Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[N:18]=1)[CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][OH:27].C1C=CC2N(O)N=NC=2C=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[N:18]=1)[CH2:12][C:13]([NH:24][CH2:25][CH2:26][OH:27])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=C(O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Agent: NC(CO)(CO)CO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1)NCCO

Procedure:
A mixture of N-[(benzyloxy)carbonyl]-N-[(6-bromopyridin-2-yl)methyl]glycine (Example 179, Step 3) (112 mg, 0.295 mmol), 2-aminoethanol (18 μL, 0.295 mmol), HOBt (59 mg, 0.325 mmol) and PS-CDI (586 mg, 0.732 mmol) in DCM (4.0 mL) was irradiated in the microwave at 100° C. for 5 min. To this mixture, MP-isocyanate (967 mg, 1.22 mmol), PS-trisamine (393 mg, 1.34 mmol) and DCM (5.0 mL) were added and irradiated in the microwave at 100° C. for 10 min. The reaction mixture was filtered, washed with DCM and the filtrate was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: [C:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C:2]=1[CH2:3][CH2:4][CH2:5][CH2:6]2.[BH4-].[Na+].Cl>O1CCCC1>[OH:11][CH:10]1[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[C:7](=[O:8])[O:9]1
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC(O)C2=C1CCCC2
Temperature: 25 °C

Procedure:
To a solution of 1-cyclohexene-1,2-dicarboxylic anhydride (25.2 g) in tetrahydrofuran (125 mL) at 0° C. was added sodium borohydride (1.51 g). The mixture was warmed to ambient temperature for 30 minutes, heated at reflux for 5 hours, cooled, treated with 1N hydrochloric acid and concentrated. The concentrate was partitioned between ethyl acetate and brine, and the organic layer was washed with brine and water and concentrated. The concentrate was purified by flash chromatography with 50% ethyl acetate in hexane.
Reaction SMILES: [F-].[Cs+].Br[C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[C:6]([F:12])[CH:5]=1.[CH:13](/B(O)O)=[CH:14]\[CH3:15].CCCCCC>O1CCOCC1.O>[F:10][C:8]1[CH:9]=[C:4](/[CH:13]=[CH:14]/[CH3:15])[CH:5]=[C:6]([F:12])[C:7]=1[F:11]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: C/C=C/B(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: CCCCCC
Solvent: O
Solvent: C1COCCO1
Product: C/C=C/c1cc(F)c(F)c(F)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
Tetrakistriphenylphosphine palladium (0) (4.66 g) and cesium fluoride (21.4 g) were added to a solution of 1-bromo-3,4,5-trifluorobenzene (8.5 g) and trans-1-propen-1-ylboronic acid (4.1 g) in dioxane (95 ml) and water (5 ml) in a nitrogen atmosphere, and the reaction solution was stirred at 80° C. for five hours. The reaction solution was returned to room temperature. Then, hexane and water were added to the reaction solution, and the insoluble matter was removed by filtration. The organic layer was separated and then washed with water, and the insoluble matter was removed by filtration again. The organic layer was separated and then sequentially washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane) to obtain 5.83 g of the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.ClC1C=CC2SC(C=C3C=C(C)C4C(=CC=CC=4)O3)=[N+](CC)C=2C=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.ClC1C=CC2SC(SCC)=[N+](CC)C=2C=1.C(#N)C>C(N(CC)CC)C>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CCSc1sc2ccc(Cl)cc2[n+]1CC
Agent: CC[n+]1c(C=C2C=C(C)c3ccccc3O2)sc2ccc(Cl)cc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O)cc1
Yield: 211.5 %

Procedure:
5.2 g of 5-chloro-3-ethyl-2-{(4-methyl-2H-chromen-2-ylidene)methyl}-benzothiazolium p-toluenesulfonate and 4.3 g of 5-chloro-3-ethyl-2-ethylthiobenzothiazolium p-toluenesulfonate were added to 140 ml of acetonitrile and dissolved under heat, and then 4.5 ml of triethylamine was added thereto and reacted for 5 minutes. After cooling the precipitated crystals were separated by filtration and recrystallized from a mixed solvent of methanol/chloroform, to obtain 3.6 g of the desired p-toluenesulfonate product. Yield: 50%. Appearance: Brilliant brown crystal. M.p.: above 240° C. (decomposition). ##STR11##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Br:16])[CH:10]=1>>[Br:8][C:9]1[CH:14]=[C:13]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=[C:11]([Br:16])[CH:10]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: Nc1cccnc1
Product: Brc1cc(Br)cc(Nc2cccnc2)c1

