Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][OH:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11](=[O:13])[N:25]([CH2:24][CH2:23][CH2:22][O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:26][CH2:27][OH:28])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: OCCNCCCOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CCO)CCCOCc1ccccc1
Yield: 66.6 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-alanine (90 mg, 0.48 mmol), 2-(3-benzyloxy-propylamino)-ethanol (100 mg, 0.48 mg), N,N-diisopropylethylamine (185 mg, 1.43 mmol), 1-hydroxybenzotriazole (71 mg, 0.52 mmol), and N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (101 mg, 0.52 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 18 h, then partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (121 mg, 67%). Colorless oil, MS (ISP)=381.4 (M+H)+.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[CH2:21][CH:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])[CH2:10][CH2:9]1.C(N(CC)CC)C.C(Cl)(=O)C>O1CCCC1>[C:3]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[CH2:21][CH:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])[CH2:10][CH2:9]1)(=[O:4])[CH3:2]
Reactant: CC(C)(C)CC1CN(C(=O)NC2CCNCC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N1CCC(NC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid piperidin-4-ylamide trifluoroacetic acid (80 mg, 0.12 mmol) in tetrahydrofuran (2 mL) at 0° C. was added triethylamine (0.042 mL, 0.3 mmol) and acetyl chloride (10.4 mg, 0.13 mmol). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was recrystallized in dichloromethane and hexanes to give as rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1-acetyl-piperidin-4-yl)-amide as a white solid (65 mg, 92%)
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH2:15])=[N+:2]=[N-:3].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[CH2:23][N:22]([CH2:28][CH3:29])[CH2:21][CH:20]2[C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH:20]2[C:19]3[C:24](=[C:25]([Cl:27])[CH:26]=[C:17]([Cl:16])[CH:18]=3)[CH2:23][N:22]([CH2:28][CH3:29])[CH2:21]2)[CH:31]=1)(=[O:38])=[O:37])=[N+:2]=[N-:3]
Reactant: CCN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Solvent: ClCCl
Product: CCN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine (300 mg, 1.51 mmol, 1.00 equiv) in DCM (10 mL) was added TEA (375 mg, 3.00 equiv) followed by the portionwise addition of 3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (500 mg, 1.23 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at room temperature and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2) to afford 0.4 g (41%) of N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as yellow oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:25]=[CH:24][C:20]2[CH:21]=[CH:22][S:23][C:19]=2[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCCl>[Br:1][C:21]1[C:20]2[CH:24]=[CH:25][C:17]([O:16][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:18][C:19]=2[S:23][CH:22]=1
Reactant: c1ccc(COc2ccc3ccsc3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: Brc1csc2cc(OCc3ccccc3)ccc12
Temperature: 80 °C
Yield: 92 %

Procedure:
N-bromosuccinimide (15.70 g, 83.92 mmol) and p-toluenesulfonic add (2.70 g, 15.68 mmol) were added to a solution of 6-benzyloxy-benzothiophene (Zhengying C., CN 1370533 A, 21.2 g, 88.33 mmol) in 1,2-dichloroethane (120 ml). The mixture was maintained at 80° C. for 35 min, cooled in an ice bath, and the succinimide was removed by filtration. The solution was extracted with saturated sodium bicarbonate solution, dried over Na2SO4, filtered, and concentrated under vacuum to give an oil. Crystallisation from pentane afforded a white solid (21.60 g, 92%, mp: 68° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([CH:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][OH:17])[CH3:14].C(N(CC)CC)C.C1(C)C=CC=CC=1>CN(C)C1C=CN=CC=1.C(OCC)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:17][CH2:16][CH:15]([CH2:13][CH3:14])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCC(CC)CO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and a nitrogen inlet was added 4-nitrobenzoyl chloride (53.0 grams, 0.285 moles), 2-ethylhexanol (28.6 grams, 0.22 moles), triethyl amine (30.2 grams, 0.30 moles) and 4-dimethylaminopyridine (6.98 grams, 0.0.57 moles) and anhydrous toluene (420 ml). The contents of the flask were heated at reflux for 16 hours; cooled to room temperature. It was diluted with diethyl ether (300 ml). The ether extract was washed with diluted HCl(1wt %, 3×100 ml), followed with a saturated sodium bicarbonate solution (3×100 ml), brine (3×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 57.2 grams of crude product as a yellow oil. 1H NMR (CDCl3) δ 8.3(d, 2H), 8.2(d, 2H), 4.3(d, 2H), 1.75(heptet, 1H), 1.2-1.6(m, 8H), 0.8-1.0(m, 6H).
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3]CSC.[CH3:10][O:11][C:12](=[O:34])[C@H:13]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N[C@H](C=O)[CH2:44][S:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)(C1C=CC=CC=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(OC(C)(C)C)=O>>[CH3:10][O:11][C:12](=[O:34])[C@H:13]([CH2:30][CH:31]([CH3:32])[CH3:33])[NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:3][C@H:2]([C:7]([O:9][C:31]([CH3:33])([CH3:32])[CH3:30])=[O:8])[CH2:44][S:45][C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CSCC[C@H](N)C(=O)O
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(NC[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)cc1-c1ccccc1

