Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:4][N:3]=1.[C:26]([NH:30][S:31]([C:34]1[S:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:26]([NH:30][S:31]([C:34]1[S:38][C:37]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH:14]4[CH2:16][CH2:15]4)[NH:11][N:10]=3)[C:5]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:4][N:3]=2)=[CH:36][CH:35]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)s1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(CO[Si](C)(C)C(C)(C)C)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 90 °C
Yield: 43.5 %

Procedure:
A mixture of 2-bromo-5-((tert-butyldimethylsilyloxy)methyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (210 mg, 0.49 mmol, 1.0 equiv.), 5-(N-tert-butylsulfamoyl)thiophen-2-ylboronic acid (260.4 mg, 0.99 mmol, 2 equiv.), PdCl2(dppf)CH2Cl2 (120.0 mg, 0.15 mmol, 0.3 equiv.), K2CO3 (236.67 mg, 1.72 mmol, 3.5 equiv.) in dioxane (10 mL) and water (2 mL) was heated for 12 h at 90° C. under nitrogen atmosphere. The solvent was removed and the residue was purified by silica gel chromatography (PE/EtOAc=5:12:1 as eluant) to give N-tert-butyl-5-(5-((tert-butyldimethylsilyloxy)methyl)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (120.0 mg, 43.5%) as white solid. LC-MS (m/z)=563.1 [M+H]+;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[C:10]([O:14][C:15](=[O:31])[N:16]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH3:30])[C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15](=[O:31])[N:16]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH3:30])([CH3:13])([CH3:11])[CH3:12]
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1C
Reactant: FCc1cccc(Br)n1
Product: Cc1cc(F)ccc1N(C(=O)CCC#Cc1cccc(CF)n1)C(=O)OC(C)(C)C
Yield: 79.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (150 mg, 0.79 mmol, Example 190(E)) and (4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (241 mg, 0.79 mmol, 188(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 260 mg (0.63 mmol, 79%) of [5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-2-methyl-phenyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl:23][C:24]1[CH:29]=[C:28](I)[C:27]([O:31][CH3:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:28]2[CH:29]=[C:24]([Cl:23])[C:25]([C:33]([F:36])([F:34])[F:35])=[CH:26][C:27]=2[O:31][CH3:32])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(C(F)(F)F)c(Cl)cc1I
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(Cl)c(C(F)(F)F)cc1OC
Temperature: 100 °C
Reaction time: 24 h
Yield: 102.8 %

Procedure:
A flask was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (Bellen Chemistry Co., 3.2 g, 10.21 mmol), 1-chloro-5-iodo-4-methoxy-2-(trifluoromethyl)benzene (4.12 g, 12.25 mmol), cesium carbonate (4.66 g, 14.29 mmol), Pd2(dba)3 (0.234 g, 0.255 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.295 g, 0.511 mmol) (XANTPHOS). The flask was flushed with nitrogen and a reflux condensor was added. CPME (20.42 mL) was added and the flask was heated to 100° C. with vigorous stirring. The reaction was stopped at 24 h and cooled to RT. Water and EtOAc were added (30 mL each), and the layers were separated. The aqueous layer was extracted again with EtOAc (50 mL). The combined organics were passed through a plug of Celite/silica to remove Pd, and the orange filtrate was concentrated. The residue was triturated with isopropanol, filtered through a medium glass frit, and the solid was dried under high vac to provide (E)-ethyl 3-(5-(benzylthio)-2-((5-chloro-2-methoxy-4-(trifluoromethyl)phenyl)amino)phenyl)acrylate (5.48 g, 10.50 mmol, 103% yield). m/z (ESI) 520.2 (M−H)−.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:22][C:12]2=[C:13]3[N:18]([N:19]=[C:11]2[CH2:10]1)[CH:17]=[C:16]([Cl:20])[C:15]([CH3:21])=[N:14]3)=O)(C)(C)C>CC(O)=O.C(Cl)Cl>[Cl:20][C:16]1[C:15]([CH3:21])=[N:14][C:13]2[N:18]([N:19]=[C:11]3[CH2:10][NH:9][CH2:22][C:12]3=2)[CH:17]=1
Reactant: Cc1nc2c3c(nn2cc1Cl)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2cc1Cl)CNC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
A 32% solution of HCl (1.79 mL) was added to a solution of 6-chloro-5-methyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (1.70 g; 5.51 mmol; 1 eq.) in AcOH (5.8 mL) and the reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with DCM, washed with 1M NaOH (2×), dried over sodium sulfate and concentrated in vacuo to afford the title compound (900 mg, 78%) as a yellow solid. 1H NMR (DMSO-d6) δ 9.37 (s, 1H), 4.09-3.98 (m, 4H), 3.70-3.53 (m, 1M), 2.55 (s, 3H). HPLC (max plot) 99.8%, Rt 1.20 min. UPLC/MS: (MS+) 209.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].[CH3:11][S-:12].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([S:12][CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)cncc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cncc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.9 %

