Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2.[N:14]([O-:16])=[O:15].[Na+]>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:14]([O-:16])=[O:15])[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: O=N[O-]
Reactant: COc1ccc2c(c1)CCC(=O)N2
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone (400 mg, 2.25 mmol, Precursor Chemicals) in trifluoroacetic acid (4 mL, Aldrich) was treated with sodium nitrite (156 mg, 2.26 mmol, added slowly in about 4 portions, Aldrich). The dark brown reaction was stirred for 1 h after which an aliquot was taken out, diluted with water and extracted with ethyl acetate. TLC analysis of the ethyl acetate layer revealed that starting material remained. More sodium nitrite (50 mg, 0.72 mmol) was added and the reaction stirred for another 2 h at which point some precipitation was observed in the reaction. The reaction was poured over ice and then extracted with ethyl acetate. The organic layer, which still had undissolved solids in it, was concentrated to give 6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (372 mg, 70%) as a white powder. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.45-2.49 (m, 2 H), 2.98 (t, J=7.5 Hz, 2 H), 3.88 (s, 3 H), 7.29 (s, 1 H), 7.38 (s, 1 H), 10.18 (bs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:27])=[C:12]3[CH:18]=[C:17]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:27])[C:12]3[CH:18]=[C:17]([C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[O:20])[S:16][C:13]=3[N:14]([CH3:30])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C(=O)N3CCOCC3)cc2c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C(=O)N3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylcarbonyl)thieno[2,3-b]pyridine-5-carboxamide (0.527 g) from Example No. 47 in DMF (10 mL) is added potassium carbonate (0.337 g) followed by iodomethane (0.11 mL). The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is then poured into water (25 mL). The resulting off-white solid is filtered off and recrystallized from acetonitrile to yield 0.448 g (82%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=O)[N:12]([C:16]3[C:17]([CH3:36])=[C:18]([CH3:35])[C:19]4[O:23][C:22]([CH3:25])([CH3:24])[C@H:21]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)[C:20]=4[C:33]=3[CH3:34])[C:11](=O)[CH2:10]2)=[CH:5][CH:4]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:16]3[C:17]([CH3:36])=[C:18]([CH3:35])[C:19]4[O:23][C:22]([CH3:25])([CH3:24])[C@H:21]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)[C:20]=4[C:33]=3[CH3:34])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CC(=O)N(c3c(C)c(C)c4c(c3C)[C@@H](c3ccc(C)cc3)C(C)(C)O4)C(=O)C2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)[C@@H](c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Yield: 59 %

Procedure:
Using (3R)-4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)piperidine-2,6-dione obtained in Example 26, the title compound was synthesized in the same manner as in Example 28. Yield 59%. mp. 183–185° C. (ethyl acetate-hexane).
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5].[I-:17].[Na+]>CC(C)=O>[I:17]/[CH:2]=[CH:3]/[C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5]
Reactant: [I-]
Reactant: O=C(/C=C/Cl)C1CCC2(CCCCC2)CC1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(/C=C/I)C1CCC2(CCCCC2)CC1
Yield: 70.9 %

Procedure:
In a procedure as described in Example 9H, 1-chloro-3-(spiro[5.5]undec-3-yl)-1E-propen-3-one was reacted with sodium iodide in acetone to yield 1-iodo-3-(spiro[5.5]undec-3-yl)-1E-propen-3-one (70.9%).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][NH:9][C:10](=[O:27])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:26])[C@@H:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH2:18])=[CH:6][CH:5]=1)#[N:3].[CH:30]([NH:33][S:34](Cl)(=[O:36])=[O:35])([CH3:32])[CH3:31]>>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10](=[O:27])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:26])[C@@H:17]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:18][S:34]([NH:33][CH:30]([CH3:32])[CH3:31])(=[O:36])=[O:35])=[CH:28][CH:29]=1)#[N:3]
Reactant: CC(C)NS(=O)(=O)Cl
Reactant: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2C(=O)[C@H](N)Cc2ccccc2)cc1
Agent: Cl
Product: CC(C)NS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)cc1

Procedure:
D-Phenylalanylproline (p-cyanobenzyl)amide hydrochloride was reacted with isopropylaminosulfonyl chloride as in Example 1c.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[NH:10][C:11]([NH2:13])=[O:12])=O)=[CH:5][CH:4]=1.C(O)C>[OH-].[K+]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[C:7]([C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:13][C:11]([OH:12])=[N:10]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)N(NC(N)=O)c2ccc(OC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Temperature: 60 °C
Yield: 84.2 %

