Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C(Cl)Cl>[C:27]([NH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A portion (70 mg) of the compound obtained in Example 81 was dissolved in anhydrous methylene chloride (15 ml) and to the solution were added triethylamine (69 μl) and benzoyl chloride (29 μl). The mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, followed by extraction with methylene chloride. The organic layer was washed with 1N aqueous solution of sodium hydroxide, water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield 90 mg (91%) of the titled compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][S:10]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:29]([CH2:30][C:31]([O:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])=[O:32])[N:28]=[C:27]([C:39]([F:42])([F:41])[F:40])[CH:26]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11]>>[Br:1][C:26]1[C:27]([C:39]([F:42])([F:41])[F:40])=[N:28][N:29]([CH2:30][C:31]([O:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])=[O:32])[C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([S:10]([CH3:9])(=[O:12])=[O:11])[CH:14]=2)=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Product: CN(C)CCOC(=O)Cn1nc(C(F)(F)F)c(Br)c1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1

Procedure:
Following bromination with N-bromosuccinimide, the title compound 40 is prepared starting from 2-(dimethylamino)ethyl 2-(5-(3′-(methylsulfonyl)biphenyl-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate 39.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(Nc3cccc(F)c3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3-fluoroaniline gave the title compound as a tan solid, mp 192-195° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].I[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:27]1[CH:36]=[CH:35][C:34]2[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=2[CH:28]=1>C(O)C>[CH2:1]([NH:4][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)=[CH:12][C:11]=1[C:27]1[CH:36]=[CH:35][C:34]2[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=2[CH:28]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: CCCN
Solvent: CCO
Product: CCCNCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 93.6 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 1.3 ml (15.8 mmol) of n-propylamine and 960 mg (1.6 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (obtained in Example 1b) in 50 ml of ethanol. 790 mg of ethyl 4′-(3-propylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=120° C., yield=56%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:2]=1.S(Cl)([Cl:18])=O>C(Cl)Cl>[Cl:18][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OCCCCCCCCc1cccnc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCCCCCCCCc1cccnc1

Procedure:
A 3-L flask equipped with a mechanical stirrer, thermometer, and addition funnel was charged with 145.8 g of 3-pyridineoctanol and 1.0 L of methylene chloride. The solution was cooled in an ice bath and 72 mL of thionyl chloride, diluted to 500 mL with methylene chloride, was added dropwise over 15 minutes. The cooling bath was removed and the mixture was heated at a gentle reflux for 1.0 hour. The mixture was again cooled in an ice bath and treated with 750 mL of 3N sodium hydroxide. The separated aqueous phase was extracted with 2×250 mL=500 mL of methylene chloride. The combined organic solutions were dried over sodium sulfate to which was added 10 g of Norite A charcoal. The mixture was filtered through Celite and the solvent was stripped on a rotary evaporator at 45°. The residue was co-stripped with 100 mL of toluene to give 191.3 g (overweight) of the desired 3-(8-chlorooctyl)pyridine as a brown oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:20][OH:21])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1cn(Cc2ccccc2)c2ccccc12
Agent: Cl
Product: ON=Cc1cn(Cc2ccccc2)c2ccccc12
Yield: 60 %

Procedure:
1-Benzyl-1H-indole-3-carbaldehyde oxime (1.752 g, 60%) was prepared from 1-benzyl-1H-indole-3-carbaldehyde and hydroxylamine hydrochloride using a procedure similar to Step 6 of example 1. 1H NMR (400 MHz, DMSO-d6); δ 11.30 (s, 1H), 8.40 (s, 1H), 7.88 (d, 1H), 7.80 (s, 1H), 7.50 (d, 1H), 7.22 (m, 7H), 5.50 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:11]([NH2:13])=O)[O:3]1.[CH3:20][C:21](N)([CH3:24])[CH2:22][NH2:23].C1(C)C=CC=CC=1>O>[OH:3][C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2](=[O:1])[N:23]2[CH2:22][C:21]([CH3:24])([CH3:20])[N:13]=[C:11]12
Reactant: NC(=O)C1(c2ccccc2)OC(=O)c2ccccc21
Reactant: CC(C)(N)CN
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CN2C(=O)c3ccccc3C(O)(c3ccccc3)C2=N1
Temperature: 25 °C

