Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[NH2:15][C:16]([NH:18][C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][C:25]([Br:32])=[CH:26][CH:27]=3)[CH2:22][C:21]=2[CH:20]=1)=[S:17]>>[BrH:1].[Br:32][C:25]1[CH:24]=[C:23]2[C:28]([C:29]3[CH:30]=[CH:31][C:19]([NH:18][C:16]4[S:17][CH:2]=[C:3]([C:5]5[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=5[CH3:10])[N:15]=4)=[CH:20][C:21]=3[CH2:22]2)=[CH:27][CH:26]=1
Reactant: NC(=S)Nc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3ccc4c(c3)Cc3cc(Br)ccc3-4)n2)c(C)s1
Yield: 84.7 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol) was allowed to react with amino[(7-bromofluoren-2-yl)amino]methane-1-thione (92.8 mg) as described in Example 154, step (a) to give 141 mg (82% yield) of methyl 4-{2-[(7-bromofluoren-2-yl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ2.70 (s, 3H), 3.83 (s, 3H), 3.93 (s, 2H), 7.33 (s, 1H), 7.51 (dd, 1H, J=1.9, 8.0 Hz), 7.65 (dd, 1H, J=2.0, 8.4 Hz), 7.74 (ad, 2H, J=8.3 Hz), 7.83 (ad, 1H, J=8.4 Hz), 8.18 (s, 1H), 8.23 (d, 1H, J=1.4 Hz), 10.47 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[Cl:7][CH2:8][C:9](Cl)=[O:10]>C1(C)C=CC=CC=1>[Cl:7][CH2:8][C:9]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])=[O:10]
Reactant: O=C1CCCN1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: O=C(CCl)N1CCCC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.2 %

