Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:16])[C:9]2=[O:14])([O-])=O.CO>[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:16])[C:9]2=[O:14]
Reactant: CC(c1ccccn1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: CC(c1ccccn1)n1ccc2c(N)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Into a round bottom flask was combined 5-nitro-2-(1-(pyridin-2-yl)ethyl)isoquinolin-1(2H)-one (0.85 g, 0.0029 mol), Palladium/C (0.05 g, 0.0005 mol) and methanol (200 mL, 5 mol). The reaction mixture was stirred under hydrogen balloon at room temperature for 40 mins. The mixture was filtered over celite, MeOH was removed and the solid was yield (0.54 mg). MS m/z=266.0 (M+1). 1H NMR (DMSO) δ 8.55 (d, J=4.8 Hz, 1 H), 7.77 (td, J=7.7, 1.8 Hz, 1 H); 7.44 (d, J=7.8 Hz, 1 H), 7.35-7.25 (m, 3 H), 7.17 (t, J=7.8 Hz, 1 H), 6.95-6.85 (m, 1 H), 6.78 (d, J=7.8 Hz, 1 H), 6.28 (q, J=7.2 Hz, 1 H), 5.66 (s, 2 H), 1.75 (d, J=7.2 Hz, 3 H).
Reaction SMILES: C(O[C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[C:17]([NH2:20])(=[NH:19])[CH3:18]>>[CH3:18][C:17]1[N:20]=[C:4]([OH:15])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][N:19]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(=N)N
Agent: Cl
Product: CCOC(=O)c1cnc(C)nc1O
Yield: 67 %

Procedure:
The title compound was prepared by (a) reaction of diethylethoxymethylenemalonate (6 g, 28 mmol) with acetamidine hydrochloride (3 g, 31 mmol) to afford 67% of ethyl 2-methyl-4-hydroxypyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 2-methyl-4-hydroxypyrimidine-5-carboxylate (2.8 g, 15 mmol) with POCl3 (46 g, 300 mmol) to afford 28% of ethyl 4-chloro-2-methylpyrimidine-5-carboxylate, (c) reaction of ethyl 4-chloro-2-methylpyrimidine-5-carboxylate (0.25 g, 1.25 mmol) with hydrazine (0.2 g, 6.3 mmol) to afford 96% of 4-hydrazino-2-methylpyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of 4-hydrazino-2-methylpyrimidine-5-carboxylate (0.24 g, 1.2 mmol) with citraconic anhydride (0.16 g, 1.44 mmol) to afford 70% (0.24 g) of the title compound (m.p. 98-99° C.) in analogy to Example 21.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:28](=[O:30])[CH3:29])[N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)n1nc(C(=O)NC2CN(C)CCN(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide (1.0 g) in dichloromethane (10 ml), acetic anhydride (0.56 g) is added; and the mixture is stirred at 25° C. for 16 hours. The reaction mixture is washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.92 g) as an oil. The free base thus obtained is converted to the fumarate 1/4 hydrate of the title compound in a usual manner, m.p. 166-168° C. (recrystallized from ethanol).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.ClC1C=CC(C(OC)=O)=CN=1>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: COC(=O)c1ccc(Cl)nc1
Product: Cc1ccc(CO)cn1

Procedure:
The reaction procedure of Reference Example 20 (3) was repeated except that methyl 6-methylnicotinate was used in lieu of methyl 6-chloronicotinate to give crude 6-methyl-3-pyridylmethanol as a yellow oil.
Reaction SMILES: C(=O)=[O:2].C[C@@H](NC)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.C[C@@H]1[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@@]2(O)O[C@H:55]([C@H:56]([C:88]([OH:90])=[O:89])[C@@H](O)C2)[CH2:54][C@@H:53](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=C1>>[C:88]([O:90][OH:2])(=[O:89])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]/[CH:49]=[CH:48]\[CH2:47]/[CH:46]=[CH:45]\[CH2:44][CH2:43][CH2:42][CH2:41][CH3:40]
Reactant: O=C=O
Reactant: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CC=CC=CC=CC=CC=C[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)NC)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OO

