Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[CH:6]=[CH:5]2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2cc(Br)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc2cc(Br)ccc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Dichlorobis(triphenylphosphine)-palladium(II) (0.289 g, 0.412 mmol) was added to a solution of 6-bromo-2-chloroquinoline (1.0 g, 4.1 mmol) and tributyl(1-ethoxyvinyl)stannane (1.79 g, 4.95 mmol) in dioxane (8 mL) and the mixture was stirred at 100° C. for 5 h, desired product was identified by LC-MS. The crude reaction mixture was concentrated and purified by flash silica gel chromatography (eluted with 1:1 hexanes/DCM) to yield product 6-bromo-2-(1-ethoxyvinyl)quinoline (720 mg) as white solid. LC-MS retention time 4.091 min; m/z 279.84 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [CH:1]([CH:4]([CH:8]=[C:9]([Cl:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[O:17]([C:24]1[N:29]=[C:28]([CH2:30]O)[CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]([CH:4]([CH:8]=[C:9]([Cl:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([O:7][CH2:30][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:29]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: OCc1cccc(Oc2ccccc2)n1
Reactant: CC(C)C(C=C(Cl)c1ccccc1)C(=O)O
Product: CC(C)C(C=C(Cl)c1ccccc1)C(=O)OCc1cccc(Oc2ccccc2)n1

Procedure:
The acid chloride of 2-isopropyl-4-chloro-4-phenyl-3-butenoic acid is reacted with (6-phenoxy-2-pyridyl)methanol using the procedure of Example 1 to give (6-phenoxy-2-pyridyl)methyl 2-isopropyl-4-chloro-4-phenyl-3-butenoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].C[Al](C)C.[F:17][C:18]1[C:23]([C:24]2[CH:25]=[C:26]([C:36](OC)=[O:37])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:28][CH:29]=2)=[CH:22][C:21]([CH3:40])=[CH:20][N:19]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][C:36]([C:26]1[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:28][CH:29]=[C:24]([C:23]2[C:18]([F:17])=[N:19][CH:20]=[C:21]([CH3:40])[CH:22]=2)[CH:25]=1)=[O:37]
Reactant: COC(=O)c1cc(-c2cc(C)cnc2F)cnc1-c1ccccn1
Reactant: COc1ccc(CN)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cnc3F)cnc2-c2ccccn2)cc1OC
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3,4-dimethoxybenzylamine (0.15 g, 0.89 mmol, 8.0 equiv) in toluene (2.2 mL) was added a solution of trimethylaluminum (0.39 mL, 0.78 mmol, 7.0 equiv, 2 M in toluene) at ambient temperature and the reaction mixture was stirred for 45 minutes. To the reaction mixture was added a solution of methyl 2″-fluoro-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxylate (0.036 g, 0.11 mmol, 1.0 equiv) in toluene (2 mL) and the reaction mixture was heated to 100° C. for 15 h. The reaction mixture was cooled and diluted with ethyl acetate (30 mL) and quenched with Rochelle's salts (20 mL, saturated solution). The organic phase was washed with Rochelle's salts (3×20 mL, saturated solution), dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (15 to 100% EtOAc in hexanes, silica) to afford the desired product (11-4) as a white solid after concentration. 1H NMR (500 MHz, CDCl3) δ 8.92-8.90 (m, 1H), 8.35 (d, J=4.0 Hz, 1H), 8.25 (bs, 1H), 8.07 (bs, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.82 (td, J=7.6, 1.6 Hz, 1H), 7.78 (dd, J=9.6, 2.0 Hz, 1H), 7.70 (bs, 1H), 7.30-7.27 (m, 1H), 6.83-6.79 (m, 3H), 4.51 (d, J=5.6 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 2.41 (s, 3H). HRMS [M+H] C26H23FN4O3 calc'd 459.1827. found 459.1827.
Reaction SMILES: [N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)C=CN=[CH:2]1.[N:32]1C=CC=[CH:34][CH:33]=1.N1C=CC=N1.N1C=CN=C1>C(N(CC)CC)C.C1COCC1.C1(C)C=CC=CC=1>[N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:2]=[CH:34][CH:33]=[N:32]1
Reactant: c1ccncc1
Reactant: COc1cc(C(=O)c2c(-n3ccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Agent: c1c[nH]cn1
Agent: c1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(-n3cccn3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
This material was prepared according to the procedure outlined above for 2-(N-imidazolyl)-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (entry 27, Table 1), above, except pyridine was used as the solvent in place of toluene, THF and triethylamine and pyrazole was used as the nucleophile in place of imidazole. 1H NMR (300 MHz, CDCl3) δ 7.82 (d, 1H, J=2.55 Hz), 7.65 (d, 1H, J=1.51 Hz), 7.18 (d, 1H, J=8.57 Hz), 7.01 (s, 2H, benzoyl Hs), 6.96 (d, 1H, J=8.61 Hz), 6.30 (t, 1H, J=1.88 Hz), 3.96 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.75 (s, 6H, 2×OMe).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:4]1[CH:5]=[CH:6][C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:3]1=[O:2])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCc1ccnc(O)c1
Reactant: ClCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCc1ccn(Cc2ccccc2)c(=O)c1
Reaction time: 0.75 h
Yield: 81.7 %

