Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:37]1([CH2:42][CH2:43]O)[CH2:41][CH2:40][CH:39]=[CH:38]1>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:43][CH2:42][CH:37]3[CH2:41][CH2:40][CH:39]=[CH:38]3)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCCC1C=CCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCCC2C=CCC2)cc1

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-cyclopent-2-enyl-1-ethanol in place of 2-ethyl-1-hexanol (yield: 95 mg, 48%). mp 126–127° C. 1H NMR (300 MHz, DMSO-d6) δ 1.30 (m, 1H), 1.57 (sextet, J=7 Hz, 1H), 1.69 (sextet, J=7 Hz, 1H), 1.87 (m, 2H), 2.57 (m, 1H), 3.30 (s, 3H), 4.45 (m, 2H), 5.60 (m, 1H), 5.68 (m, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 473 (M+H)+; (APCI−) m/z 507 (M+Cl)−. Anal. calc. for C24H22F2N2O4S: C, 61.00; H, 4.69; N, 5.92. Found: C, 60.76; H, 4.65; N, 5.80.
Reaction SMILES: [CH3:1][C:2]([N+:12]([O-])=O)([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:15][C:16]([OH:18])=[O:17]>[Pd].CO>[C:16]([OH:18])(=[O:17])[CH3:15].[NH2:12][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(N)Cc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A one-gallon high-pressure reactor was charged with 4(2-methyl-2-nitropropyl)phenol (120 g, 614 mmol), HOAc (35.2 mL, 614 mmol), 5% Palladium on carbon (24 g) wetted with 2Bβ3EtOH (60 mL), and MeOH (1230 mL). The mixture was heated to 50° C. with agitation (600 rpm), and the reactor was purged with N2 and pressurized to 50 psi with H2. After 15.5 h the reactor was purged with N2, and the cooled mixture was filtered. The filter cake was washed with MeOH and the filtrate was concentrated to 514 g of slurry on a rotary evaporator. To this slurry was added EtOAc (2 L) with vigorous agitation. After stirring for 1 h, the resulting crystals were filtered and washed with a small amount of EtOAc. The product was dried overnight in a 45° C. vacuum oven to yield 118.83 g (86%) of product as small white needles (mp 211°-216° C. dec). This material was 99% pure by HPLC analysis, and while another 9.00 g of material was obtained from the mother liquor it was found to be only 88 % pure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:30])[N:24]([CH3:29])[C:25](O)=[N:26][CH:27]=2)=[CH:18][C:17]=1[F:31].CN(C)C1C=CC=CC=1.[Cl-:41]>O=P(Cl)(Cl)Cl>[Cl:41][C:25]1[N:24]([CH3:29])[C:23](=[O:30])[C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:17]([F:31])[CH:18]=2)=[CH:27][N:26]=1
Reactant: COc1cc2nccc(Oc3ccc(-c4cnc(O)n(C)c4=O)cc3F)c2cc1OC
Reactant: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COc1cc2nccc(Oc3ccc(-c4cnc(Cl)n(C)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-2-hydroxy-3-methyl-3H-pyrimidin-4-one (Step 2, 678.8 mg, 1.605 mmol) was dissolved in POCl3 (16 mL) and N,N-dimethylaniline (1.6 ml) and heated at 125° C. for 8.5 h then cooled to RT and stirred overnight. The reaction was concentrated, diluted with CH2Cl2 (125 mL) and washed with saturated NaHCO3 (25 mL, 17 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Because of the propensity of title compound to hydrolysis, the crude chloride was used for the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[CH2:6][CH2:5]2.IC.[C:15](=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[OH:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:12])=[CH:3][C:2]=1[O:1][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2cc(O)c(O)cc21
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2c(cc1O)C(=O)CC2

Procedure:
A mixture of Example 63 (2.0 g, 12 mmol), iodomethane (1.9 mL, 30 mmol), and lithium carbonate (2.2 g, 30 mmol) in N,N-dimethylformamide (40 mL) was heated to 55° C. for 24 hours. The solution was concentrated under vacuum and was diluted with a 2% solution of hydrochloric acid in water. The precipitate was collected by filtration and was dried under high vacuum to provide the desired product. 1H NMR (500 MHz, CD3OD): δ 2.63 (t, J=6 Hz, 6H), 3.05 (t, J=6 Hz, 6H), 3.98 (s, 3H), 7.05 (s, 2H).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.C(N(CC)[C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[S:25][CH3:26])C>C1COCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]2[C:16](=[O:27])[CH2:26][S:25][C:18]=2[CH:19]=1
