Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH:11]=O>C(O)C>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH:11]=[C:2]1[CH2:3][CH2:4][CH2:5][C:6](=[CH:11][C:10]2[C:9]([Cl:8])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:17])[C:1]1=[O:7]
Reactant: O=C1CCCCC1
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: CCO
Product: O=C1C(=Cc2c(Cl)cccc2Cl)CCCC1=Cc1c(Cl)cccc1Cl
Reaction time: 4 h

Procedure:
(76) Cyclohexanone (10 mmol), 60 ml of ethanol, and 2,6-dichlorobenzaldehyde (20 mmol) were used. The reaction stirred for 4 hours. A solid formed and was filtered. Recrystallization from ethanol yielded 3.24 g (78.6%) of bright-yellow flakes: mp 185.0-186.0° C. (lit. mp 183° C., Smith et al., supra). 1H NMR (250 MHz) δ 7.60 (s, 2H), 7.37-7.18 (m, 6H), 2.45 (t, 4H), 1.73 (p, 2H); 13C NMR (62.7 MHz) 188.2, 140.3, 134.6, 134.4, 132.4, 129.6, 128.1, 28.4, 22.1 ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([Cl:14])=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[Na+].NC(N)=O.[N-:24]=[N+:25]=[N-].[Na+].[S:28](=[O:32])(=[O:31])([OH:30])[OH:29]>O>[S:28]([OH:32])([OH:31])(=[O:30])=[O:29].[N:1]([C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([Cl:14])=[CH:4][CH:3]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CN1CCc2c(N)ccc(Cl)c2CC1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CN1CCc2c(Cl)ccc(N=[N+]=[N-])c2CC1
Temperature: 25 °C

Procedure:
To a solution of 630 mg (3 mmol) of 9-amino-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 2 ml of concentrated sulfuric acid and 10 ml of water was added 280 mg (4 mmol) of sodium nitrate in 5 ml of water. The mixture was stirred in an ice bath during addition, then, allowed to warm to room temperature. After stirring at room temperature for one hour, 60 mg of urea was added to destroy excess nitrous acid. To this solution was added 330 mg (5 mmol) of sodium azide and the resulting solution stirred at room temperature. Nitrogen was evolved and a white precipitate formed. After stirring overnight, this was removed by filtration, stirred with a small amount of cold ethanol, filtered again and washed with ether to leave 545 mg (58%) of slightly off-white crystals, 9-azido-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine sulfate. This material was crystallized from ethanol to give 390 mg as a slightly yellow crystalline solid, m.p. 71°-75° (dec), IR and NMR spectra support structure.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=CCCCNC(=O)C1C=CC=CC=1>>[C:1]([N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]=[O:17])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCN(CCO)CC1
Agent: O=CCCCNC(=O)c1ccccc1
Product: O=CCN1CCN(C(=O)c2ccccc2)CC1

Procedure:
(4-Benzoyl-piperazin-1-yl)-acetaldehyde (38B) is prepared from 38A as described for 1E.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12](=[O:14])[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-:27].[Na+].OO.Cl>CCO>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12](=[O:14])[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)=[O:27]
Reactant: [OH-]
Reactant: N#Cc1cccc(C2=NC(c3ccccc3)(c3ccccc3)C(=O)N2)c1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc(C2=NC(c3ccccc3)(c3ccccc3)C(=O)N2)c1
Reaction time: 3 h
Yield: 63 %

Procedure:
To a 50 mL flask was added 0.300 g (0.889 mmol) of the 3-cyano derivative (Example 2) and 6 mL of 95% EtOH. The solution was stirred until homogeneous and then 1 mL of 6M NaOH and 1 mL of 30% hydrogen peroxide were added and the rxn was heated to reflux and allowed to stir for 3 h. Upon completion the reaction was cooled to rt and neutralized with conc. HCl. The solvent was evaporated in vacuo, and the crude residue was purified by column chromatography (Silica gel/Hexanes:Acetone 4:1) producing 0.20 g (63%) of the desired amide as a white solid. LRMS m/z (ESI) 356.2 (M+H)+ ; 1H-NMR (DMSO-d6, 300MHz) δ=8.74 (s, 1H), 8.32 (d, 1H, J=6.0 Hz), 8.10 (d, 1H, J=6.0 Hz), 7.66 (t, 1H, J=6.0 Hz), 7.48 (d, 4H, J=6.0 Hz), 7.33 (m, 6H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([CH3:27])[CH:14]=1)=[N:5][CH:6]=[N:7]2.[CH3:28][NH:29][C@H:30]([CH3:33])[CH2:31][OH:32]>>[CH3:28][NH:29][C@H:30]([CH3:33])[CH2:31][O:32][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([CH3:27])[CH:14]=1)=[N:5][CH:6]=[N:7]2
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Reactant: CN[C@H](C)CO
Product: CN[C@H](C)COc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Yield: 75 %