Procedure:
To an initial charge of 81.0 g of 2-pyrrolidone in 200 ml of toluene there are added, dropwise and with ice cooling, 54.7 g of chloroacetyl chloride such that the temperature of the reaction mixture remains at 5° C. Following the addition the reaction mixture is stirred at room temperature for 6 hours. The resulting precipitate is filtered off with suction and the solvent is removed in vacuo to give 74.5 g of N-(chloroacetyl)pyrrolidone, corresponding to a yield of 97%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.[Cu]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:13][CH:12]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=Cc1cccc(O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1cccc(Oc2ccc(F)cc2)c1
Yield: 33.9 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.0 g, 40.9 mmol, 1.0 eq) and 4-fluorobromobenzene (14.3 g, 81.7 mmol, 2 eq) in pyridine was added K2CO3 (8.5 g, 61.4 mmol, 1.5 eq) followed by copper powder (1.3 g, 20.5 mmol, 0.5 eq). The reaction mixture was refluxed for 60 h before being filtered to remove the copper powder. The filtrate was then distilled under reduced pressure to remove pyridine. The resultant residue was taken in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under in vacuo. The residue was purified by silica gel column chromatography eluting with 10-20% ethyl acetate in hexane to afford the desired compound (3.0 g, 35%). 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 7.61-7.58 (t, 1H), 7.50-7.48 (t, 1H), 7.42-7.41 (t, 1H), 7.28-7.24 (m, 1H), 7.11-6.99 (m, 4H). MS (ESI): 218.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39]>CN(C=O)C>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=1)[CH2:6][N:7]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CO[C@H](c1ccc(C(F)(F)F)cc1CBr)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (26.7 mg, 0.082 mmol) in DMF (1 ml) at 0° C. under nitrogen was added sodium hydride (6 mg, 0.1 mmol, 60% dispersion in mineral oil). The reaction was stirred for 30 minutes while allowing it to warm to room temperature. The reaction mixture was then treated with (S)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4-trifluoromethyl-benzene (25 mg, 0.068 mmol) at 0° C. The ice bath was removed after the addition and the reaction was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on 12+S Biotage silica column, eluting with ethyl acetate in heptane 0-30% (10CV) and 30% (3CV) to yield the title compound (20 mg, 48%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (m, 4H) 1.2 (m, 2H) 1.46 (m, 1H) 1.57 (m, 2H) 1.61(m, 1H) 1.90 (d, J=12.4, 1H) 3.06 (s, 3H) 4.08 (d, J=7.1, 1H) 4.2 (s, 3H) 4.70 (d, J=15.7, 1H) 4.89 (d, J=15.7, 1H) 7.35 (s, 1H) 7.50 (d, J=7.9, 1H) 7.55 (d, J=7.9, 1H) 7.65 (s, 2H) 7.77 (s, 1H). [α]D20=−26.6 deg (c=13 mg/mL, acetone).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].O.[CH:6]([N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([CH2:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10]1)([CH3:8])[CH3:7]>CC(O)=O.CCOC(C)=O>[CH:6]([N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16](=[N:1][OH:3])[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:24])=[N:10]1)([CH3:8])[CH3:7]
Reactant: O=N[O-]
Reactant: CC(C)n1nc(CC(=O)c2ccccc2)ccc1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1nc(C(=NO)C(=O)c2ccccc2)ccc1=O
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A solution of sodium nitrite (1.725 g) of water (5.42 ml) was added in portions to a solution of 2-isopropyl-6-(2-oxo-2-phenylethyl)-3(2H)-pyridazinone (2.57 g) in a mixture of AcOH (2 ml) and EtOAc (8 ml) at 20-25° C. and the mixture was stirred at the same temperature for 8 hours. EtOAc was added to the mixture, washed with sat. aq. NaHCO3 solution and brine, dried over MgSO4 and concentrated under reduced pressure to give a solid. The solid was triturated with IPE and collected by filtration to give 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione 1-oxime as a solid (1.71 g), which was identical to the authentic sample (the product of Preparation 1) by melting point and IR, MS and NMR spectra.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([OH:19])=[C:13]([CH3:20])[C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:1])=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:28])=[CH:25][CH:24]=1
Reactant: Cc1oc2c(C)c(C)c(O)c(C)c2c1-c1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Oc2c(C)c(C)c3oc(C)c(-c4ccccc4)c3c2C)cc1
Yield: 64 %

Procedure:
Using 2,4,6,7-tetramethyl-3-phenylbenzofuran-5-ol and 4-methoxybenzoyl chloride, the title compound was obtained in the same manner as in Example 26.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([OH:11])=O)[CH3:3].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([NH:27][C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1)=[O:11])[CH3:1]
Reactant: Nc1cccnc1
Reactant: CC(C)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
A solution of 5-(1-methylethyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 3; 300 mg, 1.11 mmol), pyridin-3-amine (157 mg, 1.67 mmol), EDC (319 mg, 1.67 mmol) and HOBT (255 mg, 1.665 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (20 ml), filtered and the solid was washed with water and dried to yield a white solid. The crude product was purified by silica gel chromatography, eluting with petroleum ether:ethyl acetate (3:1) to yield the title compound as a white solid. 140 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18](=[NH:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:28]=[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCCCCCCCC(=N)NO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Reaction time: 1.25 h

Procedure:
To a solution of 0.547 g (2.6 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 8 mL of toluene, 0.46 g (2.8 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thick mixture, 1 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxy-decanimidamide (compound of Example 32; 1.0 g, 5.3 mmol) in 3 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h and further at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The combined organic layers was washed with 5 mL of 1N HCl solution, 5 of 5% sodium bicarbonate solution and 5 mL of 10% sodium chloride solution. The organic layer was distilled to yield a crude material, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Br.[O:26]=[C:27]1[C:36]2[CH2:35][CH2:34][NH:33][CH2:32][C:31]=2[NH:30][C:29]2[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([O:43][CH3:44])=[O:42])[C:28]1=2.[CH3:45][C:46]1([C:49](O)=[O:50])[CH2:48][CH2:47]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:45][C:46]1([C:49]([N:33]2[CH2:32][C:31]3[NH:30][C:29]4[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([O:43][CH3:44])=[O:42])[C:28]=4[C:27](=[O:26])[C:36]=3[CH2:35][CH2:34]2)=[O:50])[CH2:48][CH2:47]1
Reactant: CC1(C(=O)O)CC1
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCNC3
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C1(C)CC1)C3
Yield: 24.8 %

