Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[CH3:12][O:13][C:14]([C:16]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1)=[O:15]
Reactant: Clc1ncnc2ccccc12
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3ccccc23)CCN(C(=O)OC(C)(C)C)CC1
Yield: 109 %

Procedure:
A mixture of 4-chloroquinazoline (2.02 g, 12.3 mmol), prepared as described in the preceding step, and piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (3.13 g, 12.8 mmol), as prepared in Example 1b, was treated with 1.08 M LiHMDS/THF in one portion by syringe at 0° C. with stirring under argon. After stirring for an additional 5 min at 0° C., the ice bath was removed and the homogeneous amber solution was stirred at rt for 4.5 h. The reaction was quenched with 1 M NaH2PO4 (30 mL) and extracted with DCM (2×30 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to give the crude title compound as a clear amber syrup (4.98 g). 1H-NMR (300 MHz, CDCl3) δ 9.29 (s, 1H), 8.06 (m, 2H), 7.87 (m, 1H), 7.59 (m, 1H), 3.72-3.52 (m, 4H), 3.60 (s, 3H), 2.50-2.40 (br m, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 371.2, found 372.2 (MH)+.
Reaction SMILES: C([O:9][C:10]1[C:15](=[O:16])[CH:14]=[CH:13][O:12][C:11]=1[CH3:17])(=O)C1C=CC=CC=1.[OH-].[Na+]>>[OH:9][C:10]1[C:15](=[O:16])[CH:14]=[CH:13][O:12][C:11]=1[CH3:17]
Reactant: Cc1occc(=O)c1OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1occc(=O)c1O
Yield: 40 %

Procedure:
3-Benzoyloxy-2-methyl-4-pyrone (40.60 g, 176.5 mmol) is stirred at 20°-25° C. for 3 hours with 265 ml (530 mmol) of 2N sodium hydroxide solution. The solution is adjusted to pH 6.5 and extracted three times with 200 ml of dichloromethane each time. The combined organic phases are dried over sodium sulphate and concentrated on a rotary evaporator. The crude product is recrystallized in acetone and gives 8.90 g (40%) of 3-hydroxy-2-methyl-4-pyrone, m.p. 156°-158° C.
Reaction SMILES: [CH:1]1([C:7]2[S:11][C:10]([N:12]=[C:13]=[O:14])=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][NH:16][CH2:17][CH:18]=[O:19]>C1C=CC=CC=1>[CH3:15][N:16]([CH2:17][CH:18]=[O:19])[C:13]([NH:12][C:10]1[S:11][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[N:8][N:9]=1)=[O:14]
Reactant: O=C=Nc1nnc(C2CCCCC2)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(C2CCCCC2)s1

Procedure:
A mixture of 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer (12 grams), the dimethyl acetal of 2-methylaminoacetaldehyde (6.9 grams) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized from methanol to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde having a melt point of 133° to 134° C.
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].[CH:6]1[C:12](=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH:11]=[CH:10][C:8](=[NH:9])[CH:7]=1.Cl.[CH:29]1C(C(C2C=CC(N)=CC=2)=C2C=CC(=N)C=C2)=CC=C(N)C=1.[N+]([O-])([O-])=O.[OH-:55].[Na+]>NC1C=CC=CC=1>[CH:6]1[C:12]([C:13]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[C:21]2[CH:22]=[CH:23][C:24](=[NH:27])[CH:25]=[CH:26]2)=[CH:11][CH:10]=[C:8]([NH2:9])[CH:7]=1.[CH3:29][OH:55]
Reactant: [OH-]
Agent: Cl
Agent: N=C1C=CC(=C(c2ccc(N)cc2)c2ccc(N)cc2)C=C1
Agent: O=[N+]([O-])[O-]
Solvent: Nc1ccccc1
Product: CO

