Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:15])=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10](O)=[O:11])=[O:4].C(Cl)(=O)C([Cl:19])=O>ClCCl>[Cl:19][C:10]([C:9]1[C:8]([CH3:14])=[CH:7][C:6]([CH3:15])=[C:5]([CH:13]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:11]
Reactant: COC(=O)c1cc(C(=O)O)c(C)cc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)Cl)c(C)cc1C
Temperature: 40 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 5-(methoxycarbonyl)-2,4-dimethylbenzoic acid (compound 255.1, 100 mg, 0.48 mmol) in dichloromethane (10 mL). Oxalyl chloride (80 μL, 0.95 mmol) was added and the resulting solution was stirred for 1 h at 40° C., then concentrated under reduced pressure to obtain the title compound as a white solid (80 mg, 74%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:20]2[N:21]=[CH:22][NH:23][CH:24]=2)=[CH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[N:21]=[CH:22][NH:23][CH:24]=2)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(C(=CCCCc2ccccc2)c2c[nH]cn2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Fc1ccc(C(CCCCc2ccccc2)c2c[nH]cn2)cc1
Yield: 82 %

Procedure:
4-[1-(4-fluorophenyl)-5-phenyl-1-pentenyl]-1H-imidazole hydrochloride (2,0 g) is dissolved in ethanol and a catalytic amount 10% Pd/C is added. The reaction mixture is agitated vigorously at room temperature in a hydrogen atmosphere until the uptake of hydrogen ceases. The mixture is filtered and the filtrate is evaporated to dryness. The residue which is the product is purified by flash chromatography eluting with methylene chloride-methanol mixture. Yield 82%.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:11]([CH3:12])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[CH3:12][C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:24]3[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3ccc(S(N)(=O)=O)s3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20) (300 mg, 1 mmol) and commercially available 5-bromothiophene-2-sulfonamide (230 mg, 1 mmol) according to general procedure II. Obtained as a light brown solid (200 mg, 50%). MS (ISP) 462 [(M+H)+]; mp 270° C.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](O)[CH2:9][CH2:10][OH:11]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:7]1[C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1CCCCC1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1CCC2(CC1)OCCCO2
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Cyclohexanone (7.94 g) was dissolved in toluene (200 mL), 1,3-propanediol (12.3 g) and p-toluenesulfonic acid monohydrate (0.1 g) were added thereto, and the mixture was heated under reflux for 1.5 hr while removing water being produced. The temperature was allowed to cool to room temperature, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (12.4 g) as a colorless oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NCc1ccccc1
Reaction time: 18 h
Yield: 93.1 %

Procedure:
Benzaldehyde (2.2 g, 21.0 mmol) was added to a stirred solution of 3-amino-4-methoxy-N-phenyl-benzamide (5.0 g, 21.0 mmol) in dichloromethane (250 mL) under an inert atmosphere at room temperature, followed by acetic acid (1.26 g, 21.0 mmol). After 1 hour sodium triacetoxyborohydride (4.7 g, 21.0 mmol) was added in one portion. After 18 hours, saturated aqueous sodium bicarbonate (200 mL) was added and the mixture stirred for 2 to 3 hours. The layers were separated, the organic phase was washed with water then saturated aqueous sodium chloride, then dried over MgSO4. The solution was filtered and stripped of solvent under reduced pressure to afford the product (6.5 g); m.p. 164-165° C. after recrystallization from ethanol.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]/[C:22](=[C:29]2\[C:30](=[O:41])[NH:31][C:32]3[C:37]\2=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=[O:12])C)=O)(C)(C)C.C(OCC)(=O)C.[ClH:48]>>[ClH:48].[CH3:6][NH:8][CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]/[C:22](=[C:29]2\[C:30](=[O:41])[NH:31][C:32]3[C:37]\2=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=[O:12]
Reactant: CN(CC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z)-3-{1-[4-(N-tert.butoxycarbonyl-N-methylamino)methylcarbonylaminomethyl-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone and ethyl acetate/hydrogen chloride.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[CH3:25][C:26]1[S:30][CH:29]=[N:28][CH:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[S:30][C:26]([CH3:25])=[CH:27][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1cncs1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4cccnc4F)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12i and 5-methylthiazole
Reaction SMILES: C1([C@@H]([N:9]2[C@@H:17]3[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:11][C@H:10]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])C)C=CC=CC=1>[Pd].C(O)C>[NH:9]1[C@@H:17]2[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][C@H:10]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)[C@@H]1C[C@H]2CCCC[C@@H]2N1[C@@H](C)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H]2CCCC[C@@H]2N1
Temperature: 60 °C
Yield: 109.2 %