Procedure:
To a solution of 3,5-dichloroisonicotinonitrile (346 mg, 2 mmol) in N,N-dimethylformamide (2 mL) was added sodium thiomethoxide (141 mg, 2 mmol) at 0° C. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solution was concentrated under reduced pressure. To the resulting residue was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The combined organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the desired product (92 mg, 25% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:38][CH:39]2[CH2:45][CH:44]3[CH:42]([CH2:43]3)[CH2:41][CH:40]2[C:46](O)=[O:47])=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O>[C:4]([CH2:3][NH:2][C:46]([CH:40]1[CH:39]([CH2:38][S:37][C:34]2[CH:35]=[CH:36][C:31]([S:30][CH3:29])=[CH:32][CH:33]=2)[CH2:45][CH:44]2[CH:42]([CH2:43]2)[CH2:41]1)=[O:47])#[N:5]
Reactant: CSc1ccc(SCC2CC3CC3CC2C(=O)O)cc1
Reactant: N#CCN
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1ccc(SCC2CC3CC3CC2C(=O)NCC#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of aminoacetonitrile hydrochloride (153 mg, 1.65 mmol) and benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (800 mg, 1.54 mmol) was added 1S/R,3R/S,4R/S,6R/S)-4-({[4-(methylsulfanyl)phenyl]sulfanyl}methyl)bicyclo[4.1.0]-heptane-3-carboxylic acid and dimethylformamide (4 mL). After adding triethylamine (0.52 mL, 3.7 mmol) the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was partitioned between water and ethyl acetate. The product was extracted into ethyl acetate and the combined organic phases were washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvents were removed and the residue was chromatographed on a silica gel with methanol:dichloromethane (1.5:98.5) as eluent to give crude product which was purified in 1.4 mg portions by preparative RP HPLC (Waters, RCM, C18, μBondapak, 1×24 mm) by gradient elution with acetonitrile:water (containing 25 mM ammonium acetate)/30:70 to 50:50, 6.0 mL/min flowrate, UV detector set at 300 nM to give the title compound as a colorless solid. 1H NMR (500 MHz, acetone-d6): δ=7.83 (1H, br s), 7.28 (2H, d), 7.19 (2H, d), 4.20 (2H, m), 3.12 (1H, dd), 2.62 (1H, dd), 2.46 (3H, s), 2.26 (1H, m), 2.21 (1H, m), 2.10 (1H, m), 1.67 (1H, m), 1.58 (1H, m), 1.52 (1H, m), 0.99 (1H, m), 0.90 (1H, m), 0.57 (1H, m), −0.06 (1H, m). MS [ESI, (M−H)] m/z=345.2 amu.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]2[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-(trifluoromethyl)-2-furanyl)-1-propanol (300 mg, 099 mmol) in ethyl acetate (10 ml) were added 3-phenylpropionyl chloride (220 ml, 1.48 mmol) and saturated aqueous sodium hydrogen carbonate (10 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (321 mg, 75%).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCCCCCCC.NC(N)=[O:23].C(=O)(O)[O-].[Na+].OO>O.ClCCl.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[CH2:1]1[O:23][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(N)=O
Reactant: C=Cc1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCCCCCCCCCCC
Solvent: O
Product: c1ccc(C2CO2)cc1
Yield: 56 %