Procedure:
The procedure described in Example 103, preparation of starting materials, was repeated using 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103, preparation of starting materials) and (2R)-2-(methylamino)propan-1-ol (obtained as described in Becker et al., J. Chem. Soc. 1957, 858) to give 5-{[(2R)-2-(methylamino)propyl]oxy}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine in 75% yield; NMR Spectrum: (CDCl3) 1.30 (d, 3H), 2.28 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.20 (m, 1H), 4.09 (m, 1H), 4.21 (m, 1H), 6.89 (m, 2H), 7.14-7.07 (m, 2H), 7.45 (d, 1H), 7.63 (m, 2H), 8.26 (s, 1H), 8.63 (s, 1H), 10.3 (bs, 1H); Mass spectrum: MH+ 430.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.ClC1C=CC(C(O)=O)=NC=1SC.[CH3:26][S:27][C:28]1[CH:29]=[CH:30][C:31](C(O)=O)=[N:32][C:33]=1[S:34][CH3:35]>C1(C)C(C)=CC=CC=1>[CH3:35][S:34][C:33]1[C:28]([S:27][CH3:26])=[CH:29][CH:30]=[CH:31][N:32]=1
Reactant: CSc1ccc(C(=O)O)nc1SC
Agent: CSc1nc(C(=O)O)ccc1Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CSc1cccnc1SC
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A stirred solution of 250 ml of diphenyl oxide was heated to 200° C. A 54 g quantity of the 5-chloro-6-(methylthio)-2-pyridinecarboxylic acid/5,6-bis(methylthio)-2-pyridinecarboxylic acid mixture described above was added portionwise as a solid. The mixture was stirred for 1 hour with the temperature being maintained below 235° C. The mixture was cooled to 100° C., diluted with xylene and cooled to room temperature, then extracted three times with 75 ml of 6N HCl. The combined aqueous fractions were back-washed with diethyl ether, then stirred with CH2Cl2 and made strongly basic with 25% NaOH. The organic layer was separated, washed with water, then brine, and dried (Na2SO4). The solids were removed from the organic layer by filtration, then the filtrate was evaporated leaving a brown oil which was purified on a Kugelrohr distillation apparatus and 23.6 g of an oil obtained. The components of the oil were separated employing high pressure liquid chromatography (Porasil, 3% diethyl ether/hexane) and 19.42 g of 2,3-bis(methylthio)pyridine (b.p. 85° C. at 0.3 mm Hg) and 0.77 g of 3-chloro-2-(methylthio)pyridine (b.p. 80° C. at 0.3 mm Hg) obtained, both as colorless oils.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][Si:5]1(C2C=CC=CC=2)[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][C:31]=1[F:32]>>[CH3:24][CH:2]([CH3:1])[CH2:3][CH2:4][Si@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[C:31]([F:32])[CH:30]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: CC(C)CC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Product: CC(C)CC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 12 was repeated using 34.3 g of 4-(4-(3-methylbutyl)-4-phenyl-4-silacyclohexyl)cyclohexanone and 3,4-difluorophenylmagnesium bromide, thereby obtaining the captioned compound.
Reaction SMILES: [CH:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:12]1COCC1.CI>>[CH3:12][C:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: CCCCOS(=O)(=O)C1CC1
Solvent: CI
Product: CCCCOS(=O)(=O)C1(C)CC1
Temperature: 0 °C
Yield: 55 %

