Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:24]([O:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[CH3:25].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:31](=[O:32])[CH2:30][NH:29][C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CCOC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CNC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A mixture of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (173 mg, 0.488 mmol), 2-(ethoxycarbonylamino)acetic acid (86 mg, 0.488 mmol), EDCl (140 mg, 0.732 mmol), DIPEA (0.128 ml, 0.732 mmol) and HOAt (100 mg, 0.732 mmol) in DMF (2.5 ml) is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, and then the precipitated solid is collected on a funnel, washed with H2O, and dried under reduced pressure to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-(ethoxycarbonylamino)acetamido)butanoate (161 mg); HPLC retention time=1.16 minutes (condition B); MS (m+1)=447.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.07 Hz, 3H) 1.29 (t, J=7.07 Hz, 3H) 2.50 (A of ABX, Jab=16.2 Hz, Jax=5.3 Hz, 1H) 2.54 (B of ABX, Jab=16.2 Hz, Jbx=5.3 Hz, 1H) 2.89 (A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1H) 2.99 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1H) 3.80 (be d, J=5.8 Hz, 2H) 4.12-4.23 (m, 4H) 4.48-4.56 (m, 1H) 5.15 (br s, 1H) 6.64 (br d, J=8.8 Hz, 1H) 7.25-7.27 (m, 2H) 7.29-7.38 (m, 2H) 7.43-7.46 (m, 1H) 7.49-7.52 (m, 2H) 7.55-7.56 (m, 1H).
Reaction SMILES: P(Cl)(Cl)Cl.[CH2:5]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O)[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8]>C(O)(=O)C>[CH2:5]([NH:11][C@@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)[CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)CCN[C@@H](CC(=O)O)C(=O)O
Solvent: ClP(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)CCN[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Phosphorous trichloride (3.7 ml, 43 mmol) was added, dropwise, to a 10° C. slurry of N-neohexyl-L-aspartic acid (11.6 g, 53.4 mmol) in glacial acetic acid (50 ml). After addition was complete (0.5 hr), the resulting clear solution was stirred at room temperature overnight. The resulting solid precipitate was collected by vacuum filtration, washed with acetic acid and methylene chloride, then dried at 35-40° C. for 3 hours to give 3.62 g (69.8%) of pure N-neohexyl-L-aspartic anhydride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]([NH2:19])=[S:18])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:21]=[C:22]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:19]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)CBr
Reactant: NC(=S)Nc1ncc(Br)cc1OCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1

Procedure:
1-(3-(Benzyloxy)-5-bromopyridin-2-yl)thiourea (2.00 g, 5.91 mmol), methyl 5-bromo-4-oxopentanoate (1.48 g, 7.10 mmol) (prepared according to Synthetic Communications (1994) 2557-2562), and triethylamine (1.44 mL, 10.3 mmol) were heated in methanol (50 mL) at reflux for 3 hours according to the method of Example 2, Step C, to provide methyl 3-(2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazol-4-yl)propanoate as a light yellow powder. 1H NMR (DMSO-d6) δ 10.26 (bs, 1H), 7.97 (s, 1H), 7.35-7.63 (m, 6H), 6.66 (bs, 1H), 5.29 (s, 2H), 3.59 (s, 3H), 2.85 (t, 2H), 2.69 (t, 2H). Mass spectrum (esi) m/z=448 (96), 450 (100).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11]([F:14])([F:13])[F:12])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:14][C:11]([F:12])([F:13])[C:7]1[O:8][CH:9]=[CH:10][C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1ccoc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccoc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-trifluoromethyl-furan-3-carboxylic acid ethyl ester (2.2 g, 10.5 mmoles) in tetrahydrofuran (150 ml) was treated portionwise during 0.5 h with lithium aluminium hydride (0.55 g, 14.5 mmoles) under a nitrogen atmosphere. When the addition was complete the mixture was stirred at room temperature