Procedure:
A mixture of 3-oxo-1-phenyl-1,3-dihydro-2-benzofuran-1-carboxamide (10 g), 2-methyl-1,2-diaminopropane (15 mL), and toluene (100 mL) was heated at reflux for 18 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature and extracted with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethanol to give the title compound (57.3 g), m.p. 186-188° C.
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]1[N:17]2[C:13]([S:14][CH:15]=[C:16]2[CH2:18][C:19]([NH2:21])=[O:20])=[CH:12][N:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH:6]([NH:8][CH2:9][C:10]1[N:17]2[C:13]([S:14][CH:15]=[C:16]2[CH2:18][C:19]([NH2:21])=[O:20])=[CH:12][N:11]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)NCc1ncc2scc(CC(N)=O)n12
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1csc2cnc(CNC=O)n12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94176.4 %

Procedure:
To 0.296 mg of the 5-(tert-butoxycarbonylamino)methylimidazo[5,1-b]thiazole-3-carboxyamide was added 8 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes, and then concentrated to dryness under reduced pressure. To the residue were added 50 ml of methylene chloride, 50 ml of tetrahydrofuran and i ml of triethylamine, and the mixture was thoroughly stirred. To this was added a mixture of 2 ml of formic acid and i ml of acetic anhydride, which had been heated to 50° C. for 10 minutes and then cooled to room temperature, and the mixture was stirred for 14 hours. The crystals precipitated were collected by filtration, and dried under reduced pressure to give 0.214 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:20][CH2:19][C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(O)[CH2:17][CH2:16]2)=[O:14])[N:12]=1.Cl>ClCCl.CCOCC>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:9]2[CH:10]=[C:11]([C:13]([N:15]3[CH2:16][CH:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)=[O:14])[N:12]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:29][CH:30]=1
Reactant: Cc1ccccc1-c1nc(C(=O)N2CCC(O)(c3ccccc3)CC2)cn1-c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccccc1-c1nc(C(=O)N2CC=C(c3ccccc3)CC2)cn1-c1ccc(Cl)cc1

Procedure:
A 30-mg sample of 1-{[2-(2-methylphenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}-4-phenyl-4-piperidinol (Table entry 414), was dissolved in 20 mL dichloromethane, and then 5 mL 2M HCl in ether was added to the solution. Evaporation of the solvent at high temperature (ca. 70° C., 16 hr) in a multiple sample evaporator (GeneVac) gave 1-{[1-(4-chlorophenyl)-2-(2-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-phenyl-1,2,3,6-tetrahydropyridine (yellow solid). 1H NMR (400 MHz, CD3COCD3) δ 8.31 (s, 1H), 7.05-7.35 (m, 13 H), 6.05 (s, 1 H), 4.2 (m, 2 H), 3.85 (m, 2H), 2.5 (m, 2H), 2.0 (s, 3H); LC-MS m/z 454 (MH+), retention time 2.92 min (method 2).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:10]=[C:9]([OH:19])[CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:19][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[N:10]=1
Reactant: COC(=O)CBr
Reactant: Oc1cc(-c2ccc(Br)s2)n(-c2ccccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(-c2ccc(Br)s2)n(-c2ccccc2Cl)n1
Temperature: 80 °C
Yield: 88.9 %

Procedure:
To a solution of 5-(5-bromo-thiophene-2-yl)-1-(2-chloro-phenyl)-1H-pyrazole-3-ol (2.21 g, 6.21 mmol) in anhydrous DMF was added K2CO3 (1.72 g, 12.43 mmol) and methyl bromoacetate (1.2 mL, 12.43 mmol). The reaction mixture was heated at 80° C. under nitrogen atmosphere overnight. Evaporate the solvent and the residue was dissolved in DCM and it was passed through a short pad of celite. The solvent was concentrated and the crude product was purified by flash column chromatography (20% ethyl acetate in hexane), resulting in the product of [5-(5-bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-1H-pyrazol-3-yloxy]-acetic acid methyl ester (2.36 g, 89% yield).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Si:13]([O:20][CH2:21][CH2:22][NH:23][CH3:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl.[OH-].[Na+]>[CH3:19][C:16]([Si:13]([CH3:14])([CH3:15])[O:20][CH2:21][CH2:22][N:23]([CH3:24])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:12])=[C:10]([F:11])[C:2]=1[F:1])([CH3:17])[CH3:18]
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
2,3,4-Trifluorobenzoyl chloride (2.32 mL, 18.16 mmol) was added slowly to a stirred mixture of (2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)methylamine (3.44 g, 18.16 mmol) in DCM (200 mL) and 10% aqueous sodium hydroxide solution (200 mL) at 0° C. The reaction was allowed to warm to RT and stirred for a further 24 hours. The phases were separated and the aqueous phase further extracted with DCM (3×100 mL), the combined organics dried (MgSO4), filtered and the solvent removed in vacuo to give a pale yellow oil. The residue was chromatographed on silica, eluting with 0-50% ethyl acetate in isohexane, to give the desired compound as a colourless oil (5.22 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:17]([O:19]CC)=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.O.[OH-].[Li+].OS([O-])(=O)=O.[Na+]>C(O)C.O>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:4]([CH2:3][O:2][CH3:1])([C:17]([OH:19])=[O:18])[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)C1(COC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 75 °C