Procedure:
From an alkali blue process stream is isolated 274 g of crude pararosaniline nitrate, formed by adding concentrated aqueous sodium nitrate to the pararosaniline hydrochloride reaction mixture. The pararosaniline nitrate is dissolved in 650 g aniline at 80° C. to which 54 g of 50 percent aqueous sodium hydroxide is slowly added to bring the pH to 11.5 to 12.5. The aqueous layer is allowed to separate, is drawn off, and the organic layer allowed to cool. Crystals of pararosaniline carbinol base are isolated as a filter cake weighing 151 g and assaying 62 percent by weight pararosaniline carbinol. Following toluene wash to remove residual aniline, the dry, slightly pink carbinol base assays at 98 percent purity.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11](Cl)(=O)[C:12](Cl)=O>CN(C)C=O.ClCCl>[CH2:11]([O:9][C:8]([C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH3:12]
Reactant: Cc1nccnc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccnc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-pyrazine-2-carboxylic acid (10 g) (commercially available) and N,N-dimethylformamide (“DMF”) (1 drop) in dichloromethane (20 ml) at ambient temperature was added drop wise oxalyl chloride (2.57 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and the residue dissolved in dichloromethane (20 ml). Triethylamine (4.04 ml) was added to this solution followed by drop wise addition of ethanol (10 ml). The reaction mixture was stirred at ambient temperature for one hour and then concentrated. The residue was purified by chromatography on silica gel (eluent: 0-10% v/v ethyl acetate in iso-hexane) to give 3-methyl-pyrazine-2-carboxylic acid ethyl ester (9.85 g). MH+=167, RT=0.73 min (Method A). 1H-NMR (400 MHz, CDCl3): 8.61 (d, 1H), 8.54 (d, 1H), 4.49 (q, 2H), 2.85 (s, 3H), 1.46 (t, 3H) ppm.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].CO.Cl>C1COCC1>[CH2:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][OH:12])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCCCCNC(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCCCCCO)OCc1ccccc1
Reaction time: 4 h
Yield: 76.4 %

Procedure:
To a solution of diisobutylaluminum hydride (49 mL, 1.5 M in toluene) in THF (150 mL) cooled to −78° C. was added a solution of 6-benzyloxycarbonylamino-hexanoic acid methyl ester (10 g, 37 mmol) in THF (100 mL) . The reaction mixture was stirred for 4 h and methanol (2.5 mL) was added carefully at −78 to −75° C. After 2 h, the mixture was poured to 250 mL of 1 N HCl solution cooled in ice-bath, extracted with ethyl acetate (300 mL), washed with brine (3×100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 50% ethyl acetate in hexane) to yield the titled compound (7.1 g, 80%); white solid, mp 67-68° C.
Reaction SMILES: [O:1]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C@H:2]1[C:3]([OH:5])=[O:4].O1[C@H](CC)[C@H]1C(O)=O.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH2:30]([NH:37][C@H:2]([C@H:6]([OH:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([OH:5])=[O:4])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCCCCCCCC[C@H]1O[C@@H]1C(=O)O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: CC[C@H]1O[C@@H]1C(=O)O
Agent: [Cl-]
Solvent: O
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@@H](NCc1ccccc1)C(=O)O
Temperature: 2.5 °C
Yield: 91 %

Procedure:
To 44.7 g (0.15 mol) of the (2S,3R)-2,3-epoxyoctadecanoic acid (V-2) obtained in (4) above were added 150 ml of water and 1.6 g (4 mmol) of a phase transfer catalyst Aliquat 336 at room temperature, followed by stirring at 2 to 3° C. To the mixture was added dropwise 48.2 g (0.45 mol) of benzylamine (VI), followed by further stirring for about 5 minutes. To the mixture was added 24.0 ml (0.12 mol) of a 5N sodium hydroxide aqueous solution, and the mixture was refluxed for 2 hours and then stirred at room temperature for 16 hours. The reaction mixture was cooled to 0 to 5° C., 6.0 ml (0.03 mol) of a 5N sodium hydroxide aqueous solution was added thereto, and the mixture was extracted with 800 ml of diisopropyl ether. The aqueous layer was adjusted to pH 5 to 6 with 2N hydrochloric acid aqueous solution, and the precipitated white crystals were extracted with 1600 ml of diisopropyl ether and collected by filtration under ice-cooling to obtain 55.3 g (0.137 mol; yield: 91.0%) of the title compound (melting point: 132° C.).
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[N:11][CH2:12][CH:13]=[CH2:14])[CH3:8]>O1CCCC1>[CH:12](=[N:11][CH:10]=[C:9]([CH2:7][CH3:8])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][CH3:14]
Reactant: C=CCN=CC(CC)CCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC=NC=C(CC)CCCC
Yield: 85.2 %