for 18 h, then quenched by the addition of excess acetone (1 ml) and then water (1 ml). After diluting with ethyl acetate (200 ml) the grey precipitate was removed by filtration. The filtrate was dried and evaporation of the solvent afforded (2-trifluoromethyl-furan-3-yl)-methanol as a colourless oil. This material was used immediately in the next step. (ii) A solution of the (2-trifluoromethyl-furan-3-yl)-methanol from (i) in dry dichloromethane (180 ml) was treated with chloro-tri-isopropyl-silane (2.6 g, 13.4 mmoles) and imidazole (1.45 g, 21.3 mmoles) and the mixture was stirred overnight at room temperature. Further aliquots of chloro-tri-isopropyl-silane (0.9 g, 4.64 mmoles) and imidazole (0.5 g, 7.34 mmoles) were added and the mixture was stirred for 3 h. The reaction mixture was diluted with water, the organic phase separated and washed sequentially with 0.1M aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and brine. After drying, evaporation of the solvents afforded a colourless oil. The oil was distilled under reduced pressure (0.05 torr) in a Kugelruhr apparatus collecting the fraction boiling at an oven temperature of 125±20° C. to afford compound 88 as a colourless oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:22]#[N:23])[N:15]([CH2:24][C:25]3[CH:29]=[C:28]([C:30]4[S:31][C:32](Cl)=[CH:33][CH:34]=4)[O:27][N:26]=3)[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH2:36][OH:37].[ClH:38].CC([O-])(C)C.[K+]>CO>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:22](=[NH:23])[NH:36][OH:37])[N:15]([CH2:24][C:25]3[CH:29]=[C:28]([C:30]4[S:31][C:32]([Cl:38])=[CH:33][CH:34]=4)[O:27][N:26]=3)[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(NC(=O)c2nn(Cc3cc(-c4ccc(Cl)s4)on3)c3cccc(C#N)c23)CC1
Reactant: Cl
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)N1CCC(NC(=O)c2nn(Cc3cc(-c4ccc(Cl)s4)on3)c3cccc(C(=N)NO)c23)CC1
Temperature: 50 °C

Procedure:
To a solution of 200 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-cyano-1H-indazole-3-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide in 3 mL methanol, 27 mg NH2OH*HCl and 44 mg KOt-Bu were added and the mixture was heated to 50° C. for 3 d. After cooling to RT the precipitated inorganic salts were filtered off. The precipitate was washed with methanol (2×5 ml) and the combined filtrates were collected and concentrated under reduced pressure. The residue was subjected to the next reaction step without further purification. Yield: 223 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C([O-])(=[O:30])C.[Na+].OO>C1COCC1.CCCCCC.CCOC(C)=O>[OH2:5].[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]1[CH2:12][CH2:13][OH:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: CC(=O)[O-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)C[C@H]1CCO
Product: O
Temperature: 25 °C
Reaction time: 2 h
Yield: 140.6 %

Procedure:
To a solution of (1R,2S)-ethyl 1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate (15.3 g, 59.9 mmol) in THF (100 ml) was added 9-BBN (180 ml, 90 mmol) dropwise at 0° C. The formed solution was stirred at room temperature for 2 hr. The final solution was cooled back to 0° C. while 3 M aqueous solution of sodium acetate (180 ml, 540 mmol) was added. To this well stirred mixture, Hydrogen peroxide (89 ml, 30%, 869 mmol) was added dropwise (Caution should be exercised since the addition was exothermic). The formed warm two layer mixture was stirred overnight. The upper organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel column, eluted with 4:1, 3:1, 2:1, then 3:2 Hexane-EtOAc to afford the desired product (1R,2S)-ethyl 1-(tert-butoxycarbonylamino)-2-(2-hydroxyethyl)cyclopropanecarboxylate (11.50 g, 42.1 mmol, 70.2% yield) as a viscous oil, which solidified upon standing on the bench. 1H NMR (CDCl3) δ 1.18-1.21 (m, 1H), 1.25 (t, J=7 Hz, 3H), 1.35-1.40 (m, 1H), 1.44 (s, 9H), 1.61-1.65 (m, 1H), 1.70-1.75 (m, 1H), 1.91-1.98 (m, 1H), 3.61-3.65 (m, 1H), 3.71-3.75 (m, 1H), 4.10-4.21 (m, 2H), 5.17 (b, 1H).