Procedure:
5% palladium on carbon (0.27 g) was added to a solution of (2S,3aR,7aS)-ethyl 1-((S)-1-phenylethyl)octahydro-1H-indole-2-carboxylate (15) (2.7 g) in ethanol (20 mL) and the mixture was heated at 60° C. under hydrogen (14.5 psi) atmosphere for NLT 3 hours. The catalyst was filtered and washed with fresh ethanol (15 mL). The combined filtrate was concentrated under vacuum to afford 1.93 g of (2S,3aR,7aS)-Ethyl octahydro-1H-indole-2-carboxylate (16) as a viscous oil.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[S:6][CH:7]=1)#[CH:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)#[CH:2]
Reactant: C#Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1csc(C2CCNCC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of tert-butyl 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.87 g, 6.40 mmol) in anhydrous dichloromethane (16 ml) was added at 0° C. trifluoroacetic acid (16 ml). After stirring at 0° C. for 30 mins, the mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was concentrated to dryness. The residue was washed with dichloromethane (extracted from solid phase) and the washing solution was concentrated to give 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine (1.176 g, yield 98%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C@@H:11](O)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].C1C=CC(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:30]([C@@H:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]1=2)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CCC[C@@H]2O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)CCC[C@H]2N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a 500 mL three-neck round-bottomed flask equipped with argon inlet/outlet, thermometer, and magnetic stirring was added 5(S)-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (29 g, 140 mmol) in 280 mL of toluene. The reaction mixture was cooled in a ice-salt bath, and DPPA (36 mL, 170 mmol, Aldrich) was added (internal temp.=−4° C.). DBU (25 mL, 170 mmol, Aldrich) was added over 10 min at such a rate that the internal temperature was kept below 1° C. The ice in the bath was allowed to melt, and the reaction continued for 12 h during which time the mixture stopped stirring because a precipitate had formed. Stirring was resumed, and the reaction mixture was stirred at RT for another 11 h. The reaction contents were poured into a 2 L sep funnel, and the lower dark-brown layer was removed. Water (250 mL) was added to the remaining top layer, and the mixture was extracted with Et2O (3×250 mL). The combined organic layers were washed with 1M H3PO4, water, satd NaHCO3, and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (330 g Isco Redisep® column, 1:1 hexane-CH2Cl2) of the crude material provided the title compound. MS (+ion ESI) m/z =232 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH3:21]>CC(=O)CC>[CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH2:19][CH2:20][CH3:21])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCCBr
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1ccc([N+](=O)[O-])c(C)c1
Reaction time: 0.08 h
Yield: 193.6 %

Procedure:
Compound 403 (1.5 g, 9.8 mmol) was dissolved in 2-butanone (40 mL). Potassium carbonate (3.4 g, 24.5 mmol) was added and the solution heated at reflux. After 5 min, 1-bromopropane (18 μL, 5 mmol, 2 mL) was added drop-wise and the reaction mixture continued to stir for 18 h. The solvent was evaporated in vacuo and the crude residue was partitioned between EtOAc (150 mL) and saturated NaHCO3 (150 mL). The organic layer was separated, washed with brine (100 mL) and dried over Na2SO4. The resulting oil was purified by column chromatography (0% to 20% EtOAc/hexanes) to yield a yellow oil (1.89 g, 99%): TLC Rf 0.70 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.09-8.07 (d, 1H, J=8.76 Hz), 6.79-6.77 (m, 2H), 3.99-3.97 (t, 2H, J=6.54 Hz), 2.63 (s, 3H), 1.85-1.82 (sex, 2H, J=7.44 Hz), 1.06-1.04 (t, 3H, J=7.44 Hz). 13C NMR (150 MHz, CDCl3) δ 162.9, 142.2, 137.3, 127.8, 118.1, 112.4, 70.3, 22.60, 21.98, 10.6. Elemental analysis calculated for C10H13NO3.0.03 hexanes: C, 61.81; H, 6.84; N, 7.08. Found: C, 62.20; H, 6.78; N, 7.23.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.C(O)C>O>[O:18]1[CH:16]([CH2:14][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:17]1
Reactant: ClCC1CO1
Reactant: Oc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc2c(OCC3CO3)cccc2c1
Yield: 93 %