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1SC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)SCC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (1.6 M in hexanes, 13 mL, 20.8 mmol) was added slowly to a solution of diisopropylamine (2.91 mL, 20.8 mmol) in THF at −78° C. The mixture was stirred under nitrogen for 30 min and N,N-diethyl-4-methoxy-2-(methylthio)benzamide (2.4 g, 9.47 mmol), dissolved in 10 mL of anhydrous THF was added to the reaction dropwise. Stirring was continued at −78° C. for 1 h and the cooling bath was removed. After 12 h, the reaction was cooled back down to −78° C. and a 1:1 mixture of methanol and acetic acid (10 mL) was added to the mixture. The reaction was stirred for 15 min and the cooling bath was removed and allowed to warm up to room temperature. The reaction was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 15 to 40% ethyl acetate in hexanes to obtain an off white solid. Yield=1.4 g. MS (M−H)− 179.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:18]3[CH2:19][CH:20]4[N:25]([S:26]([C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=5)(=[O:28])=[O:27])[CH:24]([C:17]=3[CH:16]=[N:15]2)[CH2:23][CH:22]([CH:36]=O)[CH2:21]4)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([S:45]([N:48]2[CH:52]=[C:51]3[CH:53]4[N:59]([S:60]([C:63]5[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=5)(=[O:62])=[O:61])[CH:57]([CH2:58][C:50]3=[N:49]2)[CH2:56][CH:55]([CH:70]=O)[CH2:54]4)(=[O:47])=[O:46])=[CH:41][CH:40]=1>CCO.N1C=CC=CC=1.C(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:18]3[CH2:19][CH:20]4[N:25]([S:26]([C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=5)(=[O:28])=[O:27])[CH:24]([C:17]=3[CH:16]=[N:15]2)[CH2:23][CH:22]([CH:36]=[N:2][OH:3])[CH2:21]4)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([S:45]([N:48]2[CH2:52][C:51]3[CH:53]4[N:59]([S:60]([C:63]5[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=5)(=[O:62])=[O:61])[CH:57]([CH2:58][C:50]=3[NH:49]2)[CH2:56][CH:55]([CH:70]=[N:2][OH:3])[CH2:54]4)(=[O:47])=[O:46])=[CH:41][CH:40]=1
Reactant: O=CC1CC2Cc3nn(S(=O)(=O)c4ccc(Cl)cc4)cc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=CC1CC2Cc3c(cnn3S(=O)(=O)c3ccc(Cl)cc3)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2Cc3c(cnn3S(=O)(=O)c3ccc(Cl)cc3)C1CC(C=NO)C2
Product: O=S(=O)(c1ccc(Cl)cc1)N1CC2=C(CC3CC(C=NO)CC2N3S(=O)(=O)c2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydroxylamine hydrochloride (18 mg, 0.252 mmol) was added to a solution of 1,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole-6-carbaldehyde and 2,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-6-carbaldehyde (59) (91 mg, 0.168 mmol) in EtOH/pyridine (2 ml, 1/1, v/v) and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic phase was dried (Na2SO4), filtered and concentrated to give 1-{1,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazol-6-yl}-N-hydroxymethanimine and 1-{2,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazol-6-yl}-N-hydroxymethanimine (60). MS (ESI) 555.0 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([C:16](=[C:22]([NH2:27])[C:23]([F:26])([F:25])[F:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH3:14].[F:28][C:29]([F:36])([F:35])[C:30](OCC)=O.Cl>CCCCCC.O1CCCC1>[F:24][C:23]([F:25])([F:26])[C:22]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:13]([OH:15])[CH:14]=[C:30]([C:29]([F:36])([F:35])[F:28])[N:27]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a flame dried, 3-liter, four-necked flask equipped with nitrogen inlet, low temperature thermometer, 500 ml addition funnel and mechanical stirrer was charged 91.0 g (126 ml, 0.899 mol) of diisopropylamine and 500 ml of dry tetrahydrofuran. The resulting solution was cooled to -78° C. using an acetone-dry ice bath. To this was slowly added 383 ml (0.880 