Procedure:
A mixture of 2-(4-methoxybenzoyl)-2-(4-methoxyphenyl)hydrazinecarboxamide (1.9 g, 6.03 mmol) in 10% potassium hydroxide solution (16 mL)-ethanol (8 mL) was heated at 60° C. for 1.5 hours. After cooling, the solvent was removed under reduced pressure. Water was added to the residue and the mixture was adjusted pH to ca. 2. A generated precipitate was isolated by filtration, washed with water, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (1.51 g, 84.3% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]>COCCOC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:13]([C:15]2[N:20]3[N:21]=[CH:22][N:23]=[C:19]3[N:18]=[CH:17][CH:16]=2)[CH3:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(Br)c1ccnc2ncnn12
Reactant: N#Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(C#N)cc1)c1ccnc2ncnn12
Reaction time: 0.5 h

Procedure:
A solution of 4-cyanophenol (1.19 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 below) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (in the ratio 6:4 respectively), followed by recrystallisation from ethyl acetate, to give 7-[1-(4-cyanophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 1.07 g, (m.p. 163°-164° C.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O>[C:22]([O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)(=[O:24])[CH3:23]
Reactant: O=[N+]([O-])c1cccc(C#CCCOCCCCCCBr)c1
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCCCCOCCC#Cc1cccc([N+](=O)[O-])c1
Temperature: 75 °C
Yield: 75.6 %

Procedure:
A mixture of 1-{4-[(6-bromohexyl)oxy]but-1-ynyl}-3-nitrobenzene (4.18 g), sodium acetate (9.68 g), tetrabutylammonium bromide (384 mg) in DMF (15 ml) and water (10 ml) was heated to 75° C. for 6 h. The mixture was then allowed to cool to 20° C. and then extracted with Et2O. The organic solution was concentrated and purified by chromatography on a Biotage (40 g) eluting with Et2O-petroleum ether(1:19 increasing to 1:1) to give the title compound (2.973 g). LCMS RT=3.84 min.
Reaction SMILES: Br[C:2]1[N:11]=[C:10](C(NCC2C=CC(F)=CC=2)=O)[C:9](O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(C([Sn])=C(CCCC)CCCC)CCC.[C:39]([NH:46]CCN)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:39]([NH:46][N:7]1[C:2]2[C:3](=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:4]=[CH:5][CH2:6]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NN1CC=Cc2cccnc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide (2.00 g, 5.33 mmol), tri-n-butylvinyl tin (3.12 mL, 10.70 mmol), bis (triphenylphosphine)palladium(II) chloride (0.75 g, 1.10 mmol), N-Boc-ethylenediamine (4.23 g, 26.6 mmol) in dioxane (50 mL) was purged with nitrogen and heated with stirring at 100° C. in a sealed tube overnight. The resultant product mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum. The residue was dissolved in DMSO, and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title N-Boc amino napthyridine.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH-:24]
Reactant: Nc1ccccn1
Agent: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: [NH-]c1ccccn1

Procedure:
Boc-L-Asp(OBzl)-OH (1.0 g), 2-aminopyridine (0.35 g), HOBT (0.50 g), WSCD (0.71 g) and DMF (20 ml) were reacted in a similar manner to that of Preparation 1-1) to give Boc-L-Asp(OBzl)-2-pyridylamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][C:32]1[N:33]=[C:34]([C:37]([NH:39][NH2:40])=O)[S:35][CH:36]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:34]3[S:35][CH:36]=[C:32]([CH3:31])[N:33]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: Cc1csc(C(=O)NN)n1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1csc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)n1
Temperature: 25 °C