Procedure:
Into a 500 mL three-necked round bottom flask, 10.03 g 1-naphthol, 3.1 g NaOH, 20.4 g epichlorohydrin (SIR) and 0.5 g KI were added, then 330 mL ethanol was added. The flask was then placed in a microwave reactor. The reaction was performed at 30° C. under stirring and 300 W microwave irradiation for 12 min. The reaction mixture was then removed and suction filtrated, and the filtrate was concentrated to obtain an oily substance. H2O was added to the oily substance, and the mixture was extracted with ethyl ether. The ethyl ether layers were combined and washed with a solution of NaOH, then washed with H2O once. The ether layer was dried using anhydrous magnesium sulfate and concentrated to obtain 12.95 g of the product in a yield of 93.2%.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>O1CCCC1>[C:2]1([CH2:9][CH2:10][CH2:11][Si:12]([O:13][CH2:14][CH3:15])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH2:1][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCC=C1
Reactant: CCO[Si](CCCCl)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[Si](CCCC1=CC=CC1)(OCC)OCC
Yield: 90 %

Procedure:
27.5 g (417 mmol) of freshly distilled cyclopentadiene are added dropwise to a suspension of 15 g (417 mmol) of sodium hydride in 250 ml of absolute tetrahydrofuran at room temperature over a period of one hour. 100.3 g of (3-chloropropyl)triethoxysilane are subsequently added dropwise over a period of 30 minutes. The solution becomes warm during this process. After taking off the solvent, the mixture is fractionally distilled in an oil pump vacuum to give 96.1 g of (3-cyclopenta-dienylpropyl)triethoxysilane (yield: 90%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[O:10][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[Cl:22])(=[O:3])[CH3:2]>[Pd]>[C:1]([NH:4][C:5]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[Cl:22])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c3c(oc12)CCCC3
Agent: [Pd]
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1oc1ccccc12
Temperature: 230 °C

Procedure:
A mixture of 1 g methyl 1-acetylamino-2-chloro6,7,8,9-tetrahydrodibenzofuran-4-carboxylate and 0.5 g of 5% palladium-charcoal is heated under nitrogen at 230° C. for 5 hours. The cooled residue is extracted with toluene and the solvent evaporated to dryness. The residue is crystallized from ethyl acetate/hexane to give methyl 1-acetylamino-2-chlorodibenzofuran-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:29])[N:20]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[C:8]2[NH:7][C:6]=1[CH3:30])=[O:4].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.CCN(CC)CC>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:29])[N:20]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[C:8]2[N:7]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=2)[C:6]=1[CH3:30])=[O:4]
Reactant: COC(=O)C1=C(C)Nc2nn(Cc3ccccc3)c(=O)n2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(Cc3ccccc3)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.3 %

Procedure:
Intermediate 6 (100 mg, 0.24 mmol), 3-trifluoromethylphenylboronic acid (95 mg, 0.5 mmol), Et3N (250 μl, 1.8 mmol), and copper (II) acetate (50 mg, 0.4 mmol) were dissolved in DCM (10 mL), and stirring at RT was continued for 48 hours. The reaction mixture was filtered to remove the solid and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-15% MeOH in DCM. Appropriate fractions were combined and concentrated in vacuo and the resulting residue further purified using preparative HPLC system 2 to yield the title compound as a white solid (20 mg).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:8](=[O:23])[CH:7]=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[Br:29][C:7]1[C:8](=[O:23])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Reaction time: 14 h
Yield: 74 %