Procedure:
The procedure is carried out as described in Example 1 with the use however in this case of 10 g of potassium tert-butylate, 800 g (4.79 mols) of (2-ethylhexylidene)-allylamine and 600 ml of tetrahydrofuran. After a reaction time of 2 hours at 35° C., there is obtained 682 g (4.08 mols) of N-propylidene-(2-ethylhexen-1-yl-amine), corresponding to a yield of 85.2% of theory (isomeric mixture in the weight ratio of 55:45); b.p. 53°-56° C./1 Torr; nD20 =1.4698.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.CC[Mg+].[Br-].I[C:31]1[CH:51]=[CH:50][CH:49]=[CH:48][C:32]=1[CH2:33][CH2:34][C@H:35]1[C:40]([O:41][CH3:42])=[N:39][C@H:38]([CH:43]([CH3:45])[CH3:44])[C:37]([O:46][CH3:47])=[N:36]1>C1COCC1.C(Cl)Cl.[Cl-].[Cl-].[Zn+2].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>[CH:43]([C@@H:38]1[C:37]([O:46][CH3:47])=[N:36][C@@H:35]([CH2:34][CH2:33][C:32]2[CH:31]=[CH:51][CH:50]=[CH:49][C:48]=2[C:2]2[N:3]=[CH:4][N:5]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=2)[C:40]([O:41][CH3:42])=[N:39]1)([CH3:45])[CH3:44]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCc1ccccc1I
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.5 %

Procedure:
To a stirred solution of 4-iodo-1-trityl-1H-imidazole (300 mg, 0.688 mmol) in anhydrous THF (4 mL) at room temperature was added EtMgBr (1.0 M in THF, 0.802 mmol, 0.8 mL) dropwise, under an atmosphere of N2. The resulting solution was allowed to stir for 90 min and anhydrous ZnCl2 (109 mg, 0.802 mmol) was added. The resulting white suspension was allowed to stir for 90 min and a solution of the (2S,5R)-2-(2-iodophenethyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (237 mg, 0.573 mmol) in THF (1 mL) was added followed by the immediate addition of Pd(PPh3)4 (33 mg, 0.029 mmol). The reaction mixture was allowed to stir at 70° C. for 12 h under an atmosphere of N2. After cooling to room temperature, the solution was diluted with CH2Cl2 (10 mL) and the organic layer was washed with an EDTA (aq) buffer (pH=9) (2×5 mL) and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to afford the desired product as yellow oil (87 mg, 0.146 mmol, 29%). 1H NMR: 0.70 (d, 3H, J=6 Hz), 1.02 (d, 3H, J=7.2 Hz), 1.72-1.81 (m, 1H), 2.01-2.08 (m, 1H), 2.15-2.24 (m, 1H), 2.80-3.09 (m, 2H), 3.54 (s, 3H), 3.56 (s, 3H), 3.86-3.91 (m, 214), 6.94 (d, 1H, J=1.2 Hz), 7.15-7.22 (m, 9H), 7.27 (d, 1H, J=1.6 Hz), 7.32-7.36 (m, 8H), 7.48 (d, 1H, J=1.2 Hz), 7.58-7.61 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[N:12][C:10]=3[NH:11][C:7]=2[CH:6]=[N:5][C:4]=1[C:16]#[N:17])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:25][C:14]1[CH:13]=[N:12][C:10]2[NH:11][C:7]3[CH:6]=[N:5][C:4]([C:16]#[N:17])=[C:3]([CH2:1][CH3:2])[C:8]=3[C:9]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1c(C#N)ncc2[nH]c3ncccc3c12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1c(C#N)ncc2[nH]c3ncc(Br)cc3c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To a solution of 5-ethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (48 mg, 0.21 mmol) in DMF (1 mL) was added NBS (54 mg, 0.30 mmol) then the reaction mixture was stirred for 18 h at ambient temperature. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with saturated aqueous sodium carbonate (10 mL). The aqueous phase was washed with DCM (2×10 mL), the combined organic phase was washed with saturated brine (2×10 mL) and concentrated in vacuo to afford the title compound as a yellow solid (50 mg, 79%). LCMS (Method B): RT=3.34 min, M+H+=301/303.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2=[N:12][CH:13]=[N:14][C:15]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[C:10]2[CH:9]=[N:8]1.Cl.CCO.C(=O)([O-])[O-]>CO>[NH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:17]([NH:16][C:15]2[N:14]=[CH:13][N:12]=[C:11]3[NH:7][N:8]=[CH:9][C:10]=23)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCCCC(Nc2ncnc3c2cnn3COCC[Si](C)(C)C)C1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CO
Product: c1nc(NC2CCCCNC2)c2cn[nH]c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Tert-butyl 3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)azepane-1-carboxylate (0.5 g, 1.1 mmol) was dissolved conc HCl:EtOH (1:3, 10 mL) and the solution was heated to 60° C. for 4 h. The reaction mixture was concentrated in vacuo and the residue obtained was dissolved in MeOH and treated with solid supported carbonate resin to neutralize the solution. The reaction mixture stirred for 2 h and filtered off slurry, washed solid with MeOH (2×20 mL). The filtrate was concentrated in vacua to afford the titled intermediate (200 mg, 80%), which was used in the next step without further purification. LCMS: m/z [M+1]=233.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:18])([CH3:17])[CH:15]=[CH2:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:19].[Na].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:18])([CH3:17])[CH2:15][CH2:16][NH2:19])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C=CC(C)(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: N
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(O)(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
24.2 g of 3-(4'-fluoro-4-biphenylyl)-1-buten-3-ol (obtainable from 4-acetyl-4'-fluorobiphenyl and vinylmagnesium bromide) are heated with 8 g of ammonia and 0.25 g of sodium for 8 hours at 180° - 200°, and the mixture is cooled and worked up with water and chloroform to give 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutylamine, m.p. 144° - 146°.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]([CH:22]([CH3:24])[CH3:23])[C:7]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8])=[O:4].[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C@H:6]([NH:5][C:3](=[O:4])[CH2:2][N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)[CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:11]2)=[CH:16][CH:17]=1
Reactant: CC(C)[C@@H](NC(=O)CCl)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)[C@@H](NC(=O)Cn1cccn1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 75 °C
Yield: 93.4 %