Procedure:
A solution of HATU (340 mg, 0.9 mmol) in DMF (2 ml) was added to a mixture of methyl 5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (200 mg, 0.77 mmol) from Example 13 (Step 2), 1-methylcyclopropanecarboxylic acid (102 mg, 1.02 mmol), diisopropylethylamine (0.5 mL, 5.09 mmol) and DMF (8 ml). The resultant mixture was stirred at ambient temperature for 8 hours. The DMF was evaporated and the residue was purified by pre-TLC to give methyl 2-(1-methylcyclopropanecarbonyl)-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (65 mg, 25%) as yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=C(I)C4C(=O)NC(=O)C=4[C:5]=3[C:4]=2[CH:3]=1.[Br-].[Cl:22][C:23]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([Cl:51])[C:24]=1[CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].[CH3:53]C([N-]C(C)C)C>>[Cl:51][C:45]1[CH:46]=[C:47]([O:49][CH3:50])[CH:48]=[C:23]([Cl:22])[C:24]=1/[CH:25]=[CH:9]/[C:10]1[NH:11][C:12]2[C:4]([CH:5]=1)=[CH:3][C:2]([O:1][CH3:53])=[CH:14][CH:13]=2
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Agent: [Br-]
Agent: [Li+]
Product: COc1cc(Cl)c(/C=C/c2cc3cc(OC)ccc3[nH]2)c(Cl)c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (1) was reacted with (2,6-dichloro-4-methoxybenzyl)(triphenyl)phosphonium bromide (521), prepared as described in example 112, using the procedure described in example 37, except that the aldehyde was added at 0° C., the ratio of LDA:aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (522) as a cream solid (the pure E isomer) (70%), mp 128–129° C. 1H NMR (CDCl3) δ 8.17 (br s, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.17 (d, J=16.8 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.93 (s, 2H), 6.88 (d, J=16.8 Hz, 1H), 6.86 (dd, J=8.7, 2.5 Hz, 1H), 6.57 (br d, J=1.7 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H). Found: C, 62.01; H, 4.23; N, 4.21. C18H15Cl2NO2 requires C, 62.09; H, 4.34; N, 4.02.
Reaction SMILES: [H-].[Na+].OC1C=C([C@]23CC4N=[C:21]5[C:26](=[CH:27]C=4C[C@H]2CN(C)CC3)[CH:25]=[CH:24][CH:23]=[CH:22]5)C=CC=1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C=[O:41])C>>[CH2:29]([O:41][CH2:27][C:26]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1
Reactant: CN1CC[C@@]2(c3cccc(O)c3)Cc3nc4ccccc4cc3C[C@H]2C1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60%, 79.2 mg) and anhydrous DMF (1 ml) were added to a reactor. A solution of (4aR, 12aR)-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-quinolino[2, 3-g]isoquinoline (530 mg, 1.58 mmol) in anhydrous DMF (23 ml), and benzyl bromide (0.20 ml, 1.66 mmol) were added to the reactor, followed by stirring at room temperature for 1 hour. After reaction was completed, an aqueous saturated sodium bicarbonate solution (50 ml), distilled water (50 ml), and toluene (250 ml) were added to the reaction solution, followed by fractionation. The aqueous layer was extracted twice with toluene (150 ml), and the organic layers were together dried over sodium sulfate, filtered, and then concentrated to obtain 531 mg of benzyl ether compound. The thus-obtained compound was supplied to next reaction without purification.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]=[C:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[Cl:3][CH:6]=[C:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)C(=O)C(=CO)Oc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)C(=CCl)Oc1ccc(F)cc1
Reaction time: 12 h
Yield: 81 %