Procedure:
3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (5.9 g, 15.2 mmol) (from step 3 above) was taken up in dichloromethane (25 ml). N-Bromosuccinimide was added and the reaction stirred for 14 hours. The dichloromethane was removed in vacuo and the residue was taken up in acetonitrile. The precipitate was collected on a filter pad and rinsed with acetonitrile to yield the desired product as a white solid (5.2 g, 74%). 1H NMR (300 MHz, CD3OD) δ 7.87 (dd, J=7.85, 1.61,Hz, 1H), 7.82 (d, J=1.81 Hz, 1H), 7.69 (app q, J=8.06 Hz 1H), 7.57 (d, J=8.06 Hz, 1H), 7.09 (dt, J=8.66, 2.22 Hz, 1H), 6.70 (s, 1H), 5.40 (s, 2H), 2.14 (s, 3H), 2.02 (s, 3H); ES-MS m/z 464 (M+H). ES-HRMS m/z 464.0275 (M+H calcd for C21H17BrF2NO4 requires 464.0304).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1N=C(C)SC=1C1C=CC(F)=CC=1)=O.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([C:35]2[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=2)=[C:30]([CH:34]=1)[C:31]([OH:33])=O>>[NH2:1][CH2:2][C@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:31]([C:30]1[CH:34]=[C:26]([CH3:25])[CH:27]=[CH:28][C:29]=1[C:35]1[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=1)=[O:33]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for rac-trans-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone in Example A65 using 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid. MS (ESI) 327 (M+H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][NH:4][C:3]2=[O:21].[CH:22](Cl)(Cl)Cl.CO>>[CH2:22]=[C:9]1[C:10]2[C@:15]([CH3:16])([CH:14]=[CH:13][C:12](=[O:20])[CH:11]=2)[C@@H:17]2[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]2)([CH3:1])[C:3](=[O:21])[NH:4][CH2:5]3)[CH2:8]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)NC[C@@H]12
Reactant: ClC(Cl)Cl
Solvent: CO
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)NC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12

Procedure:
The procedures of Example 14 were repeated using 21 mg of 16-azaandrosta-1,4-diene-3,17-dione in place of 16-oxaandrosta-1,4-diene-3,17-dione, and the resultant crude product was purl fie d by TLC [developing solvent; chloroform: methanol (9:1 )] to obtain 2 mg of 6-methylene-16-azaandrosta-1,4-diene-3,17-dione.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[O:16])[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1sc(C(=O)O)cc1-c1c(C)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (130 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (278 mg, 0.43 mmol, 82% yield) as a yellow oil: LCMS (ES) m/e 581 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:14][C:15](=[CH:17][CH2:18][CH2:19][CH:20]([CH2:22][CH2:23]O)[CH3:21])[CH3:16]>C1CCCCC1.CCOCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:21][CH:20]([CH2:19][CH2:18][CH:17]=[C:15]([CH3:16])[CH3:14])[CH2:22][CH2:23][O:6][C:5](=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CC(C)=CCCC(C)CCO
Reactant: CCCCCCC(=O)CCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CCCCCCC(=O)CCC(=O)OCCC(C)CCC=C(C)C
Yield: 91 %

Procedure:
A solution of 20.0 g 4-oxo-1-decanoic acid (Synthesis, 1987, 408), 16.8 g citronellol extra and 0.5 g p-toluene-sulfonic acid in 150 ml of cyclohexane was refluxed in a flask equipped with a Dean-Stark trap for 3 hours. Then the reaction mixture was cooled, diluted with ether, washed with saturated NaHCO3 and water. The organic phase was dried, filtered and evaporated to dryness. The resulting oil was purified by chromatography to yield 31.7 g of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:29][CH2:28][C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:11]([CH3:10])[CH:12]2[CH2:29][CH2:28][C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]3)[CH2:14][CH2:13]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CNC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(c1nc(Cl)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (300 mg, 1.64 mmol) and tert-butyl 9-(methylamino)-3-azaspiro[5.5]undecane-3-carboxylate (511.18 mg, 1.81 mmol) in ethanol (15 mL) was added N,N-diethylethanamine (331.90 mg, 3.28 mmol). The reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/5) to give the title compound as yellow oil (101.83 mg, 14.5%).