Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C@H:14]([C@H:18]([OH:20])[CH3:19])[C:15]([OH:17])=O)=[CH:5][CH:4]=1)#[N:2].[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C@H:14]([C@H:18]([OH:20])[CH3:19])[C:15]([NH:30][NH:29][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)O
Reactant: NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a pre-cooled (−45° C.) solution of (2R,3R)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoic acid (1.50 g, 5.55 mmol) and benzohydrazide (756 mg, 5.55 mmol) in anhydrous THF (80 mL) was added 1-hydroxybenzotriazole monohydrate (850 mg, 5.55 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (2.13 g, 11.1 mmol) at −45° C. followed by triethylamine (1.55 mL, 11.1 mmol). The reaction mixture warmed to room temperature and stirred for 24 h, then quenched with 5% aq. citric acid (300 mL). The solution was extracted with EtOAc (300 mL). The organic extract was washed with 5% aq. citric acid (2×150 mL), sat. aq. NaHCO3 (3×150 mL), H2O (2×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a off white solid (1.80 g, 83%): 1H NMR (400 MHz, CDCl3, δ in ppm) 10.58 (br s, 1H), 10.34 (br s, 1H), 8.48 (d, J=9.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.88 (d, J=7.2 Hz, 1H), 7.74 (t, J=7.4 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.57 (t, J=8.6 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 6.93 (d, J=8.6 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 5.26 (d, J=4.9 Hz, 1H), 4.32-4.22 (m, 1H), 4.16 (t, J=7.8 Hz, 1H), 1.33 (d, J=6.3 Hz, 3H).
Reaction SMILES: B(Br)(Br)Br.ClCCl.[O:8]1[CH:12]=[CH:11][C:10]([C:13]([N:15]([C:17]([C:19]2[O:20][CH:21]=[C:22]([C:32]3[CH:37]=[CH:36][C:35]([O:38]C)=[CH:34][CH:33]=3)[C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=2)=[O:18])[NH2:16])=[O:14])=[CH:9]1>O>[O:8]1[CH:12]=[CH:11][C:10]([C:13]([N:15]([C:17]([C:19]2[O:20][CH:21]=[C:22]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[C:23]=2[C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)=[O:18])[NH2:16])=[O:14])=[CH:9]1
Reactant: COc1ccc(-c2coc(C(=O)N(N)C(=O)c3ccoc3)c2-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: NN(C(=O)c1ccoc1)C(=O)c1occ(-c2ccc(O)cc2)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Boron tribromide (1 M dichloromethane solution: 12.00 ml) was added dropwise to a dichloromethane (5 ml) solution of the compound of Example 84 (0.86 g) at 0° C., and stirred overnight at 25° C. After water was added to the reaction solution, the thus-precipitated crystals were filtered and purified by silica gel column chromatography (eluent: methanol/chloroform=1/9), thereby giving 0.40 g of the desired compound. Melting point: 168-172° C. (Recrystallized from ethyl acetate)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([SH:17])([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].Cl[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1>CC#N>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([S:17][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CCCCl)cc1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)S
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)SCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
To a CH3CN (60 mL) solution containing methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-mercapto-3-methylbutanoate (as described above) (1.51 g, 5.73 mmol, 1.0 eq) was added sodium tert-butoxide (716 mg, 7.45 mmol, 1.3 eq). The resulting pale yellow mixture was allowed to stir at RT for 10 min at which time 1-(3-chloropropyl)-4-fluorobenzene (as described above) (1.09 g, 6.3 mmol, 1.1 eq) was added. The resulting solution was allowed to stir at RT for 18 hr. The reaction was then quenched with a sat NH4Cl solution, poured into H2O, and extracted (2×) with EtOAc. The combined extracts were dried over MgSO4 and concentrated in vacuo and then purified via flash chromatography using 5:1 hexanes/EtOAc as the mobile phase. Isolated 700 mg (1.75 mmol, 31% yield).
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[N:14]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=1)=O)(C)(C)C.[N+]1([O-:39])C=CC=CC=1>>[CH3:31][C:25]([CH3:32])([CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:13][NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:6][N+:8]=2[O-:39])=[CH:19][CH:20]=1)[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: [O-][n+]1ccccc1
Reactant: COC(=O)CC(C)(C)Cc1ccc(OCCc2cccc(NC(=O)OC(C)(C)C)n2)cc1
Product: COC(=O)CC(C)(C)Cc1ccc(OCCCNc2cccc[n+]2[O-])cc1