Procedure:
This compound was prepared using the same method as for the preparation of methionine derivative (See Example 26, section B), using 4-amino-2-phenylbenzoyl-(S)-leucine methyl ester and N-Boc-S-trityl-(L)-cysteinal as starting materials. 1H NMR (CDCl3) δ 7.68 (d, 8.6 Hz, 1H), 7.33-7.41 (m, 11H), 7.17-7.29 (m, 9H), 6.50 (d, 8.6 Hz, 1H), 6.31 (s, 1H), 5.43 (d, 7.8 Hz, 1H), 4.60 (d, 6.1 Hz, 1H), 4.47 (ddd, 1H), 4.19 (br t, 1H), 3.77 (br m, 1H), 3.62 (s, 3H), 3.09 (t, 5.9 Hz, 2H), 2.45 (br m, 2H), 1.40 (s, 9H), 1.27-1.33 (m, 1H), 1.03-1.18 (m, 2H), 0.75 (dd, 6H); 13C (CDCl3) δ 173.2, 168.2, 155.6, 149.4, 144.4, 141.7, 141.2, 131.4, 129.5, 128.8, 128.5, 127.9, 127.6, 126.8, 122.7, 113.6, 111.3, 79.6, 67.1, 51.9, 50.9, 49.5, 47.1, 41.2, 34.3, 28.3, 24.4, 22.7, 21.8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].C(N(CC)CC)C.CN(C)C=O>O1CCCC1>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1)=[O:23]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)CCCCl)c2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
2-Amino-4-(4-nitrophenoxy)pyridine (300 mg), 4-chlorobutyryl chloride (0.18 ml), triethylamine (0.77 ml), dimethylformamide (1 ml) and tetrahydrofuran (1 ml) were stirred at room temperature for 10 minutes, and then silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with silica gel, for column purification (hexane:ethyl acetate=3:1, followed by 2:1 and 1:1). The solvent was distilled off under reduced pressure, and then 300 mg of iron powder, 600 mg of ammonium chloride, 2 ml of DMF, 1 ml of ethanol and 1 ml of water were added to 150 mg of the resulting residue and the mixture was stirred at 100° C. for 20 minutes. After filtration with celite, water and ethyl acetate were added for extraction. The organic layer was washed 5 times with ammonium chloride water and then dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 110 mg of the target substance as an oil.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:42])[C:6]([NH:8][C:9]1[C:10]([I:41])=[C:11]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C:12]([I:35])=[C:13]([C:33]=1[I:34])[C:14]([NH:16][CH:17]([CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])=[O:7])(=[O:3])[CH3:2].[C:43]([O:46][CH2:47][CH2:48]Br)(=[O:45])[CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:43]([O:46][CH2:47][CH2:48][N:8]([C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:42])[C:9]1[C:10]([I:41])=[C:11]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C:12]([I:35])=[C:13]([C:33]=1[I:34])[C:14]([NH:16][CH:17]([CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])(=[O:45])[CH3:44]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)OCc1c(I)c(NC(=O)C(C)OC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)OCCN(C(=O)C(C)OC(C)=O)c1c(I)c(COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I