Procedure:
To a cooled solution of sodium (3.25 g) in ethanol (75 ml) was added a solution of ethyl β-(2-hydroxy-4-pyridyl)propionate (25.38 g) in ethanol (150 ml). This mixture was stirred for 45 minutes and then benzyl chloride (16.58 g) in ethanol (125 ml) was added. The reaction mixture was stirred under reflux for 9 hours, allowed to cool and evaporated under reduced pressure. The residue was taken up in water (150 ml) and diethyl ether (150 ml), the aqueous layer was separated and washed with diethyl ether (2×120 ml). The combined ether extracts were washed with water, dried over MgSO4 and evaporated under reduced pressure to yield ethyl β-(N-benzyl-2-oxo-4-pyridyl)propionate (30.29 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([CH2:13][OH:14])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1F.CN(C)C=[O:25]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]3[CH:6]([CH2:7][N:8]=[C:20]4[C:15]=3[CH:16]=[CH:17][CH:18]=[CH:19]4)[C:13](=[O:14])[O:25][C:9]2=[CH:10][CH:11]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2F)c1CO
Reactant: CN(C)C=O
Solvent: O
Product: O=C1Oc2ccc(Cl)cc2C2=c3ccccc3=NCC12

Procedure:
Sodium hydride suspension (50% in mineral oil), 10 g, was washed with hexane and added to a solution of 20 g (0.066 mol) of the 6-chloro-4-(2-fluorophenyl)-3-hydroxymethylquinolin-2(1H)one in 350 ml of dimethylformamide. This mixture was stirred and refluxed under an atmosphere of nitrogen for 5 min. The cool reaction mixture was diluted with water and the product was precipitated by acidifying with 1N hydrochloric acid. It was collected, washed with water and recrystallized from dimethylformamide to yield final product with mp>350°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14])[CH3:2]>N.CO.[Ni]>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH2:11][NH2:12])[CH:8]=[CH:7][C:6]=1[C:13]([F:15])([F:14])[F:16])[CH3:2]
Reactant: CCOC(=O)c1cc(C#N)ccc1C(F)(F)F
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOC(=O)c1cc(CN)ccc1C(F)(F)F
Reaction time: 17 h