Procedure:
Human endothelial cells were cultivated at 37° C. in Leighton tubes and in an atmosphere of saturated humidity constituted by a gaseous mixture of 95% air and 5% of CO2. The culture medium was constituted by an EGM (Clonetics) medium, pH=7.4 containing 2% of foetal calf serum, 10 ng/ml of recombinant human growth factor EGF, 10 μg/ml of heparin, 50 μm/ml of gentamicin and 50 μg/ml of amphotericin B.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:18][CH:17]=3)=[O:15])[C:6]=2[CH:27]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:27][C:6]=2[C:7]=1[C:14](=[O:15])[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:20][CH:21]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCC#N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCC#N)cc1
Temperature: 32.5 °C
Reaction time: 3 h

Procedure:
4.0 g of (5-amino-2-butyl-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (VI) is dissolved in 40 ml of dichloromethane. The mixture is warmed to 30-35° C. and 1.05 g of pyridine is added at this tempereature in 5 minutes. At this temperature 1.5 g of methane sulfonyl chloride is added in 5 minutes and the mixture is stirred at 30-35° C. for 3 hours: The mixture is cooled to 20° C. and washed with 2×15 ml of water, 2×15 ml of NaHCO3 of 5% and 1×15 ml of water. The phases are separated and the dichloromethane is evaporated.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)C([Cl:24])=O>CCCCCC>[C:1]([Cl:24])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Yield: 100.6 %

Procedure:
Linoleic acid (100 g; purity 95%, 356 mmoles) was added dropwise over a period of 0.5 hours to a stirred mixture of oxalyl chloride (42 ml; 481 mmoles) and of hexane (120 ml) under nitrogen. After the addition the mixture was refluxed for 1.5 hours and then evaporated under reduced pressure (60° C.; 0.5 mm Hg) to give 107 grams of linoleoyl chloride as an oil.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:9]1(=[O:15])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.Cl[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH:10]2[C:11](=[O:14])[CH2:12][CH2:13][C:9]2=[O:15])=[CH:39][CH:40]=1
Reactant: O=C1CCC(=O)C1
Reactant: Fc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: O=C1CCC(=O)C1c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 30.8 mL of THF in a stirred autoclave was added sequentially 17.31 g (81.54 mmol) of K3PO4, 4.0 g (40.8 mmol) of 1,3-cyclopentanedione, 268 mg (0.989 mmol) of 2-(di-t-butylphosphino)biphenyl, 91.5 mg (0.405 mmol) of Pd(OAc)2, and 6.92 g (53.0 mmol) of 1-chloro-4-fluorobenzene. The sides of the reaction vessel were washed with an additional 10 mL of THF and the vessel purged 3 times with vacuum and nitrogen. The heterogeneous reaction mixture was then heated to 100° C., generating 25 psig pressure in the vessel. The reaction was aged at 100° C. for 12 h, cooled to rt and diluted with 150 mL of water. The resulting homogeneous mixture was distilled to remove THF and then heated to 50° C. The aqueous solution was then slowly acidified using conc. HCl until a final pH of 3 was obtained (10.6 mL). The slurry was cooled to rt and filtered. The wet cake was washed with 40 mL of water, 40 mL of toluene, and dried under vacuum at 60° C. for 24 h to give 2-(4-fluorophenyl)-1,3-cyclopentanedione as a light brown solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:5]#[CH:6].Cl[C:21]1[N:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>CN(C=O)C.CCOC(C)=O>[CH2:3]([C:7]([C:21]1[N:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:5]#[CH:6]
Reactant: C#CCCC(C(=O)OCC)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCCC(C(=O)OCC)(C(=O)OC(C)(C)C)c1ncc([N+](=O)[O-])cn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (60%, 2.5 g, 62.4 mmol) in 100 mL of DMF was added tert-butyl ethyl but-3-yn-1-ylpropanedioate (15 g, 62.4 mmol) drop-wise at 25° C. The mixture was stirred at 40° C. for 30 minutes and 2-chloro-5-nitropyrimidine (10.0 g, 62.4 mmol) in 50 mL of DMF was added dropwise. The resulting suspension was stirred at 50° C. for 2 hours and diluted with 500 mL of EtOAc. The mixture was washed with water (3×100 mL), brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (Petroleum ether:EtOAc=10:1) to afford the title compound; MS m/z 364 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)COc3cccnc3)C(=O)O)cc2)cc1