mol) of 2.3M n-BuLi in hexane at such a rate that the reaction temperature was kept below -60° C. After stirring at -78° C. for 1 hours, a solution of 90.0 g (0.400 mol) of ethyl 2-acetyl-3-amino4,4,4-trifluoro-2-butenoate from Example 1 in 150 ml of dry tetrahydrofuran was added at such a rate that the reaction temperature was kept below -60° C. The reaction mixture turned yellow and a solid suspension formed. After 1 hour of stirring at -78° C., the reaction mixture was treated with 184.7 g (155 ml, 1.300 mol) of ethyl trifluoroacetate at such a rate that the reaction temperature was kept below -60° C. This reaction mixture was left at -78° C. for 1 hour, then warmed to room temperature (the yellow suspension disappeared and a brown solution was formed) and stirred for 18 hours. The resulting solution was poured into 1.5 L of 10% HCl (aq.) and extracted 3 times with methylene chloride. The combined methylene chloride layers were dried (MgSo4) and reduced in vacuo affording a brown thick oil. The residue was kugelrohr distilled at 47 Pa. The earlier fraction (pot temperature 50° C.) was discarded. The later fraction (pot temperature 80° C.) afforded 80.0 g (66%) of the pyridine product, mp 70°-77° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH:13](Br)[CH3:14].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.CCOC(C)=O>[N:16]([CH:13]([C:3]1[N:4]=[C:5]2[S:11][CH:10]=[C:9]([CH3:12])[N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:14])=[N+:17]=[N-:18]
Reactant: Cc1csc2nc(C(C)Br)c(Br)c(=O)n12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of 6-bromo-7-(1-bromo ethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (11.1 g, 31.5 mmol) and sodium azide (6.15 g, 94.6 mmol) in dimethyl formamide (DMF) (100 mL) was stirred at room temperature for 2 h. After diluting with EtOAc, the mixture was washed with water, brine, dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexane, to provide the product (8.68 g, 87.6%). LCMS calculated for C9H9BrN5OS (M+H)+: m/z=314.0. Found: 313.9. 1H NMR (DMSO-d6, 300 MHz) δ 7.15 (1H, s), 4.83 (1H, q, J=6.6 Hz), 2.69 (3H, s), 1.48 (3H, d, J=6.6 Hz) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH:22]=O)[CH:15]=[CH:14]1.C(O)(=O)C>C1(C)C=CC=CC=1>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH2:22][NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=2[O:2][CH3:1])[CH:15]=[CH:14]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: COc1ccc(CN)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(CNCc2cccc3cc[nH]c23)c(OC)c1

Procedure:
Add 2,4-dimethoxybenzylamine (27.64 g, 165.3 mmol) to a solution of indole-7-carboxaldehyde (20.0 g, 137.7 mmol) and acetic acid (8.26 ml, 137.7 mmol) in toluene (250 ml). Reflux and collect water using a Dean-Stark trap while replacing with fresh anhydrous toluene. Concentrate under reduced pressure, dissolve the residue in methanol and add sodium borohydride in portions. Dilute with ethyl acetate and wash sequentially with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure to provide the desired compound as a brown oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][CH:11]([O:22][CH3:23])[CH2:12][N:13]1[CH2:16][CH2:15][CH:14]1C(OCC)=O.[O:24]=O>O1CCCC1.ClCCl.[Zn]>[CH3:9][O:10][CH:11]([O:22][CH3:23])[CH2:12][N:13]1[CH2:16][CH2:15][C:14]1=[O:24]
Reactant: O=O
Reactant: CCOC(=O)C1CCN1CC(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Zn]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(CN1CCC1=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 2.2 mmol of lithium diisopropylamide in 15 ml tetrahydrofuran at -78° was added dropwise 0.43 g (2 mmol) of N-(2,2-dimethoxyethyl)-2-carbethoxy azetidine in 3 ml of tetrahydrofuran. After stirring at -78° for 30 minutes, the deep yellow anion was silylated in the usual way and warmed to room temperature. Removal of all volatiles by rotary evaporation with a high vacuum pump gave a purple residue which was redissolved in dichloromethane. Internal photooxidation using 5 g of Photox (trademark for photoconductive lead-free zinc oxides available from The New Jersey Zinc Co.) as the sensitizer required less than 5 minutes for oxygen uptake. The mixture was then filtered free of sensitizer and worked up by aqueous extraction in the usual manner. The pink residue obtained was applied to a 17×2 cm neutral alumina column. Elution with 10:3 ethyl acetate-hexane yielded 0.18 g (56%) of pale yellow liquid, which by NMR analysis was greater than 90% pure. Comparison of its spectral properties (IR, NMR) with those of an authentic known sample confirmed the identity of the product as the expected beta-lactam.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.Cl[C:9]1[C:10]2[C:15]([C:16](Cl)=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2.C[Mg]Br.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1.Cl[Ni]Cl.C1(C)C=CC=CC=1>[C:27]1([C:9]2[C:10]3[C:15]([C:16]([C:7]4[CH:6]=[CH:21][CH:22]=[CH:9][CH:10]=4)=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCN(CC)CC
Reactant: Clc1c2ccccc2c(Cl)c2ccccc12
Agent: Cl[Ni]Cl
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
Under a nitrogen atmosphere, 194.4 mg (1.5 mmol) of dry NiCl2 and 303 mg (3 mmol) of triethylamine were added to 29.99 g of toluene and were stirred at room temperature for 10 minutes. Subsequently, 7.41 g (30.0 mol) of 9,10-dichloroanthracene was added at that temperature and reduced-pressure nitrogen replacement was conducted. To the reaction mixture, 3.8 ml (3.8 mmol) of a 1.0 mol/l solution of methylmagnesium bromide in tetrahydrofuran was added and then stirred at 25° C. for another 10 minutes. To the resulting reaction mixture, 69 ml (69 mmol) of a 1 mol/l solution of phenylmagnesium bromide in tetrahydrofuran was added dropwise over 50 minutes and stirred for 4 hours while being heated under reflux. The resulting mixture was washed once with 54.7 g of a saturated aqueous ammonium chloride solution and twice with 50.4 g of ion exchange water. To the organic layer, 50.4 g of methanol was added dropwise and then cooled to room temperature. Crystals formed were separated by filtration, washed with 30.4 g of in ethanol and dried, resulting in 7.97 g of desired 9,10-diphenylanthracene (yield: 80.4%, purity: 99% or higher). No triethylamine was detected in the crystals. The filtrate contained 12%, in terms of yield, of 9,10-diphenylanthracene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.Cl.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:28]1([C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:26]3[CH:22]([CH2:23][N:24]([C:8](=[O:10])[CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccnc3)CC12
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
N,N'-Carbonyldiimidazole (0.81 g) is added to a solution of 2-(3-pyridyl)acetic acid (0.685 g) in dry dichloromethane (15 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.6 g) and triethylamine (0.7 cc) in dichloromethane (10 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in a mixture of ethyl acetate (100 cc) and water (75 cc). The organic phase is washed with saturated sodium chloride solution (50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a basic alumina column (diameter 2 cm, height 15 cm), eluting with ethyl acetate and collecting 50 cc fractions. Fractions 4 to 24 are concentrated to dryness under reduced pressure (2.7 kPa). The crystals obtained are recrystallized from acetonitrile (cc) to give (3aRS,7aRS)-7,7-diphenyl-2-[2-(3-pyridyl)acetyl]-4-perhydroisoindolone (0.9 g) in the form of white crystals melting at 208° C.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:18][C:19]([F:37])([F:36])[C:20]1[CH:21]=[C:22]([C:30](=O)[C:31]([F:34])([F:33])[F:32])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.[OH-].[Ca+2].[OH-].CN(C)C=O>COC(C)(C)C>[F:18][C:19]([F:36])([F:37])[C:20]1[CH:21]=[C:22]([C:30]([C:31]([F:34])([F:33])[F:32])=[CH:2][C:1]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=2)=[O:3])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(C(C)=O)c2ccccc12
