Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:37])[C@H:24]([CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:37])=[O:22])[CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2cccc3ccccc23)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to β-(1-naphthyl)alanine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:44]3[CH2:45][CH2:46][N:41]([C:38](=[O:40])[CH3:39])[CH2:42][CH2:43]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H40N6O3Cl2 [(M+H)+] 651.2612, observed 651.2615.
Reaction SMILES: [CH2:1]([N:4]([CH:8]=[N:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[OH:16])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27]>O1CCCC1>[CH3:24][N:25]([CH3:29])[C:26]([O:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[N:9]=[CH:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[O:27]
Reactant: CN(C)C(=O)Cl
Reactant: CCCN(C=Nc1ccncc1O)CCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(C=Nc1ccncc1OC(=O)N(C)C)CCC

Procedure:
A mixture prepared from 4-[[(dipropylamino)methylene]amino]-3-pyridinol (3.22 g), triethylamine (3.15 g), dimethylcarbamyl chloride (2.01 mL) and tetrahydrofuran (100 mL) was refluxed for 1 hour, cooled, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate. The eluate was concentrated and the solid was recrystallized from diethyl ether to yield 2.99 g of product, m.p. 84°-85° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1)(=O)C>C(O)C>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH2:4])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CCO
Product: Nc1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
A suspension of N-acetyl-4-(quinolin-2-ylmethoxy)aniline (Step A, 108.9 g) in 1 L of 95% ethanol containing 10M KOH (120 mL) was heated at reflux under nitrogen in a heating mantle. When the hydrolysis was complete (approx. 36 h), the reaction mixture was cooled and ethanol was partially removed under vacuum. The mixture was then diluted with water (200 mL) and the fine off-white crystals were collected and thoroughly rinsed with water. The material, after air-drying, yielded the title compound which was used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:31](O)[CH2:32][OH:33]>C1(C)C=CC=CC=1.C(OC(=O)C)C>[CH3:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]3[O:33][CH2:32][CH2:31][O:17]3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: OCCO
Reactant: Cc1cc(Oc2ccc(C=O)cc2)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2ccc(C3OCCO3)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98 %

Procedure:
4-[(3-Methyl-4-nitrophenyl)oxy]benzaldehyde (1.72 g, 6.4 mmol), p-toluenesulfonic acid (120 mg, 0.64 mmol), and ethylene glycol (1.7 mL, 32 mmol) were heated to reflux in 70 mL toluene for 16 hours in a round bottom flask equipped with a Dean-Stark trap. The reaction mixture was cooled to room temperature, diluted with ethylacetate and extracted with 1N NaOH. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.89 g crude 2-{4-[(3-methyl-4-nitrophenyl)oxy]phenyl}-1,3-dioxolane, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[H-].[Na+].[CH3:13]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:13])[C:5]#[N:6]
Reactant: CI
Reactant: N#Cc1ccc(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1Cl
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Under N2, a solution of 3-chloro-4-hydroxybenzonitrile (15.4 g, 0.1 mole) in dry DMF (75 ml) was added rapidly dropwise to a stirred suspension of sodium hydride (4.0 g, 0.1 mole, 60% oil dispersion) in dry DMF (25 ml). After heating at 70° C. for 2 hours, the mixture was cooled to 20° C. and a solution of methyliodide (30 ml) in dry DMF (50 ml) was added dropwise. Following an 18 hour period at room temperature, the precipitate of sodium iodide was removed by filtration and the solvent was stripped from the filtrate under reduced pressure. The crystalline residue was slurried in water and the product was collected to yield 16.8 g (quant.) of 26, m.p. 105°-108° C. A sample recrystallized from IPA--H2O melted at 107°-109° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=O)C.C([NH2:24])=O.[O-]CC.[Na+]>CN(C)C=O>[C:4]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)(=[O:3])[NH2:24]
Reactant: CCOC(=O)CCCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCC(N)=O)CC1
Temperature: 100 °C