Procedure:
Example 55 is prepared from 3-hydroxypyridine and 1d using the procedure described for compound 20.
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[C:28]2[CH:37]=[CH:36][C:35]3[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=3[CH:29]=2)[CH2:5][CH2:4]1>O1CCCC1>[CH:3]1([NH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[C:28]2[CH:37]=[CH:36][C:35]3[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=3[CH:29]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCNC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3OCCCNC3CC3)ccc21
Yield: 49.5 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 260 mg (6.5 mmol) of sodium hydroxide with 340 mg (0.65 mmol) of ethyl 4′-(3-cyclopropylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (Example 3a) in 30 ml of tetrahydrofuran. 160 mg of 4′-(3-cyclopropylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=192° C., yield=50%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26][CH3:33])=[O:25])=[CH:19][CH:18]=3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)C1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(C(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(4-(tert-butoxycarbonyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid (509.7 mg, 1.10 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL), potassium carbonate (762.3 mg, 5.52 mmol, 5.00 equiv). The resulting solution was stirred 30 min at room temperature. Then CH3I (783.3 mg, 5.52 mmol, 5.00 equiv) was added dropwise with stiffing at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of water. The resulting aqueous solution was extracted with 6×20 mL of dichloromethane. The organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 285.5 mg (54%) of methyl 3-(4-(tert-butoxycarbonyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16])(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16])(=[O:7])=[O:8])([CH3:1])[CH3:3]
Reactant: Ic1ccccc1
Reactant: CSc1ccccc1S(=O)(=O)NC(C)(C)C
Agent: [Li]CCCC
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1cccc(-c2ccccc2)c1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A solution of 11.3 g (0.0436 mol) N-(1,1-dimethylethyl)-2-(methylthio)benzenesulfonamide in 300 ml tetrahydrofuran (THF) was treated with 60.5 ml (0.096 mol) 2M n-butyllithium in hexanes at -30° under a nitrogen atmosphere. The mixture was stirred for 1 hour at ambient temperature then recooled to -20° and treated with 8.3 g (0.0436 mol) of cuprous iodide (anhydrous). After 10 minutes at -15°, 4.9 ml (0.0438 mol) iodobenzene was added and the mixture was then heated to reflux overnight. Acetic acid (10 ml) was added after cooling the mixture to 15°, then 200 ml concentrated ammonium hydroxide plus 200 ml ethyl acetate was introduced and the mixture was stirred vigorously in the presence of air to facilitate removal of the copper salts. The aqueous phase was separated, extracted with more ethyl acetate and the combined organic extracts were washed successively with concentrated ammonium hydroxide, water and brine, then dried (MgSO4) and evaporated to an oil. The product crystallized from ether/hexanes to afford 10 g of material, m.p. 162°-165°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:26]=[C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cccc(C(C)=O)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-acetylphenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.34 (s, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.39 (m, 2H), 7.19 (dt, J=7.4, 1.9 Hz, 1H), 7.12 (dd, J=8.8, 2.5 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.94 (d, J=2.5 Hz, 1H), 3.27 (s, 3H), 2.52 (s, 3H), 1.99 (m, 4H), 0.83 (t, J=7.4 Hz, 6H); MS (ESI) m/z 353 ([M+H]+); MS (ESI) m/z 351 ([M−H]−); Anal. calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C, 69.83; H, 6.78; N, 7.86.
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:45])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:44])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:43])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:42])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:41])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:40])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:39])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:38])=[CH:35]/[CH2:36][OH:37].[CH:47]1([C:53](Cl)=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>N1C=CC=CC=1.CCCCCC>[CH:47]1([C:53]([O:37][CH2:36][CH:35]=[C:34]([CH3:38])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:39])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:40])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:41])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:42])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:43])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:44])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:45])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:46])[CH2:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCCCCCCCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 Grams of solanesol were dissolved in 50 ml of pyridine and the solution was added dropwise with of 15% solution of 4.6 g of cyclohexylcarboxylic acid chloride in pyridine over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for two hours to complete the reaction. Then, the reaction product was diluted with n-hexane, washed with water and concentrated. The concentrate was purified by chromatography with 80 g of silica gel in n-hexane/benzene solvent mixture as elution solvent to obtain the final product as a white solid (m.p. 34.0°-35.0° C.). Yield: 6.2 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([C:8]3[N:9]=[C:10]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(Br)cc1
Product: COc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)oc3C)c2)cc1