Procedure:
To a solution of 1-tert-butyl 4-ethyl 4-(methoxymethyl)piperidine-1,4-dicarboxylate from step A (732 mg, 2.63 mmol) in 1:2 ethanol/water (9 mL) was added lithium hydroxide monohydrate (700 mg). The mixture was heated to 75° C. for 1 hour. The reaction was cooled to room temperature and poured into 50 mL of sat. aq. NaHSO4. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum to give the title compound as a viscous yellow oil, which was carried on to the next step without further purification. MS (ES+) [M+H]+=274.2.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([CH2:14][S:15]([CH2:18][S:19]([CH2:22][C:23](O)=O)(=[O:21])=[O:20])(=[O:17])=[O:16])(O)=O>C(O)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:14]/[S:15]([CH2:18][S:19](/[CH:22]=[CH:23]/[C:7]1[CH:6]=[CH:3][C:2]([F:1])=[CH:9][C:8]=1[F:10])(=[O:21])=[O:20])(=[O:17])=[O:16]
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: O=Cc1ccc(F)cc1F
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccc(F)cc1F)CS(=O)(=O)/C=C/c1ccc(F)cc1F
Yield: 75 %

Procedure:
A solution of 2,4-difluorobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 75% yield. m.p. 193-195° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][CH:37]=1.C(N(CC)CC)C>C(#N)C>[OH:43][CH2:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:34][C:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)=[O:9])=[CH:37][CH:38]=1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: NCc1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1cnc(C(=O)NCc2ccc(CO)cc2)c1
Yield: 65.3 %

Procedure:
Stir a mixture of 1-methyl-1H-imidazole-4-carboxylic acid (4.0 g, 31.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.6 g, 34.5 mmol) and 1-hydroxybenzotriazole hydrate (5.29 g, 34.5 mmoles) in anhydrous acetonitrile (150 mL) at room temperature for 1 hr. Add to the reaction mixture (4-aminomethyl-phenyl)-methanol hydrochloride (5.0 g, 28.8 mmol) and triethylamine (8.4 mL, 60.5 mmol). Stir the reaction mixture at room temperature overnight. Quench the reaction mixture with water and extract with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to provide the title compound (4.6 g, 18.8 mmol). MS (m/z): 246 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:14][CH2:13]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:28](=O)[CH3:29].Cl>>[CH2:28]([N:11]([C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:16][CH2:17]1)[CH3:29]
Reactant: C[C@H](CCc1ccccc1)N[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: CC=O
Agent: Cl
Product: CCN([C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1)[C@H](C)CCc1ccccc1

Procedure:
Coupling of 6-{trans-4-[(R)-1-methyl-3-phenylpropylamino]cyclohexyl}-3H-benzoxazol-2-one (370 mg, 1.01 mmol) and acetaldehyde (44 mg, 1.01 mmol) following the procedure described in Example 24, followed by formation of the HCl salt, gave 6-(trans-4-{ethyl-[(R)-1-methyl-3-phenylpropyl]amino}-cyclohexyl)-3H-benzoxazol-2-one (70 mg, 25%), as a pale yellow solid (a mixture of diastereomers): mp 139-158° C.; IR (KBr): 2941, 1772, 1497, 1451 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.52 (s, 2H), 9.11 (s, 2H), 7.35-7.21 (m, 10H), 7.18 (m, 4H), 7.00 (s, 2H), 3.20 (m, 2H), 2.81 (m, 2H), 2.54 (m, 2H), 2.20-1.51 (m, 28H), 1.44 (d, J=7 Hz, 3H), 1.32 (d, J=7 Hz, 3H), 1.26 (m, 6H); API-MS (methane) (m/z): 393 [M+H]+; calcd for C25H32N2O2, 393.2542; found, 393.2540; HPLC: method C, 5.77 minutes (97.4%), method D, 11.47 minutes and 11.57 minutes (98.1%); Anal. Calcd for C25H32N2O2HCl.0.5H2O: C, 68.55; H, 7.82; N, 6.40. Found: C, 68.67; H, 8.03; N, 6.27.
Reaction SMILES: C(OC(OC(C)(C)C)=O)([O:3][C:4](C)(C)[CH3:5])=O.Cl.[OH:17][C@H:18]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:19][NH:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1>C(O)(C)(C)C.[OH-].[Na+]>[C:4]([O:17][C@H:18]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:19][NH:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1)(=[O:3])[CH3:5]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(O)Cc1ccc(OCCNC[C@H](O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(=O)O[C@@H](CNCCOc1ccc(CC(=O)O)cc1)c1ccccc1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 639.9 %