Procedure:
The procedure for the preparation of the product of STEP 7, EXAMPLE 4 was repeated using 2-[3-hydroxy-1-propyl)amino]pyridine-N-oxide (Ref: WO 98/30542) in the place of the product of STEP 6, EXAMPLE 4 to provide the above product as a colorless gum.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.C(=O)([O-])[O-].[K+].[K+].[OH:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][CH:23]([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=1.CC(N(C)C)=O>CC(=O)CC>[O:31]([CH2:30][CH2:29][CH:23]([CH2:22][C:21]1[CH:38]=[CH:39][C:18]([O:17][CH2:2][CH2:3][O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)=[CH:19][CH:20]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(O)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCC(C)=O
Product: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCOC2CCCCO2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
2-(2-bromoethoxy)tetrahydropyran (1.24 g) and potassium carbonate (1.09 g) were added to a solution of ethyl 2-(4-hydroxybenzyl)-4-phenoxybutyrate (620 mg), which is the product of Reference example 3(d), in 2-butanone (8 ml). The mixture was stirred at 100° C. for 5 hours. To the reaction mixture dimethylacetamide (10 ml) was added and the mixture was stirred at 100° C. for 1.5 hours. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=4/1 as the eluant to afford the desired compound (738 mg) as a syrup.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[F:10].Br[CH2:13][C:14]([O:16]C)=[O:15].O>CS(C)=O.CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[F:10])[O:11][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CBr
Reactant: Oc1ccc(F)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)COc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To a stirring solution of finely ground KOH (1.2 g, 20.4 mmol) in DMSO (6 mL) was added 3-chloro-4-fluorophenol (1.0 g, 6.8 mmol). The mixture was stirred for 10 minutes at RT, then cooled to 0° C. Methyl bromoacetate (1.25 g, 8.2 mmol) was added, and the reaction was slowly warmed to RT and stirred overnight. H2O (10 mL) and MeOH (10 mL) were added to the mixture, and the reaction was stirred for 1 h. After removing MeOH under reduced pressure, H2O (100 mL) and Et2O (50 mL) were added, and the layers were separated. The aqueous phase was acidified to pH 2 with an aqueous concentrated HCl solution and extracted with CH2Cl2 (200 mL). The organic layer was dried over MgSO4, filtered, concentrated, and dried to give 2-(3-chloro-4-fluorophenoxy)acetic acid as a white solid (1.1 g, 79%). 1H NMR (400 MHz, CDCl3) δ 7.10 (t, J=8.8 Hz, 1H), 7.01-6.98 (m, 1H), 6.84-6.80 (m, 1H), 4.68 (s, 2H).
Reaction SMILES: [Si]([O:18][CH2:19][N:20]1[C:28]([CH2:29][CH2:30][CH3:31])=[N:27][C:26]2[C:21]1=[N:22][C:23]([C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[N:24][C:25]=2[NH:32][O:33][CH3:34])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][N:20]1[C:28]([CH2:29][CH2:30][CH3:31])=[N:27][C:26]2[C:21]1=[N:22][C:23]([C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:24][C:25]=2[NH:32][O:33][CH3:34]
Reactant: CCCc1nc2c(NOC)nc(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc2n1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1nc2c(NOC)nc(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc2n1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 44 (22 g, 30.0 mmol) is dissolved in THF (200 L) and treated with TBAF (1M in THF, 30.68 mL) and the reaction mixture is stirred at room temperature for 2 h followed by concentration. The residue is purified on a silica gel column using chloroform:methanol (100:0 to 90:10) as an eluent to give 10g (70%) of 45 as a white foam, mp 188° C.: 1H NMR (DMSO-d6): δ: 8.23 (s, 1 H), 7.89 (s, 1 H), 7.4-6.9 (m, 14 H), 5.01 (bs, 1 H), 4.36 (m, 1 H), 3.84 (m, 1 H), 3.71 (s, 3 H), 3.67 (m, 1 H, partially masked by CH3 peak), 1.90 (m, 2 H), 0.73 (t, J=7.3 Hz, 3H). IR (KBr, cm−1) 3408, 3313, 2966, 1715, 1605, 1469 and 1249.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:8]([CH:9]=O)=[C:7]([CH3:11])[O:6][N:5]=1.Cl.[NH2:13][CH2:14][C:15]1[N:16]=[C:17]([NH:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[O:22])[S:18][CH:19]=1>CO>[CH3:3][C:4]1[C:8]([CH2:9][NH:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[O:22])[S:18][CH:19]=2)=[C:7]([CH3:11])[O:6][N:5]=1
Reactant: Cc1noc(C)c1C=O
Reactant: NCc1csc(NC(=O)NCc2cccc(F)c2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1noc(C)c1CNCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 6 h