Procedure:
5-(2-Acetoxypropionylamino)-3-acetoxymethyl-N-(1,3,4-triacetoxybut-2-yl)-2,4,6-triiodobenzamide (Example 37a) was N-alkylated using 2-bromoethyl acetate and cesium carbonate according to the procedure in Example 30a. The yield of isolated product was 82.4%.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:12].[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O.O>[N:13]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:12])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: [O-][n+]1c(Cl)cnc2ccccc21
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1cnc2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In this example 0.500 grams (0.0028 mol) of 2-chloroquinoxaline 1-oxide and 0.500 grams (0.0080 mol) of sodium azide were added to and dissolved in 35 ml of acetone and 35 ml of water. The solution was stirred at 25° C for 60 hours. The acetone was evaporated in vacuo and the resulting aqueous solution was extracted with methylene chloride. The organic phase was introduced onto a basic alumina column. Elution with chloroform gave 2 azidoquinoxaline-oxide in a yield of 0.080 grams or 16% of theory which was immediately decomposed in boiling benzene for 1 hour. Evaporation of the solvent gave 2-cyanobenzimidazole N-oxide which is tautomeric with N-hydroxy-2-cyanobenzimidazole in a yield of 0.020 grams or 30% of theory having a melting point of 236° C to 238° C with decomposition.
Reaction SMILES: Cl.[OH:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[C:4](=[NH:8])[O:5]CC.C(N(CC)CC)C.[C:24](Cl)(Cl)=[O:25]>O1CCCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:3]1[O:2][C:24](=[O:25])[NH:5][C:4]1=[O:8]
Reactant: CCOC(=N)C(O)c1ccccc1OC
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1C1OC(=O)NC1=O
Reaction time: 1 h
Yield: 42 %

Procedure:
Ethyl 1-hydroxy-1-(2-methoxyphenyl)methanecarboximidate hydrochloride (18 g., 0.073 mole) was suspended in 500 ml. of tetrahydrofuran, cooled to 0°-5° C., and triethylamine (23.6 g., 0.234 mole) was added. The stirred reaction mixture was perfused with phosgene for 30 minutes. Stirring at 0°-5° C. was continued for 1 hour. The reaction mixture was slowly poured over 1 l. of crushed ice and product extracted into three portions of chloroform. The combined chloroform extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to solids. The residue was recrystallized from toluene to yield 5-(2-methoxyphenyl)oxazolidine-2,4-dione (6.4 g., 42%; m.p. 175°-177° C.; m/e 207). A second drop (3.7 g., 24%, m.p. 175°-177° C.) was obtained from the toluene mother liquor.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl-].[Hf+4:13].[Cl-].[Cl-].[Cl-].[OH2:17].N1CCCCC1.[CH2:24]([OH:26])C>>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:24]([O-:26])=[O:17])[CH:8]=[CH:7]2.[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:24]([O-:26])=[O:17])[CH:8]=[CH:7]2.[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:24]([O-:26])=[O:17])[CH:8]=[CH:7]2.[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:24]([O-:26])=[O:17])[CH:8]=[CH:7]2.[Hf+4:13]
Reactant: O
Reactant: CCO
Reactant: Oc1cccc2cccnc12
Agent: [Hf+4]
Agent: [Cl-]
Solvent: C1CCNCC1
Product: O=C([O-])c1ccc2cccc(O)c2n1

Procedure:
To a solution of 8-Hydroxyquinoline (5.44 g, 37.5 mmol) in ethanol (200 mL, 95%) was added hafnium (IV) chloride (3.0 g, 9.37 mmol) in ethanol (100 mL), followed by a further 300 mL water. The pH of the solution was increased by dropwise addition of piperidine until a yellow precipitate forms. The resulting yellow precipitate was collected and washed with ethanol (100 mL, 95%), water (200 mL) and finally ethanol (100 mL, 95%). The sample was dried under vacuum at 80° C. until no further weight loss was detected. Sublimation (400° C., 10−6 Torr) yielded an analytical sample (4.5 g, 64%), m.p. 398° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:7][N:6]=[C:5]([CH3:8])[CH:4]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].O.C(O)C>N1C=CC=CC=1>[C:10]([NH:2][C:3]1[S:7][N:6]=[C:5]([CH3:8])[CH:4]=1)([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Cc1cc(N)sn1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(C)ns1
Reaction time: 0.67 h
Yield: 62.5 %

Procedure:
To a stirred solution of 6.10 g (40.5 mmole) of 5-amino-3-methylisothiazole hydrochloride in 200 ml of dry pyridine is added slowly 13.8 g (127 mmole) of ethyl chloroformate. After 2 days the reaction mixture is treated with 20 ml each of water and ethanol. After 40 min., the solution is concentrated in vacuo to a gum, which is further dried by several evaporations of aqueous ethanol. The crude product is dissolved in 75 ml of boiling ethanol to which is added water until the solution clouds. Upon cooling a crystaline solid containing some diacylated material is collected, redissolved in 100 ml of isopropyl alcohol, and treated with 40 ml of approximately 7 N HCl in isopropyl alcohol. After about 2 hours, the solution is concentrated at reduced pressure to an oily residue which is dried by multiple evaporation of ethanol. A solution of the crude solid in approximately 100 ml of water is adjusted to about pH 7 by addition of 2 N aqueous sodium hydroxide, giving the product as a precipitate. After washing with water and drying, 4.71 g (25.3 mmole) of 5-carbethoxyamino-3-methylisothiazole is obtained. Structure assignment is supported by the nmr spectrum.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=4)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[CH3:39]I>CN(C)C=O>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH3:39])[C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=4)([C:21]([F:23])([F:24])[F:22])[O:18][N:17]=3)=[CH:12][C:11]=2[CH3:33])[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CI
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)c1cccc(Br)n1
Temperature: 0 °C
Yield: 76.4 %