Procedure:
297.5 g (2.5 mols) of thionyl chloride were slowly stirred into a solution, warmed to 60° C., of 404.6 g (1.7 mols) of 1-hydroxy-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one in 3,000 ml of anhydrous toluene. The mixture was kept at this temperature for 12 hours and the solvent and excess thionyl chloride were then distilled off. The oil which remained was distilled in vacuo. 353.3 g (81% of theory) of 1-chloro-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one of boiling point 95°-103° C./0.3 mm Hg were obtained. ##STR51##
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:12]=2)[C:7]1=[O:23])[CH3:2].Br[C:25]1([CH2:34][CH2:35][O:36][CH3:37])[C:30](=[O:31])[NH:29][C:28](=[O:32])[NH:27][C:26]1=[O:33].C1CN2C(=NCCC2)NC1.C(#N)C>CO.C(O)(=O)C>[CH:11]([O:15][CH:16]([CH3:21])[CH3:17])([CH3:12])[CH3:10].[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:25]4([CH2:34][CH2:35][O:36][CH3:37])[C:26](=[O:33])[NH:27][C:28](=[O:32])[NH:29][C:30]4=[O:31])=[CH:18][CH:17]=3)[CH:12]=2)[C:7]1=[O:23])[CH3:2]
Reactant: CCOCCN1Cc2cc(Oc3ccc(O)cc3)ccc2C1=O
Reactant: COCCC1(Br)C(=O)NC(=O)NC1=O
Agent: C1CN=C2NCCCN2C1
Solvent: CC(=O)O
Solvent: CO
Solvent: CC#N
Product: CC(C)OC(C)C
Product: CCOCCN1Cc2cc(Oc3ccc(OC4(CCOC)C(=O)NC(=O)NC4=O)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 132.1 %

Procedure:
A mixture of 23 miligrams of 2-(2-Ethoxy-ethyl)-5-(4-hydroxy-phenoxy)-2,3-dihydro-isoindol-1-one (0.07 mmol), 5-bromo-5-(2-methoxy-ethyl)-pyrimidine-2,4,6-trione (0.021 grams, 0.08 mmol), 1,5,7-triazabicyclo[4.4.0]dec-5-ene bound to polystyrene (0.087 grams) and acetonitrile (0.5 mL) was shaken for 18 hours at room temperature. The mixture was treated with a solution of acetic acid in methanol (1:4 v/v), shaken for 20 minutes, and was filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography using 5% methanol in methylene chloride as eluant. Trituration of the purified product with iso-propyl ether afforded 5-(4-[2-(2-Ethoxy-ethyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy]-phenoxy)-5-(2-methoxy-ethyl)-pyrimidine-2,4,6-trione (0.023 grams) as a colorless solid. MS: 498.5 [M+H]+; 496.5 [M−H]−
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.[C:8]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C@@H:24]3[O:29][CH2:28][CH2:27][N:26](CC4C=CC=CC=4)[CH2:25]3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[O:10])[CH3:9]>ClC(Cl)C>[ClH:1].[C:8]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C@@H:24]3[O:29][CH2:28][CH2:27][NH:26][CH2:25]3)=[CH:22][CH:23]=2)[CH2:15][CH2:16]1)(=[O:10])[CH3:9]
Reactant: CC(=O)N1CCC(Oc2ccc([C@H]3CN(Cc4ccccc4)CCO3)cc2)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: CC(=O)N1CCC(Oc2ccc([C@H]3CNCCO3)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 89.5 %