Procedure:
To a solution of 1-Butyl cyclopropanesulfonate (1 g, 5.58 mmol) in THF (15 ml) butyllithium solution (3.84 ml, 6.14 mmol, 1.6M, THF) was slowly added at −78° C. under nitrogen atmosphere. After 15 minutes MeI (0.72 ml, 11.16 mmol) was added and the solution was allowed to warm to 0° C. and quenched with water (1 ml). The volatiles evaporated under reduced pressure and the residue extracted with CH2Cl2 (100 ml). The extract was washed with water, dried (MgSO4) and evaporated. The residue was purified over silica gel chromatography (eluants: hexane/CH2Cl2) to obtain the titled product (0.59 g, 55.0%) as a colorless oil. 1H NMR (300 MHz, CDCl3)) δ 0.84 (m, 2H), 0.95 (t, J=7.2 Hz, 3H), 1.43 (m, 4H), 1.53 (s, 3H), 1.74 (m, 2H), 4.21 ((t, J=6.6 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[C@@H:11]2[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C@H:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:22]([F:25])([F:24])[F:23])[C:4]=2[NH:3]1.[ClH:26]>CCOCC>[ClH:26].[F:25][C:22]([F:23])([F:24])[C:5]1[C:4]2[NH:3][C:2](=[O:1])[C@@H:11]3[CH2:12][NH:13][CH2:14][C@H:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C(=O)Nc3c(cccc3C(F)(F)F)[C@@H]2C1
Agent: Cl
Solvent: CCOCC
Product: O=C1Nc2c(cccc2C(F)(F)F)[C@@H]2CNC[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a solution of the second eluting compound from Example 7, Part B, tentatively assigned as (3aS,9bR)-tert-butyl 4-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate (50 mg, 0.14 mmol) in 4 mL of ether was added 1 mL of 12 N HCl. The resulting mixture was stirred at ambient temperature for 15 min and then was concentrated and dried in vacuo to a solid. This solid was triturated twice with ether and dried in vacuo to afford 35 mg (85%) of the title compound of Example 8 as a white solid. 1H NMR (DMSO-D6): δ 9.73 (s, 1H), 9.66 (broad s, 1H), 9.54 (broad s, 1H), 7.62 (d, 1H), 7.50 (d, 1H), 7.25 (t, 1H), 3.96-3.90 (m, 1H), 3.55-3.42 (overlapping m, 2H), 3.32-3.22 (overlapping m, 2H), 3.10-3.00 (m, 1H). LRMS (ESI): 257.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[C:19]([CH3:41])[C:20]2[O:26][C:25]3[C:27]([Cl:37])=[CH:28][C:29]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:30][C:24]=3[CH2:23][S:22](=[O:39])(=[O:38])[C:21]=2[CH:40]=1)=[O:16].C([BH3-])#N.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:13][O:14][C:15]([C:17]1[CH:18]=[C:19]([CH3:41])[C:20]2[O:26][C:25]3[C:27]([Cl:37])=[CH:28][C:29]([N:31]4[CH2:32][CH2:33][N:34]([CH2:7][C:6]5[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=5)[CH2:35][CH2:36]4)=[CH:30][C:24]=3[CH2:23][S:22](=[O:38])(=[O:39])[C:21]=2[CH:40]=1)=[O:16]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4ccc(C(F)(F)F)cc4)CC3)cc(Cl)c1O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
p-(Trifluoromethyl)benzaldehyde (0.119 g, 0.687 mmol) and titanium isopropoxide (0.26 mL, 0.858 mmol) were added to a suspension of Example 104k (0.3 g, 0.687 mmol) in methanol (30 mL). The reaction mixture was refluxed for 1.5 h, cooled to room temperature, treated with sodium cyanoborohydride (0.042 g, 0.66 mmol) and stirred for 3 h. It was concentrated, treated with water and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 20% ethyl acetate/pet.ether) to obtain the title compound. Yield: 0.12 g, (28.7%); 1H NMR (DMSO-d6): δ 2.6 (h, 4H, 2CH2), 2.7 (s, 3H, CH3), 3.2 (h, 4H, 2CH2), 3.6 (s, 2H, CH2), 3.9 (s, 3H, OCH3), 4.6 (s, 2H, CH2), 6.7 (s, H, Ar), 6.9 (s, 1H, Ar), 7.5 (d, 2H, Ar), 7.6 (d, 2H, Ar), 8.1 (s, 1H, Ar), 8.45 (s, 1H, Ar); MS: m/e (ES+) 596 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1(C(N2C=CN=C2)=O)C=CN=C1.C(N(C(C)C)C(C)C)C.[C:33]1([NH:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:40][NH:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:6]
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: NNc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Br)ccc1C(=O)NNc1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-amino-4-bromobenzoic acid (10 g, 46.30 mmol, 1.00 equiv) in tetrahydrofuran (300 mL). To the resulting mixture was then added di(1H-imidazol-1-yl)methanone (9 g, 55.56 mmol, 1.20 equiv) dropwise, with stirring at 0-5° C. The resulting mixture was warmed and stirred at 20° C. for 2 hours. To the resulting mixture was then added N-ethyl-N-isopropylpropan-2-amine (7.2 g, 55.81 mmol, 1.20 equiv) dropwise with stirring at room temperature. To the mixture was then added 1-phenylhydrazine (5 g, 46.30 mmol, 1.00 equiv) in several batches at room temperature. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 1N hydrogen chloride/H2O. The pH value of the solution was adjusted to about pH1 with 1N HCl. The resulting mixture was then neutralized to pH=7 with 50% NaOH. The resulting solution was extracted with ethyl acetate (2×250 mL) and the organic layers combined. The resulting mixture was washed with water (2×500 mL), sodium bicarbonate (2×500 mL) and saturated brine (2×500 mL). The resulting solution was concentrated under reduced pressure to yield 2-amino-4-bromo-N′-phenylbenzohydrazide as a red solid. MS: 306 (MH+)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]3)[CH2:16][CH2:15]2)[N:9]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[CH:43][C:42]3[C:41]([CH3:46])([CH3:45])[CH2:40][CH2:39][C:38]([CH3:48])([CH3:47])[C:37]=3[CH:36]=2)O1.O>C1(C)C=CC=CC=1.C(O)C.O>[CH3:45][C:41]1([CH3:46])[CH2:40][CH2:39][C:38]([CH3:48])([CH3:47])[C:37]2[CH:36]=[C:35]([C:8]3[N:13]=[CH:12][N:11]=[C:10]([N:14]4[CH2:19][CH2:18][CH:17]([N:20]5[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]5)[CH2:16][CH2:15]4)[N:9]=3)[CH:44]=[CH:43][C:42]1=2
Reactant: OC1CCCN(C2CCN(c3ncnc(Cl)n3)CC2)C1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(-c3ncnc(N4CCC(N5CCCC(O)C5)CC4)n3)ccc21
Temperature: 90 °C

