Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)(Cl)Cl>[CH2:28]([NH:35][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 70.5 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -15° C. during 20 minutes. After stirring for 5 minutes, 10.14 g (0.088 mol) of heptylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -11° C. and -16° C. during 50 minutes. The reaction mixture is stirred at the same temperature for 1 hour and then allowed to stand under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 17.0 g (70.5%) of the named product as orange yellow crystals, m.p.: 118°-120° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]([Cl:19])=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:5]=[N:6][CH:7]=1.[CH:20]1([B-](F)(F)F)[CH2:22][CH2:21]1.[K+].C1COCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:19][C:9]1[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH:20]3[CH2:22][CH2:21]3)[CH:3]=2)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:18])[N:13]2[CH3:17]
Reactant: CN1C(=O)Cc2c1ccc(-c1cncc(Br)c1)c2Cl
Reactant: F[B-](F)(F)C1CC1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1C(=O)Cc2c1ccc(-c1cncc(C3CC3)c1)c2Cl
Temperature: 125 °C

Procedure:
To 5-(5-bromo-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-one prepared as described in Example 28, (85 mg, 0.25 mmol) was added potassium cyclopropyltrifluoroborate (41 mg, 0.38 mmol), THF (2 mL) water, (0.66 mL), and tripotassium phosphate (187 mg, 0.88 mmol). The reaction mixture was degassed and placed under an argon atmosphere, and then (1,1′-bis(diphenylphosphino)-ferrocenel-dichloropalladium(II) complexed with dichloromethane (CAS#72287-26-4 10.3 mg, 0.013 mmol) was added. The reaction vessel was sealed and was heated by microwave irradiation at 125° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane and saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered through a pad of Celite®, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0 to 100%) to afford 4-chloro-5-(5-cyclopropyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 299.0955 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.78-0.82 (m, 2H), 1.01-1.18 (m, 2H), 1.94-2.04 (m, 1H), 3.26 (s, 3H), 3.61 (s, 2H), 6.83 (d, J=7.8 Hz, 1H), 7.26-7.31 (m, 1H), 7.44 (br. s., 1H), 8.36-8.54 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]/[N:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[N+]([C:22]([CH2:49][CH2:50][CH2:51][CH3:52])=[CH:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][C:25]=1[C:37]([N:39]1[CH2:48][CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40]1)=[O:38])([O-])=O>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:22]([CH2:49][CH2:50][CH2:51][CH3:52])=[C:23]([C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[CH:26][C:25]=3[C:37]([N:39]3[CH2:48][CH2:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40]3)=[O:38])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: C=CCOc1ccc(N/N=C/C(=O)OCC)cc1
Product: C=CCOc1ccc(-n2nc(C(=O)OCC)c(-c3ccc(C(=O)OC(C)(C)C)cc3C(=O)N3CCc4ccccc4C3)c2CCCC)cc1
Yield: 66.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-(allyloxy)phenyl)hydrazono)acetate (64 mg, 0.26 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (120 mg, 0.26 mmol) were converted to the title compound (114 mg, 67%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.10 (dd, J=8, 2 Hz, 1H), 8.04-8.03 (m, 1H), 7.43-6.81 (m, 9H), 6.11-6.04 (m, 1H), 5.45-5.40 (m, 1H), 5.34-5.30 (m, 1H), 5.02-4.98 (m, 1H), 4.59-4.57 (m, 2H), 4.48-4.38 (m, 1H), 4.32-4.26 (m, 2H), 4.15-3.98 (m, 1H), 3.58-3.32 (m, 1H), 2.86-2.45 (m, 4H), 1.61 (s, 9H), 1.27 (t, J=8 Hz, 1.5H), 1.20 (t, J=8 Hz, 1.5H), 1.11-0.92 (m, 4H), 0.62-0.57 (m, 3H); MS(ESI+) m/z 664.4 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OC(C)C)(C)C.C(O)C>[ClH:1].[C:8]1([CH:6]2[O:5][N:4]=[C:3]([CH2:2][N:24]3[CH2:23][CH2:22][C:21]([C:18]4[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=4)([OH:27])[CH2:26][CH2:25]3)[CH2:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCC1=NOC(c2ccccc2)C1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: OC1(c2ccc(Cl)cc2)CCN(CC2=NOC(c3ccccc3)C2)CC1
Reaction time: 6 h