Procedure:
tert-Butyl 4-(3-ethoxycarbonylpropyl)piperidine-1-carboxylate (0.60 g, 2.0 mmol, the product of Production example 43-1) and formamide (0.27 ml, 6.7 mmol) were dissolved in N,N-dimethylformamide (1.0 ml); sodium ethoxide (0.095 g, 1.4 mmol) was added thereto while stirred and heated at 100° C.; the reaction mixture was stirred for 2 hours under nitrogen atmosphere. After cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane-ethyl acetate=95:5 to 85:15). The title compound was obtained as a colorless oil (0.38 g, 1.4 mmol, 70%).
Reaction SMILES: [NH2:1][C@H:2]([CH3:35])[C:3]([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][CH2:33][CH3:34])([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])[OH:4].[CH:36](=O)[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]>C(O)C.C1(C)C=CC=CC=1>[CH:36](=[N:1][C@H:2]([CH3:35])[C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][CH2:33][CH3:34])[OH:4])[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]
Reactant: CCCCOc1ccc(C(C)(C)C)cc1C(O)(c1cc(C(C)(C)C)ccc1OCCCC)[C@@H](C)N
Reactant: O=Cc1ccccc1O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOc1ccc(C(C)(C)C)cc1C(O)(c1cc(C(C)(C)C)ccc1OCCCC)[C@@H](C)N=Cc1ccccc1O
Yield: 99.5 %

Procedure:
0.968 g (2.0 mmol) of (R)-2-amino-1,1-di(2-butoxy-5-t-butylphenyl)-propanol and 0.244 g (2.0 mmol) of salicylaldehyde were dissolved in 20 ml of ethanol and 20 ml of toluene, the solution was heated at reflux for 1 hour. The solvent was distilled off from the reaction mixture and dried to obtain 1.17 g of (R)-N-salicyliden-2-amino-1,1-di(2-butoxy-5-t-butylphenyl)-propanol as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Cl[C:13](=[O:18])[C:14]([O:16]C)=[O:15].[OH-].[Na+:20]>CO>[Na+:20].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:18])[C:14]([O-:16])=[O:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
In a manner similar to that described in Referential Example 242, 4-chloro-2-nitroaniline was condensed with methyl chlorooxoacetate. In a manner similar to that described in Referential Example 266, the condensed compound was hydrolyzed. The residue was dissolved in methanol, 1N aqueous sodium hydroxide was added thereto, and the precipitated material was recoverd by filtration, whereby the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[F:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1Br>>[F:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccc(C(F)(F)F)cc3F)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-fluoro-4-(trifluoromethyl)bromobenzene. MS (ESI): mass calcd. for C17H10F5N3, 351.08; m/z found, 351.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.11-7.97 (m, 2H), 7.90-7.83 (m, 2H), 7.71 (d, J=8.1, 1H), 7.61-7.54 (m, 2H), 6.78 (s, 2H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC(=O)OCC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(CC(=O)OCC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-ethoxycarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]([Cl:21])([Cl:20])[C@@H:11]1[N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13](=[O:19])[O:12]1.[CH3:22][O:23][CH2:24]Cl.O>C1COCC1>[CH3:22][O:23][CH2:24][C@@:14]12[CH2:18][CH2:17][CH2:16][N:15]1[C@@H:11]([C:10]([Cl:9])([Cl:20])[Cl:21])[O:12][C:13]2=[O:19]
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Reactant: COCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Temperature: -30 °C

Procedure:
A 1M of solution of lithium diisopropylamide in a 3:5 mixture of hexanes/THF (8.25 ml) is added dropwise to (3R,7aS)-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (1.51 g, prepared as described by Wang and Germanas Synlett 1999, 33-36.) in THF (5 ml) at −78° C. After stirring 30 minutes at −78° C. methoxymethylchloride (1.14 ml) is added. The reaction mixture is then allowed to warm to −30° C. over 3 hours and water is added. The aqueous layer is extracted with dichloromethane, the combined organic layers evaporated and the residue is then purified by normal phase chromatography, eluting with dichloromethane, to give the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][CH:2]1[CH2:5][C:4](=[O:6])[CH2:3]1.[CH2:7](O)[CH2:8][OH:9].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1C=CC=CC=1>[Br:1][CH:2]1[CH2:5][C:4]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:3]1
Reactant: O=C1CC(Br)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: BrC1CC2(C1)OCCO2
Reaction time: 12 h
Yield: 51 %