Procedure:
A mixture of 5-cyano-2-trifluoromethyl-benzoic acid ethyl ester (250 mg; 1.03 mmol) and 100 mg Ra-Ni in 20 mL NH3 in MeOH was stirred for 17 h under an atmosphere of hydrogen (3 bar). After filtration and concentration i.vac. the subtitle compound was obtained. Yield: 250 mg (98%); MS: [m+H]+=248; TLC (silica gel; DCM/EtOH 9/1) Rf=0.28.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:8][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: OCCc1ccc(Br)cc1
Product: Cc1cccc([N+](=O)[O-])c1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 Example 45 from 6-methyl-2-nitroaniline and 4-bromophenylethyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:4]([C:12]2[NH:11][CH:15]=[CH:14][CH:13]=2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc[nH]1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-chloronicotinoyl chloride (1 eq.) in dichloromethane (10 mL) was added slowly to a mixture of pyrrole (1.5 eq.) (Aldrich, Milwaukee, Wis.) and aluminum chloride (3.5 g, 1 eq.) in dichloromethane (8 mL) at 0° C. The mixture was stirred at 0° C. for 10 mins and at room temperature for 30 mins. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 2.27 g of (2-chloro-pyridin-3-yl)-(1H-pyrrol-2-yl)-methanone.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14].C(O)(=O)C1C=CC=CC=1>C1COCC1>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:15][CH:13]=[O:14])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=CC=O)cc1
Yield: 37.9 %

Procedure:
A solution of 0.21 g (1.25 mmoles) of 4-carbomethoxybenzaldehyde, 0.42 g (1.25 mmoles) of formylmethylenetriphenylphosphorane and a catalytic amount of benzoic acid in 25 ml of THF was refluxed under nitrogen for 18 hours. The THF was evaporated and the recovered gum extracted repeatedly with ether. The combined ether extracts were evaporated. Flash chromatography on silica gel with 50% CH2Cl2 /hexane up to 100% CH2Cl2 gave 90 mg of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])[N:12]=[C:11]([C:22]([O:24]CC)=O)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][NH2:28].CO>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])[N:12]=[C:11]([C:22]([NH:28][CH3:27])=[O:24])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(Sc2cccc(Br)c2)n(-c2cc(F)ccc2F)n1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc(Sc2cccc(Br)c2)n(-c2cc(F)ccc2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of ethyl 5-[(3-bromophenyl)thio]-1-(2,5-difluorophenyl)-1H-pyrazole-3-carboxylate (2.04 g) in methanol (2 mL) was added 40% methylamine-methanol solution (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=2:1) to give the title compound as a yellow oil (yield 1.35 g, yield 76%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:21])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH2:4][CH2:3]1.[C:22]([C:24]1[N:29]=[C:28]([NH:30][CH2:31][CH:32]2[CH2:39][CH2:38][C:35]3([CH2:37][CH2:36]3)[CH2:34][CH2:33]2)[C:27]([C:40](O)=[O:41])=[CH:26][N:25]=1)#[N:23].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:21][C:40]([C:27]3[C:28]([NH:30][CH2:31][CH:32]4[CH2:39][CH2:38][C:35]5([CH2:37][CH2:36]5)[CH2:34][CH2:33]4)=[N:29][C:24]([C:22]#[N:23])=[N:25][CH:26]=3)=[O:41])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH2:6][CH2:7]1
Reactant: N#Cc1ncc(C(=O)O)c(NCC2CCC3(CC2)CC3)n1
Reactant: CN1CCC(Oc2ccc(N)c(-c3ccccc3)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc(NC(=O)c3cnc(C#N)nc3NCC3CCC4(CC3)CC4)c(-c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1-methylpiperidin-4-yloxy)biphenyl-2-ylamine (0.27 mmol, step 58.2) and 2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.33 mmol) in DMF (2 mL) are added EDCI-HCl (0.54 mmol) and HOAt (0.54 mmol) at 0° C. After stirring at the ambient temperature overnight, the reaction mixture is purified by RP-HPLC to give the title compound as a white solid; 1H NMR (CDCl3), δ 0.18-0.21 (2H, m), 0.27-0.30 (2H, m), 0.90-0.94 (2H, m), 1.14-1.25 (2H, m), 1.58-1.78 (5H, m), 1.85-1.92 (2H, m), 2.02-2.06 (2H, m), 2.32 (3H, s), 2.70 (2H, br s), 3.41-3.44 (2H, t), 4.35 (1H, m), 6.89 (1H, d), 6.97 (1H, dd), 7.35-7.37 (2H, m), 7.45-7.52 (3H, m), 7.65 (1H, s), 7.92 (1H, s), 8.06 (1H, d), 8.90 (1H, s).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]2)=[N:17][CH:18]=1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Fc1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(O)[C@H]1CC[C@H](Nc2ccc(Br)cn2)CC1
Temperature: 130 °C