Procedure:
1-Chloroethyl chloroformate (0.92 g, 6.43 mmol) was added to a solution of (2S)-2-(4-(1-acetylpiperidin-4-yloxy)phenyl)-4-benzylmorpholine (1.68 g, 4.26 mmol) in dichloroethane (30 ml). The reaction mixture was stirred vigorously at room temperature for 10 hours. The solvent was evaporated under reduced pressure and methanol (40 ml) was added to the residue. The mixture was heated at 80° C. for one hour, and then the solvent was evaporated under reduced pressure to give a white solid, which was recrystallized from ethanol to afford (2S)-2-(4-(1-acetylpiperidin-4-yloxy)phenyl)morpholine hydrochloride (1.3 g, 100%) as white crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C.C(Cl)Cl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(-c2ncco2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Temperature: 110 °C
Yield: 76.6 %

Procedure:
A solution of 4-(2-oxazolyl)phenol (15.7 g, 97 mmol) in DMF (120 mL) was treated with cesium carbonate (41 g, 126 mmol) and 4-fluorobenzaldehyde (13.3 g, 107 mmol). The reaction was heated at 110° C. for 2.5 hours. The reaction mixture was cooled and poured onto a mixture of ice and water. The product was isolated by extraction with methylene chloride (3×). The combined organic layers were washed with water and brine, dried, and concentrated. The residue was recrystallized from aqueous ethanol to give 19.7 g of 4-[4-(2-oxazolyl)phenoxy]-benzaldehyde.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(NCC)C.[CH2:19]([O:21]/[C:22](=[CH:28]\[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][CH3:42])[CH:36]=2)=[CH:31][CH:30]=1)/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20].O>ClCCl>[CH2:19]([O:21]/[C:22](=[CH:28]\[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([N:41]([CH3:42])[C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH:36]=2)=[CH:31][CH:30]=1)/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)OCC
Solvent: CCNCC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 126.2 %

Procedure:
0.63 g (3.1 mmol) of 4-nitrophenyl chloroformate and then 0.54 mL (3.1 mmol) of diethylamine are added to a solution of 0.68 g (2.1 mmol) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate in 15 mL of dichloromethane. The reaction mixture is stirred for 1 hour 30 minutes at room temperature. The reaction is worked up by addition of 10 mL of water and then extracted with dichloromethane. The organic phases are combined and then dried over magnesium sulfate. The solvents are evaporated off. 1.3 g (100%) of ethyl (Z)-2-ethoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:3][CH3:4].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.Cl>[OH-].[Na+]>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:8][S:5]([CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:7])=[O:6])=[O:18])=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CCC(C)S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)S(=O)(=O)NC(=O)Nc1ccc(Br)cc1
Yield: 56.1 %

Procedure:
The general method of procedure A was followed with 2-butanesulfonamide (10 g, 73 mmole), 1N sodium hydroxide (73 ml), and 4-bromophenyl isocyanate (13.7 g). The filtrate from the reaction mixture was treated with 1N HCl and the resulting precipitate redissolved in 1N sodium hydroxide and reprecipitated with 1N HCl. The solid product was collected and dried at 65° C. under vacuum. The dissolution and precipitation procedure was repeated to provide 13.0 g of product which had the following analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.C(O)C.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=Cc1ccc(Cl)cn1
Yield: 39.8 %

Procedure:
5-Chloro-pyridine-2-carboxylic acid ethyl ester (146 mg, 76.3%) was obtained obtained as described in Example 11 from 5-chloro-pyridine-2-carboxylic acid (200 mg, 1.03 mmol) with ethanol (3 mL) and 4M HCl in dioxane (0.5 mL) at 90° C. for 20 h. 5-Chloro-pyridine-2-carbaldehyde (58 mg, 52%) was obtained as described in Example 11 from 5-chloro-pyridine-2-carboxylic acid ethyl ester (146 mg, 0.786 mmol) with 1 M DIBAL in toluene (1.74 mL, 1.74 mmol) in dichloromethane (4.0 mL) 20 min. GC-MS (M+): 141