Procedure:
3-Chloromethyl-5-phenyl-4,5-dihydroisoxazole (5.87 g), 6.3 g of 4-(4-chlorophenyl)-4-hydroxypiperidine, 4 g of potassium carbonate and 50 ml of ethanol are heated to 60°-70° C. with stirring for 6 hours. The reaction mixture is filtered and the filtrate is condensed by distillation under reduced pressure. To the residue are added 200 ml of ethyl acetate and 100 ml of water. The organic layer is separated off, washed with water, dried on magnesium sulfate and evaporated under reduced pressure. The residue thus obtained is dissolved in isopropyl ether and alcoholic hydrochloric acid is added to the solution. The crystals thus formed are filtered and then recrystallized from isopropyl alcohol, giving 1-(5-phenyl-4,5-dihydroisoxazol-3-ylmethyl)-4-(4-chlorophenyl)-4-hydroxypiperidine hydrochloride. Melting point: 175°-176° C. (decomposition)
Reaction SMILES: [CH:1]([C:3]([C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)=[CH:4]O)=O.[CH3:15][NH:16][NH2:17]>C(O)C>[CH3:15][N:16]1[CH:4]=[C:3]([C:6]2[N:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=2)[CH:1]=[N:17]1
Reactant: CNN
Reactant: O=CC(=CO)c1ccc(C(=O)O)cn1
Solvent: CCO
Product: Cn1cc(-c2ccc(C(=O)O)cn2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
A suspension of 6-(1-formyl-2-hydroxyvinyl)pyridine-3-carboxylic acid (1.93 g) (Eastman Chemicals) in absolute ethanol (50 ml) and methylhydrazine (0.50 g) was stirred for 18 hours at room temperature. The reaction mixture was filtered to give the product (1.30 g). The filtrate was evaporated to give a solid which was recrystallized from ethyl acetate to give an analytical sample of the title compound (0.55 g), m.p. 262-264° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[H-].[Na+].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:26](=[O:27])[N:22]3[CH2:23][CH2:24][CH2:25][N:21]3[C:20]=2[C:28]2[CH:33]=[CH:32][N:31]=[C:30](S(C)(=O)=O)[N:29]=2)=[CH:15][CH:14]=1>C1COCC1.[NH4+].[Cl-]>[Cl:9][C:3]1[C:2]([NH:1][C:30]2[N:29]=[C:28]([C:20]3[N:21]4[CH2:25][CH2:24][CH2:23][N:22]4[C:26](=[O:27])[C:19]=3[C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)[CH:33]=[CH:32][N:31]=2)=[C:7]([Cl:8])[N:6]=[CH:5][N:4]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CCC3)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1c(-c2ccc(F)cc2)c(-c2ccnc(Nc3c(Cl)ncnc3Cl)n2)n2n1CCC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-amino-4,6-dichloropyrimidine (219 mg, 1.34 mmol) in THF (4 mL) is added NaH (0.07 g, 1.00 mmol). After stirring the mixture for 5 min at room temperature, 2-(4-fluorophenyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 5, (0.25 g, 0.67 mmol) is added to the reaction mixture. The reaction mixture is heated to reflux and stirred for 1 h. The mixture is diluted with aqueous saturated NH4Cl and extracted with twice with chloroform. The organic layers are combined, dried over MgSO4, and concentrated in vacuo to afford the crude product that is purified over silica (5% MeOH/chloroform) to provide the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) □ 8.77 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.35 (dd, J=9.0, 5.1 Hz, 1H), 7.10 (dd, J=8.7, 8.7 Hz, 2H), 6.71 (d, J=5.1 Hz, 1H), 4.25 (t, J=6.9 Hz, 2H), 4.12 (t, J=6.9 Hz, 2H), 2.74 (dddd, J=6.9, 6.9, 6.9, 6.9 Hz, 2H). ESI+ MS m/z (rel intensity) 458.1 (100, M++H). This compound corresponds to analog 441 from Table X.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:22]1[CH:21]=[CH:20][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1ccc2ccccc2c1
Product: COc1ccc2c(-c3ccc4ccccc4c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-naphthaleneboronic acid to give (6-methoxy-1-naphthalen-2-yl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:11]#[N:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:17][Mg+].[Br-]>C1COCC1>[CH:14]1([CH2:13][CH:10]([C:7]2[CH:8]=[N:9][C:4]([C:1]([OH:3])([CH3:17])[CH3:2])=[CH:5][CH:6]=2)[C:11]#[N:12])[CH2:16][CH2:15]1
Reactant: C[Mg+]
Reactant: CC(=O)c1ccc(C(C#N)CC2CC2)cn1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(C#N)CC2CC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
A solution of 2-(6-acetylpyridin-3-yl)-3-cyclopropylpropanenitrile (520 mg, 2.43 mmol) in THF (6 mL) was added MeMgBr (0.89 mL, 2.67 mmol, 3M in Et2O) at 0° C. under N2 and stirred at room temperature for 2 h. The solution was quenched with water and extracted with EtOAc (3×20 mL). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc: Petroleum ether=1:10) to give 3-cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propanenitrile (200 mg, yield: 35.6%). 1H NMR (CDCl3 varian 400): δ8.41 (d, J=2.4 Hz, 1H), 7.67 (dd, J=8.0 Hz, 2.4 Hz, 1H), 7.36 (dd, J=8.4 Hz, 0.8 Hz,
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.O>C(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C:12]3[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]2=[O:15])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(F)cc1