Procedure:
To a mechanically stirred solution of styrene (0.01 mol), dodecane (0.001 mol), urea (0.208 mol), sodium bicarbonate (0.003 mol) and cobalt (II) acetate (0.2 mmol) in 10.0 ml of water and 30 ml of dichloromethane at 25° C. is added 30% aqueous hydrogen peroxide (0.5 mol) in three equal portions over a period of 4 hours. After 14 hours the reaction mixture was extracted with 4×5 ml diethyl ether. The combined organic layer was dried over anhydrous sodium sulphate. Removal of solvent yielded styrene oxide in 56% yield with selectivity 80%.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:28])(=O)=O.O>ClCCl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Cl:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CCl)c1
Temperature: 0 °C
Reaction time: 25 h

Procedure:
3-(tert-Butyldimethylsilyloxy)benzyl alcohol (101) (prepared by the process described in Wu, Y.-C. et al., J. Am. Chem. Soc., 130, 7148-7152 (2008)) (7.94 g, 31.4 mmol) was dissolved in dichloromethane (150 mL), and cooled to 0° C. To this were sequentially added triethylamine (9.10 mL, 66.7 mmol) and methanesulfonyl chloride (3.80 mL, 49.1 mmol) and stirred for 25 hours after warming up to room temperature. To this was added water, and the product was extracted with dichloromethane (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=95/1) to give 3-(tert-butyldimethylsilyloxy)benzyl chloride (102) as a colorless oily substance (5.90 g, 23.0 mmol, 73.1%).
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:28][C:18]2=[C:19]3[N:24]([N:25]=[C:17]2[CH2:16]1)[C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=[N:20]3)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[CH3:27][C:22]1[CH:21]=[N:20][C:19]2[N:24]([N:25]=[C:17]3[CH2:16][NH:15][CH2:28][C:18]3=2)[C:23]=1[CH3:26]
Reactant: Cc1cnc2c3c(nn2c1C)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cnc2c3c(nn2c1C)CNC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (10 mL; 40 mmol; 82.4 eq.) was added to a solution 6,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (140 mg; 0.49 mmol; 1 eq.) in MeOH (2 mL) and the resulting mixture was stirred at room temperature for 18 hours then concentrated in vacuo. The residue was triturated in EtOH and the precipitate filtered off and dried to afford the title compound (78 mg, 62%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 10.39 (br s, 2H), 8.91 (d, J=0.9 Hz, 1H), 6.24 (br s, 1H), 4.51-4.48 (m, 4H), 2.49 (s, 3H), 2.26 (s, 3H). HPLC (max plot) 99.9%; Rt 1.03 min. UPLC/MS: (MS+) 189.0 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](O)=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][NH:23][CH3:24].CN1CCOCC1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:19])[N:23]([O:22][CH3:21])[CH3:24])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: O
Solvent: CO
Product: CON(C)C(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C