Procedure:
3-Aminopyridine was coupled with 1,3,5-tribromobenzene to give (3,5-dibromo-phenyl)-pyridin-3-yl-amine by the method described in Example 44. The reaction was complete in 1 hour. The dibromide was converted to N-[3-bromo-5-(pyridin-3-ylamino)-phenyl]-acetamide by the method of Example 82.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.C(Cl)Cl.C(N(CC)CC)C.[C:48](Cl)(=[O:51])[CH2:49][CH3:50]>>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:34])(=[O:33])[N:35]([CH3:36])[CH3:37])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][C:48](=[O:51])[CH2:49][CH3:50])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CCO)CC2
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c(OC)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-hydroxy-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide (80.0 mg, 0.146 mmol) was stirred in Methylene chloride (1.60 mL, 25.0 mmol) with Triethylamine (30.6 μL, 0.219 mmol) at room temperature. Propanoyl chloride (12.7 μL, 0.146 mmol) was then added quickly under nitrogen. The reaction was complete after stirring over night. The reaction mixture was washed with bicarb and extracted with XS DCM. The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on an ISCO flash system (0-10% MeOH:DCM). The desired fractions were concentrated and the product was obtained as a foam from a small amount of DCM (35 mg, 40%). mp: 40° C. softened, 60-70 glass, MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.57 (t, 1H), 7.51 (s, 1H), 7.25 (m, 1H), 6.67 (s, 1H), 4.25 (t, J=6 Hz, 2H), 3.89 (s, 3H), 2.87 (m, 2H), 2.83 (t, J=6 Hz, 2H), 2.76-2.72 (m, 12H), 2.36 (t, J=7.5 Hz, 2H), 1.17 (t, J=7.5, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.C([Li])CCC.[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1.Cl>O1CCCC1.O>[OH:20][C:16]1([CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[CH2:17][CH2:18][CH2:19][N:14]([CH3:13])[CH2:15]1
Reactant: Cc1cc(C)on1
Reactant: CN1CCCC(=O)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CC2(O)CCCN(C)C2)on1
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dimethylisoxazol (4.86 g, 50 mmol) in dry tetrahydrofuran (15 ml) cooled to -78° C was added butyllithium (2.5 M in hexane, 50 mmol). The reaction mixture was stirred for 0.5 h. 1-methyl-piperidin-3-one (2.70 g, 23.9 mmol) dissolved in tetrahydrofuran (25 ml) was added. The reaction mixture was stirred for another 2 h at -78° C. Water (50 ml) was added and the reaction mixture was acidified with concentrated hydrochloric acid. The water phase was extracted with ether (2×50 ml), then made alkaline with potassium carbonate and extracted with methylene chloride (4×50 ml). The combined methylene chloride phases were dried over magnesium sulphate and evaporated giving the title compound in 4.18 g (83%) yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[CH:36]1(B(O)O)[CH2:38][CH2:37]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:36]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH2:38][CH2:37]1
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cn(-c2ccc(C3CC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 100 °C
Yield: 63.6 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (255 mg, 0.5 mmol), cyclopropylboronic acid (55.8 mg, 0.65 mmol), K3PO4 (372 mg, 1.75 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol) and tricyclohexylphosphine (14 mg, 0.05 mmol) in toluene (2.25 mL) and water (0.11 mL) was heated to 100° C. for 4 h under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (128 mg, 64% yield) as a white solid: mp 140-142° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 0.70-0.82 (2H, m), 0.96-1.10 (2H, m), 1.94-2.09 (1H, m), 3.76 (3H, s), 6.87-7.01 (3H, m), 7.09-7.18 (1H, m), 7.28-7.50 (5H, m), 7.78 (1H, d, J=1.9 Hz), 8.44 (1H, d, J=1.9 Hz). Anal. Calcd for C23H19FN4O2: C, 68.65; H, 4.76; N, 13.92. Found: C, 68.47; H, 4.82; N, 13.84.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]([NH2:24])=[O:23].CC(C)([O-])C.[K+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH2:41][C:42](OC)=O)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40].C1CCCCC1.C(OCC)(=O)C>C(O)C>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:41][C:42]1[NH:24][C:22](=[O:23])[C:3]2[C:4]([CH2:20][CH3:21])=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: CCc1nn(C(CCCc2ccccc2)C(C)O)c(N)c1C(N)=O
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCc1nn(C(CCCc2ccccc2)C(C)O)c2nc(Cc3ccc(OC)c(OC)c3)[nH]c(=O)c12