Procedure:
In a sealed vial were added consecutively (R)-2-chloro-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)acetamide (31.4 mg, 0.085 mmol), pyrazole (11.5 mg, 0.17 mmol), K2CO3 (35.2 mg, 0.26 mmol) and acetonitrile (0.4 mL). The reaction mixture was then heated at 75° C. for 36 h, cooled to rt., and the solids were filtered. The filtrate was concentrated and purified by preparative HPLC to provide Example 290, (R)—N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-2-(1H-pyrazol-1-yl)acetamide (32 mg, 94% yield) as a white solid. MS found: 403.3 (M+H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:8]=1[C:17]([F:20])([F:19])[F:18].Cl[CH2:22]Cl>>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:22])=[O:15])=[CH:9][C:8]=1[C:17]([F:20])([F:19])[F:18]
Reactant: ClCCl
Reactant: COc1ccc(CC(=O)O)cc1C(F)(F)F
Agent: BrB(Br)Br
Product: COC(=O)Cc1ccc(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.2 %

Procedure:
Boron tribromide (8.02 mL, 84.87 mmol) was added dropwise to 2-(4-methoxy-3-(trifluoromethyl)phenyl)acetic acid (3.31 g, 14.13 mmol) in dichloromethane (250 mL) while maintaining the temperature below 10° C. After complete addition the reaction mixture was removed from the ice bath and allowed to stir at ambient temperature under nitrogen for 90 minutes. The reaction mixture was added dropwise to ice cold methanol (150 mL) and the mixture was stirred at ambient temperature for a further 40 minutes. The reaction mixture was evaporated to afford to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4-hydroxy-3-(trifluoromethyl)phenyl)acetate (1.100 g, 33.2%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[N:6]([CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])[CH:7]=1
Reactant: C=CC(=O)OC
Reactant: Cc1cc(=O)[nH]cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCn1cc(Br)c(C)cc1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-4-methylpyridin-2(1H)-one (1.0 g, 5.3 mmol) in DMF (10 mL), K2CO3 (1.5 g, 10.6 mmol) was added, followed by addition of methyl acrylate (0.91 g, 10.6 mmol) at 80° C. The mixture was stirred at 80° C. for 1 h. The mixture was allowed to cool to room temperature and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][C:7]=1[CH:14]=[CH2:15])(=[O:4])=[O:3].Cl.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](O)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:29]([NH:11][CH2:10][C:9]2[CH:12]=[CH:13][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:7]([CH:14]=[CH2:15])[CH:8]=2)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: C=Cc1cc(CN)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(C=C(C(=O)O)c2ccccc2)cc1
Agent: Cl
Product: C=Cc1cc(CNC(=O)C(=Cc2ccc(C(C)(C)C)cc2)c2ccccc2)ccc1NS(C)(=O)=O
Yield: 46 %

