O)C(=O)c1ccc(SC)cc1

Procedure:
To a mixture of the ketone from Step 1 (10 g, 48 mmol) and Aliquat® 336 (20 mL) in CCl4 (40 mL) and toluene (80 mL) at r.t. was added NaOH pellets (3.8 g, 96 mmol). While stirring vigourously, the mixture was heated briefly to reflux and was then stirred overnight at r.t. After partitioning between CH2Cl2 and H2O, the whole was filtered through celite. The organic layer was dried (MgSO4), filtered, and evaporated. The residue was purified by flash chromatography (1:10 EtOAc: hexane) to give the title compound as a syrup (5.5 g).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=O)[NH:5][CH:4]=[C:3]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH2:64]([NH2:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH2:64]([NH:71][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][N:15]=[C:7]([N:6]2[C:2](=[O:1])[C:3]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:4][NH:5]2)[CH:8]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: O=C(O)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: NCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
60.0 mg (213 μmol) of the compound from Example 41 are dissolved in 24 ml DMF, 2.6 mg (21 μmol) 4-N,N-dimethylaminopyridine, 65.9 mg (510 μmol) N,N-diisopropylethylamine and 265 mg (510 μmol) (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate are added and the mixture is stirred at RT for 45 min. 68.3 mg (638 μmol) benzylamine are added and the mixture is stirred overnight at RT. To bring the conversion to completion, a further 65.9 mg (510 μmol) N,N-diisopropylethylamine and 265 mg (510 μmol) (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate are added, the mixture is stirred at RT for 45 min, a further 68.3 mg (638 μmol) benzylamine are added and the mixture is then stirred overnight at RT. It is concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([B-:8]([C:13]#[N:14])([C:11]#[N:12])[C:9]#[N:10])#[N:7].[CH3:15][N:16]([C+:18]([N:20]([CH3:22])[CH3:21])Cl)[CH3:17]>O>[C:6]([B-:8]([C:13]#[N:14])([C:11]#[N:12])[C:9]#[N:10])#[N:7].[CH3:15][N:16]([CH3:17])[C:18]([N:20]([CH3:22])[CH3:21])=[N+:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CN(C)[C+](Cl)N(C)C
Reactant: CCNCC
Agent: N#C[B-](C#N)(C#N)C#N
Solvent: O
Product: CC[N+](CC)=C(N(C)C)N(C)C
Yield: 97.4 %

Procedure:
10.5 g (143.6 mmol) of diethylamine are added with stirring and cooling to 12.0 g (47.9 mmol) of bis(dimethylamino)chlorocarbenium tetracyanoborate. The reaction mixture is stirred for 3 hours at room temperature, and 30 ml of water are then added. The lower phase is separated off and diluted with 30 ml of dichloromethane. The organic phases are subsequently washed a number of times with 30 ml of water and dried using MgSO4. The solvent is then distilled off, and the residue is dried for 3 hours under reduced pressure at 7 Pa and 60° C., giving 13.4 g of N,N,N′,N′-tetramethyl-N″,N″-diethylguanidinium tetracyanoborate as a liquid, corresponding to a yield of 97.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[CH2:23]([O:30][CH:31]1[CH2:36][CH:35]([O:37][CH3:38])[O:34][CH:33]([CH2:39][CH2:40][NH2:41])[CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][CH:31]1[CH2:36][CH:35]([O:37][CH3:38])[O:34][CH:33]([CH2:39][CH2:40][N:41]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:32]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC1CC(OCc2ccccc2)CC(CCN)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: COC1CC(OCc2ccccc2)CC(CCn2c(C(C)C)cc(-c3ccccc3)c2-c2ccc(F)cc2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-(4-(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)ethanamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:23])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18]C)=O)(=[O:11])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>C1COCC1>[Cl:34][C:35]1[N:40]=[C:39]([CH2:41][C:16]([C:15]2[C:14]([F:23])=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:11])[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:38]=[CH:37][N:36]=1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of methyl 3-(2,5-difluorophenylsulfonamido)-2-fluorobenzoate (44 g, 128 mmol (from a compilation of batches prepared as described above) in dry THF (500 mL) at −10° C., LiHMDS (1M in THF, 448 mmol, 448 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (19.4 g, 154 mmol) in THF (50 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (300 mL) at 0° C. The reaction mixture was extracted with EtOAc (500 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound (18.6 g, 33.2% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.70-13.74 (br, 1H), 8.59 (d, J=5.29 Hz, 0.3H), 8.42 (d, J=5.51 Hz, 1H), 7.75-7.79 (m, 0.3H), 7.51-7.66 (m, 3.6H), 7.12-7.28 (m, 6.6H), 6.91 (d, J=5.51 Hz, 1H), 6.03 (s, 1H), 4.37 (s, 0.6H). MS (ES+): 442 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])#[N:2].OO.[ClH:21]>>[C:1]([C:3]1[CH:18]=[C:17]([Cl:21])[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10]([CH3:11])([CH3:12])[CH3:13])#[N:2]
Reactant: Cl
Reactant: CC(C)(C)NCC(O)COc1ccccc1C#N
Agent: OO
Product: CC(C)(C)NCC(O)COc1ccc(Cl)cc1C#N
Temperature: 45 °C