Reaction SMILES: [CH:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1)=O.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:1][CH:3]2[C:12]3[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=3)[O:6][CH2:5][CH2:4]2)[CH2:30][CH2:29]1
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: N#Cc1ccc2c(c1)OCCC2C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CCN2CCN(CC3CCOc4cc(C#N)ccc43)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-formyl-3,4-dihydro-2H-chromene-7-carbonitrile (50 mg, 0.27 mmol) in DCM (3 mL) was added 4-methyl-5-[2-(piperazine-1-yl)ethyl]-2-benzofuran-1(3H)-one (57 mg, 0.27 mmol), sodium triacetoxyborohydride (27.0 mg, 0.267 mmol) and DIPEA (57 mg, 0.27 mmol). The reaction was stirred under nitrogen at room temperature for 16 hours when LC-MS indicated product formation. The mixture was diluted with DCM and the product was isolated by flash chromatography. LC-MS (IE, m/z): 432 [M+1]+. (0.18 μM)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:16]=3[O:15][CH2:14]2)=[CH:9][CH:8]=1.C1CCN2C(=NCCC2)CC1.[CH3:40][C:41]([O:44][C:45]([NH:47][CH:48](P(OC)(OC)=O)[C:49]([O:51][CH3:52])=[O:50])=[O:46])([CH3:43])[CH3:42]>C(Cl)Cl.O>[CH3:52][O:51][C:49](=[O:50])[C:48]([NH:47][C:45]([O:44][C:41]([CH3:40])([CH3:42])[CH3:43])=[O:46])=[CH:23][C:21]1[CH:20]=[CH:19][C:17]2[O:18][C@@H:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=4)=[CH:12][CH:11]=3)[CH2:14][O:15][C:16]=2[CH:22]=1
Reactant: O=Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COC(=O)C(=Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (9.9 g) was dissolved in 80 mL dry DCM under nitrogen at rt and 7.2 mL DBU (7.33 g) was added by syringe. 7.44 g of Boc-phosphonoglycine trimethyl ester in 40 mL dry DCM was added by syringe all at once and the mixture stirred at rt for 18 h. It was then diluted with 0.5 L each of DCM and water and extracted, and the organic layer was dried with brine and Na2SO4 and evaporated. The residue was purified by crystallization from EtOAc/hexanes to give 12 g desired product after drying under vacuum. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.34 (m, 2H), 7.28-7.24 (m, 1H), 7.23-7.17 (m, 2H), 7.11 (m, 1H), 6.98 (m, 2H), 6.93 (d, 1H), 5.10 (m, 1H), 5.03 (s, 2H), 4.32 (m, 1H), 4.01 (m, 1H), 3.84 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH:14]=[CH2:15])[S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].C(N(CC)CC)C>O1CCCC1>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:10]1[CH:11]=[N:12][C:8]([S:5](=[O:7])(=[O:6])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:13][CH:14]=[CH2:15])=[N:9]1)=[O:20])[CH3:17]
Reactant: C=CCN(CC=C)S(=O)(=O)c1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)S(=O)(=O)c1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 6.9 g. 3-diallylsulphamoyl-1,2,4-triazole, 4.5 g. diethylcarbamoyl chloride, 6ml. triethylamine and 25 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 1.5 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated to remove solvent. The solid residue was recrystallized from petroleum ether, b.p. 60°-80° C., to give 1-diethylcarbamoyl-3-diallylsulphamoyl-1,2,4-triazole, m.p. 49°-51° C. Elemental analysis satisfactory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][C:20]=1[O:27][CH3:28].C(N(CC)CC)C.C(OCC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([OH:18])=[C:20]([O:27][CH3:28])[CH:21]=1
Reactant: COc1cc(CN)ccc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