Procedure:
A mixture of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (170 mg, 0.585 mmol) in dry dichloromethane (DCM) (1.463 ml) was stirred at room temperature under an atmosphere of argon. Triethyloxonium tetrafluoroborate (122 mg, 0.644 mmol) was added and the resulting mixture was stirred for 2½ hours. After this time, 4-methyl-1,3-thiazole-2-carbohydrazide (I121)(115 mg, 0.732 mmol) was added and the solution was stirred for a further 18 hours at room temperature. The solution was concentrated under reduced pressure and then redissolved in 1-butanol (1.463 ml) and the resulting solution was heated at reflux for 4 hours. The solution was cooled to room temperature, diluted with DCM (approx. 50 ml) and washed with water (2× approx. 20 ml). The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oil. The residue was purified using MDAP and dried under vacuum for 4 days to give the desired product in 42 mg.
Reaction SMILES: C([Mg]Br)C.[C:5]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH2:22]=[O:23].C(N(CC)CC)C>C1COCC1.C1(C)C=CC=CC=1>[C:5]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:22]=[O:23])[C:15]=1[OH:21])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:7])[CH3:6]
Reactant: C=O
Reactant: Cc1ccc(O)c(C(C)(C)c2ccccc2)c1
Agent: CC[Mg]Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
Into a 500 ml reactor thoroughly purged with nitrogen, 21.0 ml of an ether solution containing 63.1 mmol of ethylmagnesium bromide and 40 ml of THF were introduced. To the reactor, a solution containing 13.61 g (60.1 mmol) of 2-cumyl-4-methylphenol diluted with 20 ml of a THF was dropwise added at 0° C. over a period of 1 hour, then the temperature of the system was slowly raised to room temperature, and the reaction solution was stirred at room temperature for 30 minutes. Then, 220 ml of toluene was added, and the system was heated to 100° C. to distill off about 50 ml of a mixed solution of ether and THF, whereby an opaque white slurry was obtained. After the slurry was cooled to 24° C., 4.37 g (145.5 mmol) of paraformaldehyde and 12.0 ml (86.0 mmol) of triethylamine were added, followed by stirring at 90° C. for 1 hour. The reaction solution was allowed to cool to room temperature and then quenched with 42 ml of 18% hydrochloric acid. The organic layer was concentrated, and the resulting liquid was purified by silica gel column chromatography to obtain 14.13 g (yield: 92%) of 3-cumyl-5-methylsalicylaldehyde.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(O)=O.[CH3:27][C:28]1[CH:32]=[C:31]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]2=[O:46])[S:30][C:29]=1[C:47]([OH:49])=O.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[CH3:27][C:28]1[CH:32]=[C:31]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]2=[O:46])[S:30][C:29]=1[C:47]([NH:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)=[O:49]
Reactant: NCc1cccnc1
Reactant: Cc1cc(N2CCN(CCc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(CCc3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 74 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 3-methyl-5-(2-oxo-3-phenethylimidazolidin-1-yl)thiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 74% yield: mp 95-97° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (d, J=2.2 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.35-7.18 (m, 6H), 6.12 (t, J=5.6 Hz, 1H), 6.05 (s, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.77-3.70 (m, 2H), 3.54 (t, J=7.4 Hz, 2H), 3.46-3.39 (m, 2H), 2.88 (t, J=7.4 Hz, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.6, 155.8, 149.2, 148.8, 142.6, 141.8, 138.4, 135.5, 134.1, 128.6, 126.6, 123.6, 118.7, 112.2, 45.5, 42.8, 42.6, 41.2, 34.1, 16.0; MS (ES+) m/z 421.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:21][NH2:22]>>[CH3:21][NH:22][C:9](=[O:10])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CN
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Product: CNC(=O)C(c1ccc(Cl)cc1)C(C)C

Procedure:
Following the methods of Example 1, 2-(4-chlorophenyl)-3-methylbutanoic acid is reacted with oxalyl chloride and aqueous methylamine to give N-methyl-2-(4-chlorophenyl)-3-methylbutyramide, which is then combined with 3-phenoxybenzyl bromide and AgBF4, yielding 3-phenoxybenzyl N-methyl-2-(4-chlorophenyl)-3-methylbutanimidate, MS m/e 407 (M+).
Reaction SMILES: [Na+:1].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:10])=[O:9].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[K+]>O>[Na+:1].[NH:12]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:10])=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)([O-])CCCCCBr
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCCCCNc1ccccc1
Yield: 79.9 %