Procedure:
5.7 gm (0.02 mol) of 1-(2-cyanophenoxy)-2-hydroxy-3-tert.-butylamino propane (prepared analogous to Example II) were dissolved in 32 ml of concentrated HCl and while stirring at 45° C. 2.27 gm of 35% hydrogen peroxide were added drowise so that the temperature did not exceed 65° C. Thereafter, the temperature was maintained at 60° C. for 30 minutes and the mixture was concentrated in vacuo at the end of which a solid residue remained. The raw hydrochloride was recrystallized from ethanol under an addition of ether to obtain 3 gm of 1-(2-cyano-4-chloro-phenoxy)-2-hydroxy-3-tert.-butylamino propane hydrochloric having a melting point of 180°-182° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14](=[O:23])[C:15](=[O:22])[NH:16]2>>[Cl:11][C:12]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14]([OH:23])([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[C:15](=[O:22])[NH:16]2
Reactant: COc1ccc(C)cc1Br
Reactant: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ccc(Cl)c(Cl)c21
Yield: 52.4 %

Procedure:
With 3.02 g of 2-bromo-1-methoxy-4-methyl benzene and 1.50 g of 4,5-dichloroisatin as starting materials, 1.23 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[C:12](Cl)(=O)C>CO>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1]
Reactant: O=C(O)Cc1ccccc1I
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1ccccc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
2-Iodophenylacetic acid (1.45 g) was added to a mixture of methanol (100 mL) and acetyl chloride (5 mL). After stirring at room temperature for 3 hours, the solvent was removed and the residue was dried under vacuum giving the desired 2-iodophenylacetic acid methyl ester. Yield=100%
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH:25]([C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1)[CH2:26][CH2:27][OH:28].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:28][CH2:27][CH2:26][CH:25]([NH:24][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:15])[CH:11]=1)=[O:23])[C:29]1[CH:30]=[N:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=1
Reactant: NC(CCO)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NC(CCO)c3ccc(C(F)(F)F)nc3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (17 mg, 0.055 mmol) in N,N-dimethylformamide (0.5 mL) were added 3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (47 mg, 0.21 mmol) (WO 2008/130481), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (80 mg, 0.21 mmol) and N,N-diisopropylethylamine (80 μL, 0.46 mmol). The reaction mixture was stirred for 16 hours at 30° C. The reaction mixture was purified by preparative HPLC to afford a white solid.
Reaction SMILES: ClB.CSC.[CH3:6][SiH:7]([CH2:9][CH2:10][Si:11]([CH3:21])([CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH3:8].[OH:22]O>C1COCC1>[CH3:6][SiH:7]([CH2:9][CH2:10][Si:11]([CH3:21])([CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:22])[CH3:8]
Reactant: OO
Reactant: C=CCCCCCC[Si](C)(C)CC[SiH](C)C
Agent: BCl
Solvent: C1CCOC1
Solvent: CSC
Product: C[SiH](C)CC[Si](C)(C)CCCCCCCCO
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Monochloroborane-methyl sulfide (1.10 ml, 1.16 g, 10.5 mmol) was added dropwise to a stirred, cooled (0° C.) solution of compound 9 (2.56 g, 10.0 mmol) in THF (30 ml). The reaction mixture was stirred at 0° C. for 24 h, and a solution of hydrogen peroxide (10 ml, 30% in water) added dropwise and the reaction mixture stirred at 0° C. for 4 h, washed with water and the organic layer extracted into hexane/ethyl acetate (3×30 ml, 1:1). The combined extracts were washed with brine, dried (MgS04) and the solvent removed in vacuo to yield colorless oil. The crude product was purified by column chromatography [silica gel eluted with hexane/ethyl acetate (4:1)] to yield a colorless oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:12][OH:13])[CH3:11])=[CH:6][CH:5]=1.[C:14]([OH:18])(=[O:17])[CH:15]=[CH2:16]>C(O)C.O>[CH3:11][C:10](=[N:12][O:13][CH2:16][CH2:15][C:14]([OH:18])=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: CC(=NO)c1ccc(Cl)cc1
Reactant: C=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=NOCCC(=O)O)c1ccc(Cl)cc1