Procedure:
45 mg (0.42 mmol) of sodium carbonate are added to 50 mg (0.17 mmol) of 1′-(4-chloro-1,3,5-triazin-2-yl)-1,4′-bipiperidinyl-3-ol and 139 mg (0.42 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane in 3.2 ml of toluene/ethanol/water (3.2/3.2/1). The reaction mixture is degassed a number of times, and 19 mg (0.017 mmol) of tetrakis-(triphenylphosphine)palladium(0) are added under nitrogen atmosphere, the mixture is treated in an ultrasound bath for 10 min and subsequently heated at 90° C. for 5 h. Water is added to the reaction mixture, which is then extracted three times with ethyl acetate/ether. The combined organic phases are dried over Na2SO4 and evaporated. The crude product is purified by means of preparative HPLC.
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]([O:5][C:6]2=[O:11])=O.C(N1C2C(=CC=CC=2)C=C1C)C.C(N(C1C=C(OCC)C=CC=1)CC)C.C(OC(=O)C)(=O)C.N>[Cl-].[Zn+2].[Cl-].C(O)(C)C.O.C(O)(=O)C>[C:6]1([C:7]2[C:2](=[N:1][CH:10]=[CH:9][CH:8]=2)[CH2:3][O:5]1)=[O:11]
Reactant: O=C1OC(=O)c2ncccc21
Agent: CCOc1cccc(N(CC)CC)c1
Agent: CCn1c(C)cc2ccccc21
Agent: N
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: O
Product: O=C1OCc2ncccc21
Reaction time: 2 h
Yield: 258.8 %