Procedure:
To 2.00 g (7.21 mmol) 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester in 70 mL MeOH is added at RT 844 mg (8.65 mmol) O,N-dimethyl-hydroxylamine and 1.59 mL (14.4 mmol) 4-methyl-morpholine. The mixture is stirred at RT and then 2.10 g (7.57 mmol) 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholin-4-ium chloride hydrate is added and the mixture is stirred overnight at RT. The residue is directly purified via reverse HPLC chromatography (Waters XBridge, C18; water (0.3% NH4OH)/acetonitrile (0.3% NH4OH) 90:10 to 10:90).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:20]([N:39]1[CH:43]=[C:42]([CH2:44][CH2:45][CH2:46][C:47](O)=[O:48])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([NH:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:47](=[O:48])[CH2:46][CH2:45][CH2:44][C:42]2[N:41]=[CH:40][N:39]([C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:43]=2)=[CH:9][CH:8]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C(=O)CCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.95 g of N-tert-butyl-p-bromobenzamide is dissolved in 175 ml of tetrahydrofuran at -70° under nitrogen and 20.1 ml of n-butyllithium (2.7M) is added dropwise. After 30 min, a solution of 5.35 g of 4-(1-trityl-4-imidazolyl)-butanoic acid in 10 ml of tetrahydrofuran is added slowly. The reaction mixture is allowed to warm slowly to room temperature and 20 ml of an aqueous ammonium chloride solution is added. The organic layer is separated, dried over sodium sulfate and evaporated to yield 1-(p-N-tert-butylaminocarbonylphenyl)-4-(1-trityl-4-imidazolyl)-1-butanone
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:42][N:43]([CH2:50][C@H:51]1[CH2:56][CH2:55][C@H:54]([NH2:57])[CH2:53][CH2:52]1)[CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([NH:57][C@H:54]3[CH2:53][CH2:52][C@H:51]([CH2:50][N:43]([CH3:42])[CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[CH2:56][CH2:55]3)=[O:17])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2csc(/C=C/C(=O)O)c2)cc1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2csc(/C=C/C(=O)N[C@H]3CC[C@H](CN(C)C4CCOCC4)CC3)c2)cc1
Reaction time: 2 h

Procedure:
Into a suspension of (E)-3-[4-(4-methylphenyl)-thiophen-2-yl]acrylic acid (150 mg) and 1-hydroxybenzotriazole (124 mg) in acetonitrile (10 ml) was added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (177 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (276 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (281 mg) and triethylamine (0.17 ml) in acetonitrile (15 ml), and the resulting mixture was stirred for 16 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:2) and to recrystallization (ethanol) to obtain (trans, E)-3-[4-(4-methylphenyl)thiophen-2-yl]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]acrylamide (compound 72) (191 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:20])[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:20])[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH2:11]1
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCC3(CC2)OCCO3)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1cnc(OCC2(F)CCC(=O)CC2)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of EXAMPLE 512C (1.6 g) and pyridinium p-toluenesulfonate (1.2 g) in acetone (10 mL) was added water (2 mL) and the mixture was stirred in a CEM Discover microwave reactor at 100° C. for 10 minutes. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([O:25][CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[CH:21][CH:20]=1.[H][H]>[Pd].O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[CH:33][CH:34]=1
Reactant: CCOC(=O)C=COC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
A solution of 4 g. 2-(ethoxycarbonyl)vinyl 4-(16-bromohexadecylamino)benzoate and 400 mg. 10% palladium-on-carbon in 100 ml. tetrahydrofuran is hydrogenated at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetonitrile to yield 2-(ethoxycarbonyl)ethyl 4-(16-bromohexadecylamino)benzoate.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][C@@H:30]([C:32]([O:34][CH3:35])=[O:33])[CH3:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:28][N:29]([C@H:30]([CH3:31])[C:32]([O:34][CH3:35])=[O:33])[C:10](=[O:12])[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: CN[C@H](C)C(=O)OC
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of (R/S)-α-t-butoxycarbonylmethyl-4-benzyloxyphenylacetic acid 48b (4.8 g, 13.48 mmol) and methyl N-methyl-D-alaninate hydrochloride (2.9 g, 18.9 mmol) in DMF (30 mL) cooled in an ice bath was added BOP (6.56 g, 14.83 mmol) followed by DIEA (16.5 mL, 94.5 mmol) and the solution was stirred overnight. EtOAc was added and the solution was washed with NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified on a silica gel column by eluting with 40% EtOAc/hexane to give the desired product (3.0 g, 49%) as a solid. MS (CI—NH3): (M+H)+=456.