Procedure:
A mixture of 3-bromocyclobutanone (5.90 g, 39.6 mmol), 1,2-ethanediol (8.6 mL, 158 mmol, 4 eq.) and PPTS (1.90 g, 7.92 mmol) in benzene (40 mL) was heated to reflux using Dean-Stark assembly. After 12 h, the reaction mixture was allowed to cool and washed with water (2×30 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (ethyl acetate/hexanes 1:5) to give the title compound (51% yield starting from 3-oxocyclobutanecarboxylic acid). 1H NMR (300 MHz, CDCl3): δ=2.77-2.82 (m, 4H), 2.95-3.00 (m, 4H), 4.19-4.23 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27].C(N(CC)CC)C>O1CCCC1>[Cl:22][CH2:23][CH2:24][NH:25][C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1)=[O:27]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCCl)ccc21
Reaction time: 8 h

Procedure:
4.2 g (0.015 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are heated at reflux for 3 hours in 80 ml of absolute tetrahydrofuran with 3.5 ml of chloroethylisocyanate and a catalytic amount of triethylamine. The mixture is left to stand at room temperature overnight. The solution is concentrated on a steam-bath and the residue is crystallised from ethyl acetate. There is obtained 1-(2-chloroethyl)-3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea which melts at 240° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][C:17](=[O:19])[CH2:16][CH2:15][C@@H:14]2[CH2:13][NH:12][CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[CH2:20](O)[CH2:21][OH:22].CS(O)(=O)=O.N>O.C1C=CC=CC=1>[CH2:21]1[O:22][C:17]2([CH2:16][CH2:15][C@H:14]3[C@:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)([CH2:10][CH2:11][NH:12][CH2:13]3)[CH2:18]2)[O:19][CH2:20]1
Reactant: COc1cccc([C@]23CCNC[C@H]2CCC(=O)C3)c1
Reactant: OCCO
Agent: CS(=O)(=O)O
Agent: N
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc([C@]23CCNC[C@H]2CCC2(C3)OCCO2)c1

Procedure:
25.93 g (0.1 mol) of octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone (see Example 1), 100 ml of benzene, 11.2 ml (0.2 mol) of ethylene glycol and 8.1 ml (125 mmol) of methanesulphonic acid are boiled for 3 hours in a water separator. The mixture is cooled, made basic with aqueous ammonia and extracted with methylene chloride. The organic phase is evaporated to dryness to yield octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone ethylene ketal. The ketal is dissolved in 50 ml of absolute methanol, cooled to 0° C., and 13.91 ml (0.1 mol) of triethylamine and 7.46 ml (0.12 mol) of methyl iodide are added thereto. The mixture is kept at 22° for 1 hour. The mixture, containing octahydro-4a-(3-methoxyphenyl)-2-methyl-cis-6(2H)-isoquinolinone ethylene ketal, is mixed with 20 ml of dioxane and concentrated by evaporation. 100 ml of dioxane and 100 ml of 2 N aqueous hydrochloric acid are added to the residual oil. The resultant mixture is stirred for 2 hours at 40°, made basic with aqueous ammonia, and extracted with toluene. The extracts are concentrated by evaporation to yield the title compound as an oil, which is crystallized as the hydrogen fumarate from ethanol.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[CH2:17][C:16]1=[O:24]>>[CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=[C:17]1[C:18]2[C:23](=[N:22][CH:21]=[CH:20][CH:19]=2)[NH:15][C:16]1=[O:24])([CH3:3])[CH3:2]
Reactant: O=C1Cc2cccnc2N1
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Product: COc1cc(C)c(C=C2C(=O)Nc3ncccc32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde condensed with 7-aza-2-oxindole to give 0.25 g of 3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH2:12]([OH:15])[CH2:13][OH:14]>ClCCl>[OH:14][CH2:13][CH2:12][O:15][C:7](=[O:8])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([Cl:11])=[N:4][CH:5]=1
Reactant: O=C(Cl)c1cnc(Cl)c(Br)c1
Reactant: OCCO
Solvent: ClCCl
Product: O=C(OCCO)c1cnc(Cl)c(Br)c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
5-Bromo-6-chloro-nicotinoyl chloride (W. J. Thompson et al., J. Org. Chem. 49 (1984), 5237-5243, raw material; 7.00 g, apx 50% purity) was diluted with dichloromethane (50 ml), ethylenglycol (17 g) was added slowly and the mixture was stirred at room temperature over night. The mixture was partitioned between ether and water and the aqueous phase was extracted three times with ether. Each ether extract was washed with new water. The combined organic layers were dried over sodium chloride and evaporated to dryness in vacuo to yield the title compound (6.0 g) as raw material.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[N:16]1([C:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH2:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: N#Cc1ccc(N2CC=C(N3CCCC3)CC2)cc1