Procedure:
A mixture of trans-4-aminocyclohexanecarboxylic acid hydrochloride (2.00 g, 11.1 mmol), 5-bromo-2-fluoropyridine (2.29 mL, 22.3 mmol), potassium carbonate (3.08 g, 22.3 mmol), DIEA (3.89 mL, 22.3 mmol) in NMP (50 mL) was heated to 130° C. overnight. The reaction was cooled to room temperature, filtered through a pad of CELITE, and washed with NMP (50 mL). The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2/MeOH, 0-10%) to afford trans-4-[(5-bromopyridin-2-yl)amino]cyclohexanecarboxylic acid as a off-white solid. MS ESI calc'd for C12H16BrN2O2 [M+H]+ 299 and 301. found 299 and 301.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11]C)=[C:5]([CH3:13])[C:4]=1[CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][CH2:19][CH2:20][OH:21].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].O.CCOC(C)=O>C(C#N)(C)=O.O>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17]/[C:16](/[CH3:22])=[CH:15]/[CH2:14][C:4]1[C:3](=[O:2])[C:8]([CH3:9])=[C:7]([CH3:10])[C:6](=[O:11])[C:5]=1[CH3:13]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCO)c1C
Agent: CC(=O)C#N
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(C)C(=O)C(C/C=C(\C)CCCCO)=C(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-en-1-ol (29.7 mg, 0.097 mmol) in AcCN (0.5 mL) with 2 drops of H2O was cooled to 0° C. CAN (114.7 mg, 0.209 mmol) was dissolved into AcCN (0.2 mL) and H2O (0.5 mL) and added to a stirred solution of alcohol at 0° C. The reaction was stirred at 0° C. for 1 h and H2O (2 mL) and EtOAc (2 mL) was added, the layers separated and the aqueous phase extracted 3×2 mL EtOAc. The combined organics were washed 2×2 mL saturated brine, dried over anhydrous Na2SO4 and concentrated to a yellow oil. Flash chromatography yielded (E)-2-(7-hydroxy-3-methylhept-2-enyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione (2.2 mg) as a yellow oil (8.2%). 13C NMR (100 MHz, CDCl3) δ 187.9, 187.0, 143.1, 140.4, 104.3, 134.0, 119.7, 77.2, 62.9, 39.3, 32.3, 25.6, 24.0, 16.2, 12.4, 12.3, 12.2
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8](C(=O)CN2C(=O)C(C3C=CC=CC=3)(C3C=CC=CC=3)N=C2C)=[CH:7][CH:6]=1)C.[Li+].[OH-]>O1CCOCC1>[C:4]([OH:33])(=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(C(=O)CN2C(=O)C(c3ccccc3)(c3ccccc3)N=C2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 296.8 %