Procedure:
NaBH4 (35 mg, 1 mmol) was added in portions to a MeOH (5 mL) solution of 3,5-dimethylisoxazole-4-carbaldehyde (65 mg, 0.5 mmol) and 1-(4-(aminomethyl) thiazol-2-yl)-3-(3-fluorobenzyl)urea hydrochloride (157 mg, 0.5 mmol) at 0 C. The mixture was stirred for 6 hours then quenched with dilute HCl solution. Basic aqueous work-up with CH2Cl2 followed by flash chromatography afforded Intermediate 61: 1-(4-(((3,5-dimethylisoxazol-4-yl)methylamino)methyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea. 1H NMR (400 MHz, CDCl3): δ 8.2 (1H, br), 7.27 (m, 1H), 6.92 (m, 3H), 6.60 (s, 1H), 4.37 (d, 2H), 3.66 (s, 2H), 3.33 (s, 2H), 2.22 (s, 3H), 2.11 (s, 3H). MS (ES+): M/Z 390 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[C:20]3[S:14][C:15](=[S:16])[NH:17][C:18]3=[O:19])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cc(-c2ccccc2)cs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1cc(-c2ccccc2)cs1
Yield: 87.1 %

Procedure:
A solution of 4-phenyl thiophene-2-carboxaldehyde (1 g, 5.3 mmol) and rhodanine (700 mg, 5.3 mmol) in 10 mL of glacial acetic acid was heated with anhydrous sodium acetate (1.22 g, 14.8 mmol) for 2 h. The reaction mixture was then poured into cold water. The precipitate was filtered, washed with water and dried under reduced pressure to get 5-((4-phenylthiophen-2-yl)methylene)-2-thioxothiazolidin-4-one (1.4 g, yield 87%). MS (ESI) m/z: Calculated for C14H9NOS3: 302.98. found: 302.0 (M−H)−. The crude product was carried through without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[CH3:12]I>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH:3]=[C:2]([CH3:1])[C:6]=2[CH:7]=1
Reactant: CI
Reactant: Cc1coc2ccc(O)cc12
Product: COc1ccc2occ(C)c2c1

Procedure:
5-Methoxy-3-methyl-benzofuran was prepared via methylation of 3-methyl-benzofuran-5-ol (Structure I) (prepared as above in EXAMPLEs I-III) using methyl iodide (MeI).
Reaction SMILES: [Si:1]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:17][CH2:18][CH2:19]Cl)=[O:16])([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[S-2:21].[Na+].[Na+]>C(O)C>[Si:1]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:17][CH2:18][CH2:19][S:21][CH2:19][CH2:18][NH:17][C:15]([NH:14][CH2:13][CH2:12][CH2:11][Si:1]([O:2][CH2:3][CH3:4])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])=[O:16])=[O:16])([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCO[Si](CCCNC(=O)NCCCl)(OCC)OCC
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Product: CCO[Si](CCCNC(=O)NCCSCCNC(=O)NCCC[Si](OCC)(OCC)OCC)(OCC)OCC
Temperature: 25 °C
Yield: 97.9 %