Procedure:
Di-t-butyl dicarbonate (1.25 g) in t-butanol (15 ml) was added to a stirred solution of (R)-4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid hydrochloride (2.0 g) in 1N aqueous sodium hydroxide (30 ml). The reaction mixture was stirred for 90 minutes at 20° C. The solvent was removed under reduced pressure. Water (20 ml) was added to the residue and the solution was acidified with 2N aqueous citric acid. The product was extracted into 5% methanol in dichloromethane (5×20 ml). The extracts were dried and the solvent removed under reduced pressure to yield N-t-butoxycarbonyl-(R)-[4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid as a glass (13 g); [α]25D =-6.2° (c=1.0 in methanol).
Reaction SMILES: C1(=O)OC(=O)CC1.[SH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O.NCCS.NCCSSCCN>O>[SH:8][CH2:9][CH2:10][N:11]1[C:12](=[O:18])[CH2:13][CH2:14][C:15]1=[O:17]
Reactant: O=C(O)CCC(=O)NCCS
Agent: NCCS
Agent: NCCSSCCN
Agent: O=C1CCC(=O)O1
Solvent: O
Product: O=C1CCC(=O)N1CCS

Procedure:
About one-half hour is necessary for the complete transformation of the succinic anhydride (V.P.C.). At this stage, to facilitate the cyclization reaction, the reaction mixture is placed under reduced pressure and the evolution of the reaction mixture is followed by acidimetric dosage of the nontransformed N-(2-mercapto ethyl) succinamic acid. At the end of the reaction, the mixture is cooled and 7 g of crude product are obtained and dissolved in 50 cm3 of water to which are added, with stirring, 10 g of sulfonic acid resin. After stirring for one hour, the resin, having fixed the traces of cysteamine or cystamine not having reacted, is removed by filtration. To reduce the disulfide optionally present, there are added to the stirred filtrate, 10 g of sulfonic resin and 3 g of zinc powder. After 3 hours the mixture is filtered and the filtrate is concentrated under reduced pressure. After drying, 5 g of N-(2-mercapto ethyl) succinimide are obtained in the form of a white powder whose melting point is 45° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:14][O:15]C(Cl)Cl>C(Cl)Cl.C[N+]([O-])=O>[CH:14]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH3:9])=[O:7])[NH:1][CH:5]=1)=[O:15]
Reactant: COC(Cl)Cl
Reactant: COC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1cc(C=O)c[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 2 (4.50 g, 36.0 mmol) in CH2Cl2:CH3NO2 (1:1, 40 mL) at −40° C., was added AlCl3 (12.48 g, 93.6 mmol) followed by α,α-dichloromethyl methyl ether (4.15 mL, 46.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was slowly poured onto ice (10.00 g) and allowed to warm to room temperature. The aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 3 as a dark brown solid (3.40 g, 62%). 1H NMR (400 MHz, CDCl3) δ 10.32 (bs, 1H), 9.83 (s, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.30 (s, 1H), and 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.07, 161.71, 129.15, 127.71, 124.99, 114.56, and 52.34.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F-:11].[K+].[F-].[Cs+].C1S(=O)(=O)CCC1>>[F:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Cs+]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccccc1F
Temperature: 110 °C
Yield: 85.5 %

Procedure:
1,300 parts of o-chloronitrobenzene, 960 parts of potassium fluoride and 25 parts of cesium fluoride are stirred in 1,300 parts of tetramethylenesulfone under nitrogen for 16 hours at 225° C. The solution is cooled to 110° C. and filtered, the solid residue is washed with 500 parts of methylene chloride and the filtrates are combined and distilled. 991 parts (85.5% of theory) of o-fluoronitrobenzene of boiling point 55° to 57° C/1.2 mm Hg are obtained.