Procedure:
A solution of 2.4 g of sodium hydroxide in 55 ml of 85% ethanol was mixed with 6,78 g of 4'-chloroacetophenone oxime and 2.88 g of acrylic acid. The mixture was then refluxed for 2.5 hours, subsequently diluted with 10 ml of water, and concentrated by evaporation in a vacuum after 2 hours. The residue was dissolved in 50 ml of ether and 50 ml of water, and the layers were separated. The water layer was extracted with 50 ml of ether and then acidified with 40 ml of 2 N hydrochloric acid. The acid solution was extracted with 100 ml of ether and the ethereal solution was dried over sodium sulfate. Then the solvent was distilled off and its last traces were removed together with higher boiling substances at a pressure of 0.01 mm and a temperature of 50° C. The residue was crystallized from petroleum ether. Melting point 80° C.-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:20]=O>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)=[O:13])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: C=O
Reactant: O=C(c1cc(Br)cc(C(F)(F)F)c1)C1CCNCC1
Solvent: O=CO
Product: CN1CCC(C(=O)c2cc(Br)cc(C(F)(F)F)c2)CC1
Yield: 77 %

Procedure:
Stir the mixture of (3-bromo-5-(trifluoromethyl)phenyl)(piperidin-4-yl)methanone (400 mg, 0.96 mmol), formic acid (1 mL) and formaldehyde (1 mL) at 100° C. overnight. Upon the reaction completion, concentrate under reduced pressure to provide the crude product (250 mg, 77%) which is used in next step without further purification.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[C:9]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:10]([C:15]([N:17]2[CH2:20][C:19](=O)[CH2:18]2)=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([C:15]([N:17]2[CH2:20][C:19](=[CH2:1])[CH2:18]2)=[O:16])[C:9]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 15 h
Yield: 21.2 %

Procedure:
Methyl triphenylphosphonium bromide (508 mg, 1.42 mmol) was treated with potassium tert-butoxide (159 mg, 1.42 mmol) in tetrahydrofuran (5 mL) at 0° C. for 10 minutes. 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (270 mg, 0.605 mmol), prepared using procedures similar to those described in Example 6, was dissolved in tetrahydrofuran (2 mL) and was added to the mixture. The mixture was stirred at ambient for 15 h and then the mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ethyl acetate in hexanes) gave 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-methylideneazetidin-1-yl)carbonyl]aniline (57 mg, 0.128 mmol, 21% yield): 1H NMR (400 MHz, CDCl3): 8.56 (br s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H), 7.18-7.12 (m, 1H), 6.86-6.76 (m, 1H), 6.62 (ddd, 1H), 5.14-5.00 (br, 2H), 4.74 (br d, 4H); MS (EI) for C17H12F3IN2O: 445 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[CH2:14][S:13]/[C:12]/1=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)=[CH:25][CH:24]=1)=[O:19])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH3:50][C:51]([CH3:53])=[O:52]>>[OH:52][C:51]([CH:14]1[S:13]/[C:12](=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[N:33]=[CH:32][N:31]([C:34]4[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:38][CH:39]=4)[N:30]=3)=[CH:27][CH:28]=2)=[O:19])/[N:11]([C:5]2[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:15]1=[O:16])([CH3:53])[CH3:50]
Reactant: CC(C)=O
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(C(C)C)c(N2C(=O)C(C(C)(C)O)S/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Yield: 19 %

Procedure:
To (Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea (F5) (0.40 g, 0.64 mmol) in acetone (30 mL) was added saturated aqueous sodium bicarbonate (3 mL). The reaction was heated to reflux for 12 hours, cooled, and concentrated. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried and concentrated. Purification by flash column chromatography using 100-40% A/B, where A=1:1 dichloromethane/hexanes and B=3:1 ethyl acetate/acetone, as eluent provided the title compound as a white solid (0.095 g, 19%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][NH:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26]([N:14]1[CH2:15][C@@H:16]([CH3:19])[CH2:17][CH2:18][C@H:13]1[C:11]1[NH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][N:10]=1)=[O:27])[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)NC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)CC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of 2S,5S)-2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-5-methyl-piperidine (400 mg, 1.25 mmol) and (S)-2-methoxycarbonylamino-3-methyl-butyric acid (219 mg, 1.25 mmol), HATU (475 mg, 1.25 mmol), and DIPEA (485 mg, 3.75 mmol) in DCM (20 mL) was stirred at RT overnight. The reaction mixture was concentrated and purified by thin layer chromatography (1:1 petroleum ether:EtOAc) to provide the title intermediate (550 mg, 92% yield). (m/z): [M+H]+ calcd for C22H28BrN4O3 476.13, 478.13, found 478.7.