Procedure:
20.0 g of quinolinic anhydride, 80 ml of acetic acid, 20.3 g of N-ethyl-2-methylindole and 2.74 g of zinc chloride are stirred at 20° C. for 5 hours. 23.6 g of 3-(N,N-diethylamino)-phenetole and 30 ml of acetic anhydride are then added, after which the reaction mixture is warmed to 50° to 60° C. and stirred at this temperature for 2 hours. After addition of 170 ml of 30% aqueous ammonia and 100 ml of water, the product precipitates as a paste and is isolated. 160 ml of isopropanol are added to the paste and the mixture is refluxed for 1 hour. After cooling, the recrystallised product is filtered off, washed with isopropanol and dried, affording 46.9 g of the isomer-free 4-azaphthalide compound of the formula ##STR15## of melting point 156° to 158° C.
Reaction SMILES: [C:1]([CH:9]1[NH:13][C:12](=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:2]1([CH:1]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:13]2)[OH:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(C(=O)c2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1)C1CCCN1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
65.6 g of 5-benzoyl-2-pyrrolidone prepared as indicated in above part (a) are added in small fractions, under a nitrogen atmosphere, to a suspension of 26.4 g of lithium aluminium hydride in 4 liters of anhydrous tetrahydrofuran. The mixture is then refluxed with stirring for 2 hours. It is then cooled to 0° C. and then are slowly added 30.5 ml of water, then 11 ml of a 10 N solution of sodium hydroxide and finally 110 ml of water. After having stirred for 2 hours at the ambient temperature, the precipitate formed is separated by filtration. The filtrate obtained is dried over magnesium sulfate and the solvent is distilled under reduced pressure. 53 g of α-phenyl-2-pyrrolidine methanol are obtained. These 53 g are recrystallized from 580 ml of isopropyl ether. 36 g of α-phenyl-2-pyrrolidine methanol (erythro) melting at 110° C. are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH:8]2[C:15](O)=[O:16].C(Cl)(=O)C(Cl)=O.Cl.[CH3:31][NH:32][O:33][CH3:34].N1C=CC=CC=1>C1(C)C=CC=CC=1.C(O)C>[CH3:34][O:33][N:32]([CH3:31])[C:15]([CH:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:7]1)=[O:16]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc2c(c1OC)CC(c1ccccc1)CC2C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
5,6-Dimethoxy-3-phenyl-1,2,3,4-tetrahydro 1-naphthalene carboxylic acid (5 g, 16 mmol), from Step 3, was suspended in 100 mL of toluene and 5 mL of oxalyl chloride was added. The reaction mixture was heated at reflux temperature for 1.5 h under a nitrogen atmosphere. The solvent was evaporated and the water removed from the residue as an azeotrope with toluene (2×40 mL). The acid chloride and 2 g (20 mmol) of N,O-dimethylhydroxylamine hydrochloride were dissolved in 80 mL of ethanol free chloroform. The solution was cooled to 0° C. and 3.3 mL of pyridine was added slowly. The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for approximately 4 h then evaporated to dryness. The residue was dissolved in a 1:1 mixture of diethyl ether and methylene chloride and washed with brine. The layers were separated and the organic layer dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an oil in 98% yield. The product of Step 4 was used in the next step without purification.
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)C[CH2:2]1.[C:16]([O:20][C:21]([NH:23][CH2:24][P:25]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:27])[OH:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O)C>C1COCC1>[C:16]([O:20][C:21]([NH:23][CH2:24][P:25]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:26])[O:27][CH2:1][CH3:2])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCP(=O)(O)CNC(=O)OC(C)(C)C
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOP(=O)(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
DCC (190 mg; 0.92 mmol) in THF (4 ml) is added dropwise over the course of 4 minutes to a solution of the phosphinic acid 1 (270 mg; 0.83 mmol) in dry THF (4 ml) and absolute ethanol (0.30 ml; 5.15 mmol) which is boiling under reflux. After 1.5 hours (check via DC) the reaction solution is cooled to room temperature and filtered. The filtration residue is washed with ether.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]([CH3:26])[S:23][C:24]=1I)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]([CH3:26])[S:23][C:24]=1[C:2]#[C:1][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])=[O:19])[CH3:16]
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: CCOC(=O)c1nc(C)sc1I
Product: CCOC(=O)c1nc(C)sc1C#Cc1c(-c2ccccc2)noc1C
Yield: 84 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (51 mg, 0.28 mmol) was converted (using 5-iodo-2-methyl-thiazole-4-carboxylic acid ethyl ester instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 83 mg, 84%) which was obtained as a light brown solid. MS: m/e=353.2 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([O:26][CH3:27])=[O:25])=O)C1C=CC=CC=1>CO.[Pd]>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][NH:11][CH:12]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1

Procedure:
A solution of the product from step A in methanol was hydrogenated at 60 psi in the presence of 10% Pd/C (0.250 g) for 24h. The catalyst was filtered and the methanol evaporated to yield the title compound as an oil (0.91 g).