Agent: [Ca+2]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)C=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)c2ccccc12
Reaction time: 10 h

Procedure:
A mixture of methyl 4-acetyl-1-naphthalenecarboxylate (5.36 g, 23.5 mmol), 1-[3,5-bis(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (7.28 g, 23.5 mmol), calcium hydroxide (1.40 g, 18.9 mmol), N,N-dimethylformamide (16 mL) and tert-butyl methyl ether (32 mL) was boiled with provision of the apparatus comprising a ten-plate Oldershaw column and decanter described in Example 1, Step A for removal of the tert-butyl methyl ether/water azeotrope. As the decanter trap contained an amount of tert-butyl methyl ether sufficient to dissolve all of the water formed by the reaction, the condensate in the trap did not separate into layers containing predominately water and predominately tert-butyl methyl ether. Tert-butyl methyl ether was removed by gradually draining the decanter trap until the pot temperature was 85° C. To maintain this temperature, tert-butyl methyl ether was added as needed to compensate for loss of solvent from the apparatus. The total time from beginning heating the reaction mixture to stopping distillation, not including a shutdown period overnight, was about 10 h. During this time period no additional calcium hydroxide was added to the reaction mixture.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][OH:22]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:18][C:19]([CH3:24])([CH2:20][CH2:21][OH:22])[CH3:23])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: CC(C)(N)CCO
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(CCO)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 3-amino-3-methyl-butan-1-ol (CAN 42514-50-1) as starting materials, LC-MS (UV peak area/ESI) 100%, 319.1 (M+H)+.
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(O)(=O)=O.[CH2:12]([NH:20][CH:21](N)[CH3:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C([C:31]#[N:32])C1C=CC=CC=1.N.[OH-].[Na+]>>[CH2:12]([N:20]1[CH2:21][CH2:22][N:32]=[C:31]1[CH2:9][C:8]1[CH:10]=[CH:11][CH:5]=[CH:6][CH:7]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCNC(C)N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#CCc1ccccc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCN1CCN=C1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
A mixture of N-(n-octyl)-ethanediamine tosylate (10 g, 0.029 mol) and benzyl cyanide (0.9 ml, 0.029 mol) was heated at 200° C. until evolution of ammonia ceased. The reaction mixture was cooled to 50° C. and treated with aqueous sodium hydroxide (15 ml, 5M). The resulting mixture was stirred for 15 minutes and then extracted with dichloromethane. The organic phase was separated, washed with water, and dried over anhydrous magnesium sulphate. Th solvent was removed under reduced pressure to yield a gum which was chromatographed on silica gel using increasing proportions of methanol in dichloromethane to yield 4,5-dihydro-1-n-octyl-2-phenylmethylimidazole (7.8 g) having the formula ##STR23##
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[O:6]1[CH2:12][CH2:11][C:10](=O)[CH2:9][C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]1=2.CN([CH:21]=[O:22])C>>[Cl:3][C:10]1[CH2:11][CH2:12][O:6][C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9]=1[CH:21]=[O:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCOc2ccccc2C1
Reactant: CN(C)C=O
Product: O=CC1=C(Cl)CCOc2ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Phosphorus oxychloride (1.4 ml, 15.2 mmol) was added dropwise to anhydrous DMF (5 ml) at 0° C. After 30 minutes a solution of 2,3-dihydro-5H-benzo[b]oxepin-4-one (980 mg, 6.04 mmol) in anhydrous DMF (5 ml) was added dropwise and this was allowed to stir at room temperature for 2 days. The reaction mixture was then added to ice water, and the ice allowed to melt before extracting into ethyl acetate and washing with water and brine to give 4-chloro-2,3-dihydro-benzo[b]oxepine-5-carbaldehyde.