Procedure:
1.0 g (3.03 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-3-ethyl-1H-pyrazole-4-carboxamide, 1.60 g of potassium tert-butoxide and 1.40 g (19 mmol) of methyl 3,4-dimethoxyphenylacetate are refluxed overnight in 20 ml of ethanol. The solvent is removed in vacuo, the residue is taken up in dichloromethane, the mixture is extracted with 1N HCl, the organic phase is dried over Na2SO4 and evaporated on a rotary evaporator. Purification by chromatography (cyclohexane/EA=2:1, 1% formic acid) and separation of the diastereomers by chromatography gives 232 mg (16%) of the diastereomer which elutes more rapidly, Rf=0.2 (cyclohexane/ethyl acetate=2:1) and 150 mg (10%) of the diastereomer which elutes more slowly, Rf=0.15 (cyclohexane/ethyl acetate=2:1).
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])C>C(O)=O>[CH2:1]([O:8][NH:9][CH:10]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NOCc1ccccc1
Solvent: O=CO
Product: O=CNOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
O-benzylhydroxylamine (4.63 g, 37 mmol) was dissolved into 89% formic acid (80 ml), and 30 ml of acetic anhydride was added dropwise thereto with keeping the temperature at 50 to 60° C. After adding acetic anhydride, the solution was stirred for 2 hours at room temperature. The organic layer was rinsed and dried, and the solvent was evaporated. The residue was then purified with silica gel chromatography to obtain 3.05 g of N-benzyloxyformamide (yield: 60%). The proton NMR spectrum of the compound is 4.82 bs, 4.93 bs (2H); 7.20-7.47 m (5H); 7.93 bs, 8.30 bs (1H) (solvent: CDCl3).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[NH:6][C:7](=[O:18])[CH2:8][S:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].[H-].[Na+].O.Cl>O1CCCC1>[Cl:23][C:20]1[CH:19]=[C:5]2[C:4]([C:3]([OH:2])=[C:8]([S:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:10])[C:7](=[O:18])[NH:6]2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)CS(=O)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(O)c1S(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g (2.73 mmol) of N-(benzylsulfinyl)acetyl-4-chloro-anthranilic acid methyl ester is placed in 10 ml of tetrahydrofuran at 0°, and 0.13 g (3 mmol) of sodium hydride dispersion in oil (55%) is added thereto. The mixture is then stirred for 15 minutes at 0° and for 2 hours at room temperature. Water is added and the reaction mixture is then adjusted to pH 2-3 with 1N hydrochloric acid and extracted with ethyl acetate. The organic phases are washed with water and brine, combined, dried with sodium sulfate, filtered and concentrated. Crystallisation of the crude product from ethyl acetate/petroleum ether yields 7-chloro-3-(benzylsulfinyl)-4-hydroxy-2(1H)-quinolone in the form of colourless crystals having a melting point of 234° (decomp.).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][C:12]=2[F:19])[CH2:5][CH2:4]1.[Cl:23][C:24]1[C:37]([N:38]=[C:39]=S)=[C:36]([Cl:41])[CH:35]=[CH:34][C:25]=1[CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].CC(C)N=C=NC(C)C>>[F:22][C:2]([F:1])([F:21])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C:11]2[C:12]([F:19])=[CH:13][C:14]3[NH:18][C:39]([NH:38][C:37]4[C:36]([Cl:41])=[CH:35][CH:34]=[C:25]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])[C:24]=4[Cl:23])=[N:17][C:15]=3[CH:16]=2)=[O:20])[CH2:7][CH2:8]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: Nc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(F)cc3[nH]2)c1Cl

Procedure:
The title compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-fluoro-4,5-diamino-benzoic acid amide and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide with DIC in analogy to examples 7b/7c.
Reaction SMILES: [CH2:1](O)[C:2]#[CH:3].[C:5]([CH2:7][C:8]([OH:10])=[O:9])#[N:6].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[C:5]([CH2:7][C:8]([O:10][CH2:3][C:2]#[CH:1])=[O:9])#[N:6]
Reactant: C#CCO
Reactant: N#CCC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: C#CCOC(=O)CC#N
Yield: 71 %

Procedure:
1.6 parts of propargyl alcohol and 1 part of cyanoacetic acid were dissolved in 4.7 parts of chloroform. 0.2 parts of a 98 percent by weight solution of aqueous sulfuric acid were added as a catalyst and the resultant mixture was heated for 5.5 hours at a temperature of 61° C. The crude ester was washed with water. Volatile materials were removed using reduced pressure. The ester, represented the formula N≡CCH2C(O)OCH2C≡CH, was isolated in 71 percent yield.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH:61]([C:63]1[CH:71]=[CH:70][C:66]([C:67](O)=[O:68])=[CH:65][CH:64]=1)=[O:62]>CN(C=O)C.O>[CH:61]([C:63]1[CH:71]=[CH:70][C:66]([C:67]([NH:17][CH2:18][C:19](=[O:20])[N:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]2)=[O:68])=[CH:65][CH:64]=1)=[O:62]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 44.7 %