An amount of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.3 g, 1.06 mmol) in N,N′-dimethylformamide is added to 0.2 g (1.06 mmol) of 4-hydroxyl-3-methoxybenzylamine hydrochloride, and 0.22 mL (2.12 mmol) of triethylamine. The reaction mixture is stirred at room temperature under N2 for 2 h. Diethyl ether is added and the resulting tan precipitate is collected and washed successively with methanol, ether, and hexane to yield 0.28 g (65.1% yield) of light yellow solid: mp 260-261° C.; 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.69 (m, 1H), 9.02 (bs, 1H), 8.71 (d, J=9 Hz, 1H), 8.10 (s, 1H), 7.87 (d, J=9 Hz, 1H), 7.30 (d, J=6 Hz, 1H), 7.02 (s, 1H), 6.78 (m, 2H), 4.60 (d, J=4.8 Hz, 2H), 3.78 (s, 3H); MS (ESI) m/z 403.1 (M−H)−1, Analysis for C18H15BrN2O4.(0.33H2O), Calcd: C, 52.98; H, 3.76; N, 6.96. Found: C, 52.83; H, 3.86; N, 6.85.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]1=[O:17].N1C=CC=CC=1.[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27](Cl)=[O:28])[CH3:25]>>[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27]([O:17][C:9]1[CH2:10][C:11]([CH3:15])([CH3:16])[CH2:12][C:13](=[O:14])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:28])[CH3:25]
Reactant: CC1(C)CC(=O)C(c2ccccc2Cl)C(=O)C1
Reactant: CCCCC(CC)C(=O)Cl
Solvent: c1ccncc1
Product: CCCCC(CC)C(=O)OC1=C(c2ccccc2Cl)C(=O)CC(C)(C)C1
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 1.009 (3.99 mmol) of 2-(2'-chlorophenyl)-5,5-dimethyl-1,3-cyclohexanedione and 0.03 g (8.0 mmol) of pyridine was cooled in an ice bath and stirred under N2. The 2-ethylhexanoyl chloride (0.69 g, 4.25 mmol) was added, the mixture was then allowed to warm to room temperature, stirred at room temperature for one hour and refluxed for one hour. The solvent was removed under reduced pressure and the residue taken up in ether and water. The ether was washed three times with 0.25N NaOH, three times with 10% HCl and with water. The ether was dried over anhydrous MgSO4 and decanted to give 1.23 g (82%) of 3-(2'-ethylhexanoyloxy)-2-(2'-chlorophenyl)-5,5-dimethyl-2-cyclohexenone as a clear colorless oil which was homogeneous by thin layer chromatograpy.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]([C:32](Cl)=[O:33])=[CH:24]1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:32]([C:25]3[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:23][CH:24]=3)=[O:33])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)c1csc2ccccc12
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)c3csc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 1-benzothiophene-3-carbonyl chloride: ESMS m/e: 464.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[Cs+].[Cs+].BrCCl.O>CN(C)C=O.C(OCC)C>[F:1][C:2]1[C:3]2[O:10][CH2:11][O:9][C:4]=2[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(F)c1O
Reactant: O=C([O-])[O-]
Agent: ClCBr
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Fc1cc(F)c2c(c1)OCO2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
3,5-Difluorobenzene-1,2-diol (10 g, 69 mmol) was dissolved in dry N,N-dimethylformamide (100 mL), treated with cesium carbonate (56 g, 170 mmol) and stirred for 30 min at 20° C. Bromochloromethane (12 g, 90 mmol) was added and the mixture was heated and stirred at 60° C. for 19 h. After cooling, the mixture was shaken with water (100 mL) and diethyl ether (100 mL). The aqueous phase was extracted again with ether (50 mL). The combined extracts were washed with water (2×20 mL), washed with saturated NaCl (1×10 mL) and dried (Na2SO4). The bulk of the ether was removed by atmospheric distillation through a 300 mm Vigreux column. The pressure was reduced to 75 mmHg and the product was distilled at 70-90° C. to give the title compound as a thick oil (3.0 g, 28%): 1H NMR (400 MHz, CDCl3) δ 6.45 (m, 1H), 6.42 (d, J=2.4 Hz, 1H), 6.39 (d, J=2.4 Hz, 1H), 6.02 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −117.99, −135.90; EIMS m/z 158.