Procedure:
4-Methanesulfonylamino-3-vinyl-benzylamine and HCl salt (153 mg, 0.582 mmol) were reacted with 3-(4-tert-butyl-phenyl)-2-phenyl-acrylic acid (160.4 mg) to give 3-(4-tert-butyl-phenyl)-N-(4-methanesulfonylamino-3-vinyl-benzyl)-2-phenyl-acrylamide (130.8 mg, 46%).
Reaction SMILES: [CH3:1][CH:2]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)C.Cl[CH2:20][CH2:21][N:22]=[C:23]=[S:24]>C(N(CC)CC)C>[CH3:1][CH:2]([N:8]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:23]1[S:24][CH2:20][CH2:21][N:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(C)NCc1cccnc1
Reactant: S=C=NCCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCC(C)N(Cc1cccnc1)C1=NCCS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To 3.1 g. of N-(1-methylhexyl)-[(3-pyridyl)methyl]amine dissolved in approximately 20 ml. of ethanol-free chloroform was added 1.8 g. of 2-chloroethylisothiocyanate followed by 2.08 ml. of triethylamine. The reaction mixture was stirred at room temperature overnight and then refluxed for approximately 4 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica gel while eluting with chloroform/acetone to afford approximately 4.0 g. of the desired product. Yield 91%.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]#[CH:9])[C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([CH2:10][O:11]CC=C)[C:4](=[O:22])[N:3]1[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:5]2([CH2:10][OH:11])[C:4](=[O:22])[N:3]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:24]=3)[C:2](=[O:1])[N:6]2[CH2:7][C:8]#[CH:9])=[CH:16][CH:17]=1
Reactant: C#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(COCC=C)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.45 g of 4-[2,5-dioxo-4-(4-fluorophenyl)-4-[(2-prop enyloxy)methyl]-3-(2-propynyl)imidazolidin-1-yl]-2-trifluoromethylbenzonitrile obtained in step 1 is dissolved in 5 mL of DCM under argon atmosphere. 0.2 mL of trifluoroborane-dimethylsulfide complex is added. The mixture is stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution is slowly added. The product is extracted with DCM and the organic layer is dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 6/1 DCM/ethyl acetate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9](Br)[CH:10]=[C:5]2[O:4][C:3]1=[O:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O:38][C:39]([CH3:41])=[CH2:40])(=O)C.C[O-].C([Sn+](CCCC)CCCC)CCC>C1C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([CH2:40][C:39](=[O:38])[CH3:41])[CH:10]=[C:5]2[O:4][C:3]1=[O:12]
Reactant: Cn1c(=O)oc2cc(Br)cnc21
Reactant: C=C(C)OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(=O)Cc1cnc2c(c1)oc(=O)n2C
Temperature: 70 °C

Procedure:
3-Methyl-6-bromo-oxazolo[4,5-b]pyridin-2(3H)-one (2.58 g) (0.012 mole) in 80 ml of benzene is treated with 365 mg tri-o-tolylphosphine, 138 mg palladium acetate, 1.87 g (0.018 mole) of isopropenyl acetate and 5.9 g (0.18 mole) of tributyltin methoxide. This is sealed in a high pressure tube and heated to 70° C. for 25 hours. The reaction mixture is then quenched with 20 ml sat. ammonium chloride and diluted with 50 ml ethyl acetate. The organic phase separates, dried over sodium sulfate and concentrated to dryness. The residue is dissolved in methylene chloride, washed with sat. KF solution, filtered through a cotton plug, dried over sodium sulfate and concentrated to dryness to obtain crude product. This is chromatographed using 200×60 mm SiO2, EtOAc (100%) as eluent. The desired product is identified by NMR and used directly in the next step.