Procedure:
In a solution of 0.23 g of N-(6-bromo-2-pyridyl)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-yl]-2-methyl benzoic acid amide in 5 mL of N,N-dimethylformamide, 0.02 g of 55% oily sodium hydride was added at room temperature with stirring, and stirred at the same temperature for 10 minutes. After ceasing the generation of hydrogen gas, 0.30 g of methyl iodide was added, and continued to stir further for 45 minutes. After the completion of the reaction, the reaction mixture was poured in 20 mL of ice water, extracted with ethyl acetate (50 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.18 g of the aimed product as colorless resinous substance.
Reaction SMILES: [CH3:1][N:2]1CCCC1=O.Br[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:25])[N:16]2[CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)=[N:11][CH:10]=1.[Cu](C#N)C#N>C(OCC)(=O)C>[C:1]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:25])[N:16]2[CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)=[N:11][CH:10]=1)#[N:2]
Reactant: O=c1ccc2ncc(Br)cc2n1CC1OCCO1
Reactant: CN1CCCC1=O
Agent: N#C[Cu]C#N
Solvent: CCOC(C)=O
Product: N#Cc1cnc2ccc(=O)n(CC3OCCO3)c2c1
Temperature: 25 °C

Procedure:
To 10 mL of 1-methyl-2-pyrrolidinone, 358 mg of 7-bromo-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one and 183 mg of copper cyanide were suspended, and the suspension was heated under reflux for 70 minutes. The reaction mixture was cooled to room temperature, ethyl acetate was then added thereto, the mixture was washed sequentially with water and a saturated saline water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60 made by KANTO CHEMICAL CO., INC., and an eluent of ethyl acetate:hexane 1:1 to obtain 145 mg of 7-cyano-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25](C)(C)C)=[CH:4][CH2:3]1.FC(F)(F)S(OC1C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C)(C)CC=1)(=O)=O>>[CH3:25][C:5]1[C:6]2[CH:7]=[C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:11]=2[C:2]([CH3:1])([CH3:29])[CH2:3][CH:4]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)=CCC3(C)C)cc1
Yield: 0.5 %

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71), 250 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (HPLC Partisil 10, 0.5% EtOAC-hexanes) using 70.2 mg (0.78 mmol) of cuprous cyanide, 33.2 mg (0.78 mmol) of lithium chloride and 34.5 mg (1.28 ml, 1.57 mmol) of methyllithium (1.22M solution in Et2O).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f6) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]Br.C(N(CC)CC)C>ClCCl.BrN1C(=O)CCC1=O>[C:1]([N:9]1[CH2:15][CH2:14][CH:13]([Br:21])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCN(C(=O)c2ccccc2)c2ccccc21
Reactant: BrBr
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2N(C(=O)c2ccccc2)CCC1Br
Temperature: 25 °C

Procedure:
1-Benzoyl-1,2,3,4-tetrahydro-benzo[b]azepin-5-one from Example E5.6 (54.2 g, 205 mmol), N-bromosuccinimide (3.6 g, 20.4 mmol) and bromine (11.1 ml, 214.7 mmol) were dissolved in dichloromethane (1.0 liter). Triethylamine (30 ml, 215 mmol) was added dropwise over 30 minutes then the reaction mixture was heated at reflux for 4 h. Additional bromine (1.1 ml, 21.5 mmol) and triethylamine (3.0 ml, 21.5 mmol) were added and the reaction mixture was heated at reflux for a further 4 h. Additional bromine (1.1 ml, 21.5 mmol) and triethylamine (3.0 ml, 21.5 mmol) were added again and the reaction mixture was heated at reflux for a further 4 h. On cooling to room temperature, the reaction solution was washed with 5% aqueous sodium metabisulfate solution (150 ml) and the aqueous phase was diluted with water (600 ml). The organic phase was separated, washed with saturated Na—HCO3 (aq), dried over sodium sulphate and filtered. The filtrate was diluted with EtOAc (100 ml), filtered through a silica pad (eluant; CH2Cl2) and reduced in vacuo to yield the title compound (73.6 g) which was used without further purification.