Procedure:
The mixture is washed with ether and the aqueous layer is concentrated to give white solids. The solids are dissolved in ethanol with heating, and cooled slowly to room temperature to precipitate sodium bromide. The precipitates are filtered off and the filtrate is put in a refrigerator overnight to obtain 5-bromo-t-pentanesulfonic acid sodium salt (12.9 g, 68%) as white crystals. A solution of 5-bromo-1-pentanesulfonic acid sodium salt (12.9 g, 0.05 mol) and aniline (20 g, 0.22 mol) in water (150 mL) is heated under reflux with potassium bicarbonate (6.3 g, 0.075 mol) for 8 hr. After the reaction is completed, the reaction mixture is washed with ether and the aqueous layer is concentrated to give white solids. The solid is recrystallized in methanol to obtain 5-anilino-1-pentanesulfonic acid sodium salt (10.6 g, 80%) as white crystals.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[NH:14][C:13](=[O:36])[CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1.I[CH3:38]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]([CH3:38])[C:13](=[O:36])[CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)OCC(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)COC(c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
NaH 80% in oil (0.0069 mol) was added portionwise to a mixture of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzoxazepin-2(3H)-one (see Example B1) (0.0069 mol) in N,N-dimethylformamide (35 ml). The mixture was stirred at room temperature for 30 min. Iodomethane (0.0069 mol) was added. The mixture was stirred at room temperature for 30 min, hydrolized and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (4.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone and diethyl ether. The precipitate was filtered off and dried, yielding 0.47 g (13%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-1-methyl-4,1-benzoxazepin-2(3H)-one, mp. 160° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCCC1CCCCCC1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(CCCCCC1CCCCCC1)C(=O)OCC

Procedure:
23.7 g of 7-cycloheptyl-2-methyleneheptanoic acid ethyl ester, in the form of a colourless oil, purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 35 g of 5-cycloheptylpentylmalonic acid ethyl ester, 3,8 g of paraformaldehyde, 35 ml of pyridine and 1 g of piperidine.
Reaction SMILES: COC1C(=O)C=[C:7]2[C@@H](N)C[CH2:13][C:14]3[C:19]([C:6]2=[CH:5]C=1)=[C:18]([O:20]C)C(OC)=C(OC)[CH:15]=3.C(O)(C(O)=O)C(O)C(O)=O.ON1C(=O)CCC1=O.Cl.[NH2:46][CH2:47][C:48]([NH2:50])=[O:49]>C(Cl)Cl.CCCCCC.CCOC(C)=O.CN(C=O)C.N(CC)(CC)CC>[CH3:7][C:6]1([CH3:5])[C:14]([CH3:13])([CH3:15])[CH:19]1[C:18]([NH:50][C:48](=[O:49])[CH2:47][NH2:46])=[O:20]
Reactant: NCC(N)=O
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC)c(=O)cc1[C@@H](N)CC2
Agent: Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)C(C(=O)NC(=O)CN)C1(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
To a solution of TMCA (2.82 g, 20 mmole) in dry CH2Cl2 (150 ml) were added N-hydroxysuccinimide (2.3 g, 20 mmole) and DMAPE-carbodiimide.HCl (3.92 g, 20 mmole). The substance obtained was stirred for 15 hours at room temperature. To this mixture was added (CH3CH2)3N (4.5 ml), glycinamide.Hcl (2.2 g. 20 mmole) and dry DMF (100 ml), and stirred for 24 hours at room temperature. The solvents were stripped off under reduced pressure. The residue was purified by chromatography (SiO2, CHCl3 :MeOH 97:3) followed by successive crystallization from CH2Cl2 :hexane and EtOAc:hexane, to afford 1.1 g (5.6 mmole, 28%) of a white crystalline solid, m.p.: 176° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:30])[CH:13]([NH:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[C:21]([F:29])[CH:22]=[C:23]([F:28])[CH:24]=3)[CH2:19]2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CS(C)=O>C(Cl)Cl>[CH3:4][C:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:30])[CH:13]([NH:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[C:21]([F:29])[CH:22]=[C:23]([F:28])[CH:24]=3)[CH2:19]2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH:2]=[O:1]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1nnc(C(C)(C)CO)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1nnc(C(C)(C)C=O)s1

Procedure:
A mixture of 2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [5-(2-hydroxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (60 mg) and Dess-Martin oxidizing agent (100 mg) in methylene chloride (1 mL) and DMSO(1 mL) was stirred at room temperature for 4 hr. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated and concentrated. The residue was purified by silica gel column chromatography using 20% to 50% ethyl acetate in hexane as eluent to give 2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide as a brown oil, LC-MS RT=2.1 min, M+1=436.9.0.