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[C:6]([N:13]1CCC(=O)[CH2:15][CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:9]([O:8][C:6]([N:13]1[CH2:14][CH2:15][C:4](=[CH2:5])[CH2:3][CH2:2]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a cooled suspension of methyl triphenyl phosphonium bromide (47.0 g, 132 mmol) in THF (330 mL) was added n-BuLi (85.0 mL, 136 mmol). 1-Boc-4-piperidone (25.0 g, 125 mmol) was added via cannula as a solution in THF. The resulting mixture was kept at 0° C. and allowed to warm to r.t. over 2 h. The reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl. The resulting precipitate was filtered off and the layers were separated. The remaining aqueous layer was extracted with Et2O and the combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified (FCC) to give 4-methylene-piperidine-1-carboxylic acid tert-butyl ester (22 g, 91%)
Reaction SMILES: C(N1C[C@H](OCC)[C@H](NC2C(CC)=NC(C3C=CC(Cl)=CC=3Cl)=C(CC)N=2)C1)(=O)C.[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[C:40]1[N:41]=[C:42]([CH2:58][CH3:59])[C:43]([NH:48][C@H:49]2[C@@H:53]([O:54][CH2:55][CH2:56][F:57])[CH2:52][NH:51][CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47].Cl[C:61]([O:63][CH3:64])=[O:62]>>[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[C:40]1[N:41]=[C:42]([CH2:58][CH3:59])[C:43]([NH:48][C@H:49]2[C@@H:53]([O:54][CH2:55][CH2:56][F:57])[CH2:52][N:51]([C:61]([O:63][CH3:64])=[O:62])[CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CNC[C@@H]1OCCF
Reactant: COC(=O)Cl
Agent: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OC)C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrolidin-3-yl]pyrazin-2-amine and methyl chloroformate, and making non-critical variations provided the title compound as an oil: 1H NMR (DMSO-d6) δ 1.08, 1.15, 2.37, 2.65, 3.54, 3.60, 3.71, 3.82, 4.25, 4.43, 4.54, 5.93, 6.98, 7.10, 7.26; IR (liq.) 2972, 2068 (w), 1996 (w), 1707 (s), 1607, 1566, 1484 (s), 1454 (s), 1393 (s), 1287, 1230, 1197, 1175, 1128, 1104, cm−1
Reaction SMILES: N#N.[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[CH3:28][C:29]1[NH:30][C:31]([CH3:40])=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>CCCCCC.CCOCC>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:36]3[N:35]=[C:34]([C:33]4[CH:32]=[C:31]([CH3:40])[NH:30][C:29]=4[CH3:28])[CH:39]=[CH:38][CH:37]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Brc1ccc(C2CCN(Cc3ccccc3)CC2)cc1
Reactant: Cc1cc(-c2ccccn2)c(C)[nH]1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(-c2cccc(-c3ccc(C4CCN(Cc5ccccc5)CC4)cc3)n2)c(C)[nH]1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 32.3 %

Procedure:
To a 125 mL three-necked round-bottomed flask equipped with septum and N2 inlet were added 2.93 g (8.88 mmol) N-benzyl-4-(4-bromophenyl)piperidine and 30 mL dry ether. The solution was cooled to −70° C., and 6.66 mL (10.65 mmol) of a 1.6 N solution of butyl lithium in hexane added dropwise over 5 minutes. After stirring a further 5 minutes at −70° C., the solution was warmed slowly to room temperature over 25 minutes. A solution of 1.83 g (10.65 mmol) 2-(2,5-dimethylpyrrolyl)pyridine in 10 mL dry ether was then added dropwise over 5 minutes, and the reaction, which turned slowly dark red, stirred at room temperature for 3 hours. The reaction was quenched with aqueous ammonium chloride solution, partitioned between ethyl acetate and water, and the organic layer separated, washed with brine, and dried over sodium sulfate, allowing it to stand overnight to effect rearomatization of the pyridine ring. After evaporation of the solvent, the residue was chromatographed on silica gel using ethyl acetate/hexane followed by methanol/methylene chloride as eluant to afford 1.21 g (32%) of an oil.