Procedure:
4-Fluorobenzylamine (20 g, 160 mmol) in 10 mL CH2Cl2 was added to phthalic anhydride (5 g, 34 mmol) in 20 mL glacial acetic acid. The reaction was stirred at 100° C. for 4 h as water was collected with a Dean-Stark trap. Solvent was evaporated and the product was obtained by crystallization from ethanol (7.5 g, 87%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].Br[C:25]1[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:27]([F:40])[CH:26]=1>>[CH2:1]([N:3]([C:25]1[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[C:27]([F:40])[CH:26]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2]
Reactant: Fc1cc(Br)ccc1OCCN1CCCCC1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: CCN(c1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 23.7 %

Procedure:
Synthesized from ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (200 mg) and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine (238 mg) according to an analogous synthetic method to Example 116, the title compound (81 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:23](=[O:27])[CH:24]([CH3:26])[CH3:25]>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:23]([OH:27])[CH:24]([CH3:26])[CH3:25])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C=O
Reactant: Brc1cccc(CN2CCOCC2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(O)C(c1cccc(Br)n1)N1CCOCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-[(6-Bromopyridin-2-yl)methyl]morpholine (Example 45, Step 1) (500 mg, 1.95 mmol) was placed under argon and then taken up in tetrahydrofuran (19.5 mL). The solution was cooled to −78° C. LDA (1.62 mL of 1.8 M, 2.92 mmol) was added dropwise over 30 minutes. The mixture was stirred at −78° C. for one hour. Isobutyraldehyde (0.71 mL, 7.8 mmol) was then added and the reaction was then stirred at −78° C. for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash chromatography (silica, 50-100% ethyl acetate/hexanes) afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:69][S-:70].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:70][CH3:69])[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1
Reactant: C[S-]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(SC)n1
Temperature: 90 °C
Yield: 66.4 %

Procedure:
Add toluene (20 mL), (S)-2-sec-butylamino-6-chloro-isonicotinic acid methyl ester (2.01 g, 8.29 mmol), palladium acetate (186 mg, 0.83 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (516 mg, 0.83 mmol), cesium carbonate (5.40 g, 16.6 mmol), and sodium thiomethoxide (1.16 g, 16.6 mmol) to a sealed vessel flushed with nitrogen. Heat the sealed vessel at 90° C. overnight. Cool to room temperature and filter the solution through a filtering agent and concentrate the filtrate. Purify the residue (silica gel chromatography, eluting with ethyl acetate:hexanes 90:10) to give the title compound (1.4 g, 66%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[O:60][N:59]=[C:58]([C:61](Cl)=[O:62])[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:61]([C:58]2[CH:57]=[C:56]([CH3:55])[O:60][N:59]=2)=[O:62])[CH2:49][CH2:48]1)=[O:53]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCN(C(=O)COc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 80 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 80% yield. LCMS for C28H28ClN8O4 (M+H)+: m/z=575.0.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](I)=[N:11][CH:10]=1.[OH:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+].COC(C)(C)C>N1C=CC=CC=1.[Cu-]=O>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([O:34][C:35]2[CH:42]=[CH:41][CH:40]=[C:37]([C:38]#[N:39])[CH:36]=2)=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#Cc1cccc(O)c1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: Cc1ccccc1-c1cc(Oc2cccc(C#N)c2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of 200 mg (0.346 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) and 84 mg (0.69 mmol) 3-hydroxybenzonitrile in 4 ml pyridine was deoxygenated by three freeze-thaw cycles. After addition of 5 mg (0.04 mmol) copper(I) oxide and 96 mg (0.69 mmol) potassium carbonate under a stream of argon the reaction mixture was heated at reflux for 70 h. Cooling to room temperature was followed by dilution with tert-butyl methyl ether and washing with two portions of 1 M aqueous hydrochloric acid solution. The combined aqueous layers were extracted with tert-butyl methyl ether. The combined organic layers were washed with saturated aqueous sodium carbonate solution and brine, dried with sodium sulfate and concentrated. Column chromatography afforded 174 mg (88%) of the title compound as a light brown solid.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH:27]=O>[OH-].[K+].CCO>[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[C:15](=[CH:27][C:23]2[S:24][CH:25]=[CH:26][C:22]=2[CH3:21])[CH2:14][CH2:13]3)[N:4]=[CH:3]1
Reactant: Cc1ccsc1C=O
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccsc1C=C1CCc2cc(OCCc3c[nH]cn3)ccc2C1=O
Yield: 63.1 %