Procedure:
A solution of 24 g (0.1199 mol) of the compound of (B), 15 ml (12.78 g/0.1796 mol) of pyrrolidine, 240 mg of p-toluenesulfonic acid, and 100 ml of benzene is stirred at reflux with the azeotropic removal of water for 6 hours. After cooling, the resulting precipitate is collected and triturated with ethyl ether to afford 20 (66%) of title compound: m.p. 126°-129° C.; IR (KBr) 2200, 1635, and 1600 cm-1 ; NMR (CDCl3) δ7.48 (d, 2H), 6.7 (d, 2H), 4.3-4.1 (m, 1H) 3.95-3.45 (m, 4H), 3.2-2.85 (m, 4H) 2.65-2.25 (m, 2H), and 1.95-1.75 (m, 4H).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[S:33]([NH2:36])(=[O:35])=[O:34]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:36][S:33]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1cccs1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccs2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-thiophenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method A described hereinabove. Yield (27%); 1H NMR (d6-DMSO) δ 12.34 (br s, 1H), 7.99 (m, 1H), 7.76 (m, 1H), 7.39–7.08 (m, 14H), 6.85 (d, J=8.4 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 500 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:9]1([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Brc1ccc(-c2ccccc2)nc1

Procedure:
A mixture is prepared of 2,5-dibromopyridine (10 g, 42.21 mmol), phenylboronic acid (5.1 g, 42.21 mmol), and potassium carbonate (11.7 g, 84.42 mmol) in 100 mL dimethoxyethane and 40 mL of water. Nitrogen is bubbled directly into the mixture for 30 minutes. Next, tetrakis(triphenylphosphine)palladium(0) was added (244 mg, 2.11 mmol) and the mixture is heated to reflux under nitrogen overnight. The mixture is cooled and diluted with ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue is purified by column chromatography eluting with 0, 2, and 5% ethyl acetate/hexanes.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[CH3:28][S:29]([NH:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:31])=[O:30]>>[OH:16][C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:7](=[O:8])[C:6]1[CH:17]=[C:2]([C:36]2[CH:35]=[CH:34][C:33]([NH:32][S:29]([CH3:28])(=[O:30])=[O:31])=[CH:38][CH:37]=2)[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]=1[C:18]([F:21])([F:20])[F:19]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: CS(=O)(=O)Nc1ccc(-c2cc(C(=O)N[C@@H]3CCCC[C@H]3O)c(C(F)(F)F)nc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 4-methanesulfonylaminophenylboronic acid as starting materials, MS (ISP) 556.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][N:10]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=1)[C:11]2=[O:22])[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C(O)C.[C].[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:10]2[CH2:9][C:8]3[C:12](=[CH:13][CH:14]=[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]=3[O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:11]2=[O:22])=[CH:26][CH:27]=1
Reactant: CCCCCOc1ccc2c(c1OCCCCC)CN(CCc1ccc([N+](=O)[O-])cc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCOc1ccc2c(c1OCCCCC)CN(CCc1ccc(N)cc1)C2=O
Yield: 93.5 %

Procedure:
4,5-Dipentyloxy-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one (19.69 g, 43.3 mmol, 1.0 eq) obtained in Example 7-30 was dissolved in ethanol (200 ml), and 5% palladium-carbon catalyst (3.8 g, water content 50%) was added. The reaction mixture was stirred in a stream of hydrogen at room temperature for 2.5 hours under the pressure of 3 kgf/cm2, and filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/chloroform=1/2) to give 2-[2-(4-aminophenyl)ethyl]-4,5-bispentyloxy-2,3-dihydroisoindol-1-one (17.19 g, 93.5%) as pale-yellow crystals.