Procedure:
The title compound was prepared from 4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole, and 4-methoxy-benzeneboronic acid in substantially the same manner, as described in Example 1 step c, and was obtained as a white solid, mp 93-94° C.; MS m/e 409 (M+);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCCCN)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
113.0 g (292 mmol) 2-[4-(1-tert-butoxycarbonylpiperidin-4-yl)-butyl]-isoindol-1,3-dione are dissolved in 600 ml ethanol, added to 29.3 g (585 mmol) hydrazine hydrate and heated to boiling for three hours. After cooling the solution, the mixture is filtered and the filtrate is concentrated under vacuum. The residue is dispersed in the heat (ca. 50° C.) between 500 ml toluene and 500 ml 10% sodium hydroxide solution. The organic phase is washed once with 50 ml 10% sodium hydroxide solution and twice, each with 50 ml water. The solvent is removed under vacuum and the residue is dried at 70° C. under high-vacuum and processed further without additional purification. Yield of colorless oil: 64.0 g (85%).
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[O:13])[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Na+].Cl>C(O)C>[S:1]1[C:7]2[CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)=[O:13])[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)SCCCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)SCCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
1.20 g of ethyl p-(2,3,4,5-tetrahydro-1-benzothiepine-8-carboxamido)benzoate were dissolved in 40 ml of ethanol and treated with 14 ml of water containing 1.40 g of NaOH. The mixture was stirred at room temperature overnight, poured on to ice and acidified with conc. HCl. The mixture was then extracted twice with ethyl acetate, washed with is water, dried and evaporated. Recrystallization from ethyl acetate gave 925 mg of p-(2,3,4,5-tetrahydro-1-benzothiepine-8-carboxamido)benzoic acid as colorless crystals of m.p. 261°-262° C.
Reaction SMILES: C(O[C:4]([C:6]1[CH2:7][N:8]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:9][CH2:10][C:11]=1[NH:12][C:13]([O:15]C1C=CC=CC=1)=O)=[O:5])C.[CH3:31][N:32]([CH3:34])[NH2:33].C1CCN2C(=NCCC2)CC1.[OH-].[Na+]>C1COCC1.C(O)(=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:8]2[CH2:9][CH2:10][C:11]3[NH:12][C:13](=[O:15])[N:33]([N:32]([CH3:34])[CH3:31])[C:4](=[O:5])[C:6]=3[CH2:7]2)=[O:30])=[CH:28][CH:27]=1
Reactant: CN(C)N
Reactant: CCOC(=O)C1=C(NC(=O)Oc2ccccc2)CCN(C(=O)c2ccc(Cl)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)n1c(=O)[nH]c2c(c1=O)CN(C(=O)c1ccc(Cl)cc1)CC2

Procedure:
Ethyl-4-phenoxycarbonylamino-1-(4-chlorobenzoyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (200 mg) was dissolved in THF (2 ml), N,N-dimethylhydrazine (142 μl) and DBU (10 μl) were added and the resultant mixture was shaken at 50° C. for 3 hours. 5 N sodium hydroxide solution (200 μl) was added and the resultant mixture was further shaken at 50° C. overnight. To the reaction solution, acetic acid (300 μl) was added to neutralize, and the reaction solution was then concentrated. The resultant residue was subjected to medium-pressure column fractionation (solvent; methanol:methylene chloride=0:100 to 7:93). The titled compound (105 mg) was obtained as a white powder.