Procedure:
According to the method of Example 4, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.146 g, 0.50 mmol) was reacted with 3-methyl-thiophene-2-carboxaldehyde (0.095 g, 0.50 mmol) in 5 mL of 4% KOH in EtOH to afford 0.115 g (63%) of the title compound as a coarse cream powder, mp 191-193° C.: CI-MS m/e 365 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12](Cl)=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:15][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc2cc(C(=O)Cl)oc12
Product: COc1cccc2cc(C(=O)Nc3ccccc3)oc12

Procedure:
Substantially the same procedure as in Step A of Reference Example 58 was repeated using 7-methoxybenzofuran-2-carbonyl chloride and aniline to give Compound IIbg (13.0 g, 68.2%) as a yellowish white solid.
Reaction SMILES: [CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@:14]4([O:19][C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:32]([OH:34])=[O:33])([CH3:31])[CH2:5][CH2:4][CH2:3]2)=[CH2:17].[Na].P([O-])([O-])([O-])=O.SC[C@H]([C@@H](CS)O)O.O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O>OP([O-])(O)=O.[K+].CC#N.C(Cl)(Cl)Cl.CO.O>[CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@:14]4([OH:19])[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:32]([OH:34])=[O:33])([CH3:31])[CH2:5][CH2:4][CH2:3]2)=[CH2:17]
Reactant: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O)[C@@H]2CC[C@]1(O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)C3
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])[O-]
Agent: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O)[C@@H]2CC[C@]1(O)C3

Procedure:
If Steviolmonoside, 3-sulfopropyl ester, sodium salt prepared in Part D. would be incubated anaerobically for three days at 37° C. with 5 wt% fresh rat cecal contents, at concentrations of 0.25, 0.5, and 1.0 mg/ml in sterile Krebs-Ringer 0.25 M phosphate buffer (pH 7.4) containing 0.25 mg/ml dithiothreitol and 0.25 mg/ml α-D-glucose, TLC [silica gel F-254; CHCl3 :CH3OH:H2O (15:10:2)] and HPLC [30 cm C-18 on μ-Bondapak; 15 min linear gradient of 10-40% CH3CN in 0.005 M KH2PO4 (pH 3.45); 200 nm] analysis would show all the initial ester (Rf=0.37; tR =14.6 min) to have been consumed within 24 h to yield apparently only the sulfopropyl ester of steviol, (Rf =0.63; tR =16.3 min). No steviol (Rf =0.95; tR =31.3 min) would be detected. Thereafter the bacterial cells would be sedimented by centrifugation. The sediment would be extracted (THF), as would the supernatant, after lyophilization. HPLC analysis for steviol of the two THF extracts should show none to be detectable, with a detection limit of 0.5 μg.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[CH:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:25][N:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:32]([N:26]1[CH2:27][CH:9]2[CH:8]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=[CH:11][C:10]2=[O:13])[CH2:25]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)C=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C=CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12

Procedure:
Trifluoroacetic acid (2 drops) is added to a solution of 4,4-diphenyl-2,5-cyclohexadien-1-one (7.7 g) and N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (11 cc) in dry dichloromethane (80 cc), and the reaction mixture is heated to reflux for 1 hour and a half. A further portion (5 cc) of N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine is added as well as trifluoroacetic acid (2 drops), and the reaction mixture is heated for 1 hour and a half. The reaction mixture is heated with potassium carbonate (3 g), filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in isopropyl ether (15 cc). The crystals obtained are drained, washed with isopropyl ether (2×5 cc) and dried; (3aRS,7aRS)-2-benzyl-7,7-diphenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-one (4.4 g), m.p. 132° C., is obtained.