Procedure:
4-[2-(2-Methyl-5-oxo-4,4-diphenyl4,5-dihydro-imidazol-1-yl)-acetyl]-benzoic acid ethyl ester (540 mg, 1.2 mmol) is dissolved in 12 mL dioxane and an aqueous 2 Molar LiOH solution (920 uL, 1.8 mmol) is added drop wise. The reaction mixture is stirred at room temperature for 12 hours. Subsequently the mixture is evaporated and the residue taken up in water. The mixture is stirred and concentrated hydrochloric acid is added drop wise until a pH of 2 is reached. The precipitating crystals are filtered off, re-crystallized from methylene chloride and dried to yield 4-[2-2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-benzoic acid (435 mg, 84%) light yellow solid. LC/MS at 254 nm; [M+H] 413; Rt 3.154 min.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O>C(O)C>[CH:3]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:14]=3[CH2:13][CH2:12][C:11]=2[N:4]=[CH:1][CH:2]=1
Reactant: C#CCN
Reactant: O=C1CCc2ccccc2C1
Solvent: CCO
Product: c1ccc2c(c1)CCc1ncccc1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Propargylamine (5 mL) is added to a flask charged with a stir bar, 2-tetralone (10.00 g), NaAuCl4*2H2O (0.65 g), and ethanol (50 mL) (caution: a very exothermic reaction may evolve afterwards→keep an ice bath at hand). The resulting mixture is stirred at room temperature for 15 min and then at reflux temperature for 1 h. After cooling the mixture to room temperature, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 60:40) to afford the title compound as an oil. Yield: 6.78 g (56% of theory); LC (method 1): tR=1.81 min; Mass spectrum (ESI+): m/z=182 [M+H]+. Alternatively, the reaction may be conducted in a microwave oven heating with microwave irradiation to 100° C. for 10 min.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:15]3[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: c1cc(NC2CCSCC2)ccc1CN1CCOCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(=CN(c1ccc(CN2CCOCC2)cc1)C1CCSCC1)C(=O)OCC
Temperature: 160 °C

Procedure:
A flask containing N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-thiopyran-4-amine (0.44 g) is treated with diethyl ethoxymethylenemalonate (0.35 mL). The flask is tightly capped and heated to 160° C. for 2 hours. The reaction is cooled to room temperature, treated with diethyl ethoxymethylenemalonate (0.35 mL) and pyridine (0.35 mL) and heated to 150° C. for 1 hour in a tightly sealed flask. The reaction is cooled to room temperature and azeotroped under reduced pressure with toluene (3×). The residue is flash column chromatographed on silica gel eluting with ethyl acetate. The product-containing fractions are evaporated to give 0.59 g of diethyl 2-{[4-(4-morpholinylmethyl)(tetrahydro-2H-thiopyran-4-yl)anilino]methylene}malonate as a tan solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:24]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:11]([O:21][CH3:22])=[N:10][C:9]3[C:13]2=[N:14][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][C:8]=3[NH2:23])[CH2:27][CH2:26][CH2:25]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: C1CNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCC3)c2n1
Temperature: 50 °C
Yield: 6.4 %

Procedure:
2-(Butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine (100 mg, 0.293 mmol), azetidine (0.020 ml, 0.293 mmol) and N,N-diisopropylethylamine (0.102 ml, 0.585 mmol) were dissolved in DMF (2 ml) and heated at 50° C. for 72 hours. The solvent was removed in vacuo and the residue partitioned between DCM (5 ml) and water (5 ml) and the layers separated using a hydrophobic frit. The aqueous phase was re-extracted with DCM (5 ml) and the combined organic extracts concentrated and the residue dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP (Method A). The product-containing fractions were evaporated under a stream of nitrogen to give the title compound as a clear gum (6.8 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([O:15][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Br:16])=[CH:18][CH:19]=2)[CH:6]=[C:5]([O:4][CH3:3])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: BrCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccc(Br)cc2)cc(OC)c1OC
Yield: 84.4 %

Procedure:
To a solution of 1.46 g (36.5 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (50 ml) was added 2.02 g (11.0 mmol) of 3,4,5-trimethoxyphenol in an atmosphere of argon, and the mixture was allowed to react at 0° C. for 15 min. To the reaction mixture was added 3.60 g (14.4 mmol) of 4-bromobenzyl bromide. The resulting mixture was reacted at room temperature for 24 hours. To the reaction mixture at 0° C. was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-hexane (1:1) yielded 3.28 g (9.28 mmol) of 4-bromobenzyl 3,4,5-trimethoxyphenyl ether.