Procedure:
DIPEA (77 mg, 0.60 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (103 mg, 0.24 mmol) in DMF (0.5 mL). HOBT (32 mg, 0.24 mmol) and EDCI.HCl (45 mg, 0.24 mmol) were then added at room temperature. After 2 minutes, 4-formyl benzoic acid (30 mg, 0.20 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 40 mg (45% yield) of 4-formyl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 74.2%,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (1.00 g, 4.66 mmol) in methanol (10.0 mL) was treated with SOCl2 (0.68 mL, 9.32 mmol). After stirring overnight at ambient temperature, the solution was concentrated in vacuo and taken on without purification. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.04 (d, J=2.3 Hz, 1H) 7.89 (dd, J=8.7, 2.1 Hz, 1H) 6.93 (d, J=8.6 Hz, 1H) 4.66 (qq, J=6.1 Hz, 1H) 3.88 (s, 3H) 1.41 (d, J=6.1 Hz, 6H). MS (ES+) m/e 229 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=[C:10](I)[C:3]=12.[Li][C:23](C)(C)[CH3:24].C(I)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=[C:10]([CH2:23][CH3:24])[C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2c(Cl)ccnc21
Reactant: [Li]C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cn([Si](C(C)C)(C(C)C)C(C)C)c2nccc(Cl)c12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
The 4-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (27.0 g, 62.1 mmol) in THF (300 mL) was cooled to about −75° C. then t-BuLi (1.7 M in pentane, 73.1 mL, 124 mmol) was added over about 30 min keeping the internal temperature below about −70° C. After complete addition, EtI (15.0 mL, 186 mmol) was added. The mixture was warmed slowly to about −40° C. then the mixture was allowed to warm to rt. Saturated aqueous NaHCO3 (50 mL) was added and the mixture was stirred for about 30 min. The mixture was filtered and the solids washed with EtOAc (3×50 mL). The solvents were removed under reduced pressure then the material was partitioned between EtOAc (200 mL) and water (50 mL). The layers were separated then the organic layer was washed with saturated aqueous NaCl (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting material was treated with MeOH (80 mL) then warmed to about 60° C. The mixture was cooled to rt and the resulting slurry stirred overnight at rt. The solids were collected by filtration then washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure then purified by silica gel chromatography using a 120 g silica gel column and eluting with heptane. The material was stirred with MeOH (15 mL) overnight then the solid was collected by filtration and washed with MeOH (2 mL). The solid material was combined with the first crop of solids and dried under reduced pressure to give 4-chloro-3-ethyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (17.4 g, 83%): LC/MS (Table 2, Method g) Rt=3.21 min; MS m/z 337 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[CH:9]([OH:10])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg+]
Reactant: CC(C)(C=O)c1cccc(Cl)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C(C)(C)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a stirred solution of 2-(3-chlorophenyl)-2-methylpropanal (4.6 g, 25.7 mmol) in THF (150 mL) at 0° C. was added MeMgBr (3M in ether, 17.1 mL, 51.3 mmol, 2 eq) dropwise over 2 h. After stirring 1 h at 0° C., the reaction was allowed to warm to room temperature, quenched with 1N HCl and then extracted with EtOAc. The extracts were dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography (silica, Hex/EtOAc=20:1 to 10:1) to give 3-(3-chlorophenyl)-3-methylbutan-2-ol (3.9 g, 78%). 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.28 (m, 2H), 7.18 (m, 1H), 3.85 (q, 1H), 1.32 (d, J=6.4 Hz, 6H), 1.05 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[I:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[I:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1I
Yield: 66.5 %

Procedure:
0.75 g (0.00394 mol) of 1-benzyl-4-hydroxy-piperidine and 0.546 ml (0.00394 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 1.0 g (0.00375 mol) of 2-iodo-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (4:5). 1.05 g (66%) of 1-benzyl-piperidin-4-yl 2-iodo-benzoate were obtained as yellow crystals; m.p. 73°-74°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][CH2:16][C:17]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I[CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][CH2:16][C:17]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][N:25]([CH2:32][CH3:33])[CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(CCC(=O)N1CCC(c2ccc(Cl)cc2)CC1)c1ccc2c(c1)CCNCC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN1CCc2ccc(C(=O)CCC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2CC1
Yield: 47.4 %

Procedure:
A solution of 4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxo-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-butanone (200 mg, 0.47 mmol) obtained in Example 15, iodoethane (0.0376 ml, 0.47 mmol) and potassium carbonate (138 mg, 1.0 mmol) in acetonitrile (5 ml) was stirred at room temperature for 12 hours, then poured into water and extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the residues were purified by alumina silica gel column chromatography (developing solvent; ethyl acetate), whereby 101 mg of the title compound was obtained as colorless powder.