Procedure:
In a second reaction step, (EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—Cl (100.00 g, 0.31 mol, 2.00 eq) is initially charged in ethanol (75 ml) in a 500 ml three-neck flask with stirrer, reflux condenser and internal thermometer. Dry sodium sulphide (Na2S, 14.47 g, 0.18 mol, 1.17 eq) is added and the mixture is heated to reflux. After a reaction time of 4.5 h, the mixture is cooled to room temperature and the suspension is filtered. The filtrate is freed of the solvent on a rotary evaporator and dried under reduced pressure. The (EtO)3Si—CH2CH2CH2—NH—CO—NH—CH2CH2—S—CH2CH2—NH—CO—NH—CH2CH2CH2—Si(OEt)3 product (93.34 g, 99.2% of theory) is obtained as a waxy, light green solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[N:27]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:33]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)(=[O:35])=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)N1CCCCC1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)N1CCCCC1
Yield: 29 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (200 mg, 0.510 mmol) and 1-piperidinesulfonyl chloride (0.201 mL, 1.531 mmol) the title compound of Step A was obtained as a yellow foam (193 mg, 41% and 29% yield, repeated twice). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (s, 1H), 8.15-8.44 (m, 1H), 7.45-7.67 (m, 1H), 7.22-7.42 (m, 2H), 6.61 (d, J=5.4 Hz, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.52 (t, J=4.7 Hz, 4H), 3.03 (t, J=5.0 Hz, 4H), 1.24-1.66 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCCN2
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CCCc2cc(Br)ccc21
Yield: 36.5 %

Procedure:
This compound was prepared according to the general procedure for sulfonylation of indolines and tetrahydroquinolines described in Example 4 using 6-bromo-1,2,3,4-tetrahydroquinoline (0.40 g, 1.89 mmol) and ethanesulfonyl chloride (0.26 mL, 2.8 mmol) to provide 6-bromo-1-(ethylsulfonyl)-1,2,3,4-tetrahydroquinoline (0.21 g). MS (ES) m/z 303.7; HPLC purity 94.8% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[C:23]([O:25][CH3:26])=[O:24].[O:27]1[C:36]2[CH:35]=[C:34]([CH:37]=O)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37][C:34]2[N:33]=[CH:32][C:31]3[O:30][CH2:29][CH2:28][O:27][C:36]=3[CH:35]=2)[C@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NCc1cc2c(cn1)OCCO2
Yield: 79.2 %

Procedure:
Methyl (3R,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 38) (195 mg, 0.53 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (88 mg, 0.53 mmol) and sodium triacetoxy borohydride (339 mg, 1.6 mmol) were reacted as described for Example 14 to give 216 mg (79%) of product as a colorless hard foam.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32].[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:34]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]2)[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]
Reactant: COc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Dess-Martin periodinane (13.62 g, 32.11 mmol) was added to 1-(3-methoxy-4-nitrophenyl)piperidin-4-ol (INTERMEDIATE 17, 5.4 g, 21.41 mmol) in DCM (120 mL) at 0° C. and the reaction mixture was stirred for 30 min. The reaction mixture was then allowed to warm to RT and stirred for an additional 4 h. The reaction solution was poured into a mixture of 20% aqueous Na2S2O3 (50 mL) and saturated aqueous NaHCO3 (50 mL) and the biphasic mixture was stirred at RT for 1 h. The mixture was partitioned and organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (5% MeOH/DCM) to give the title product (4.28 g, 80%). m/z 251.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:20]([N:8]1[C:7](=[O:16])[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]1=2)[CH2:21][CH3:22]
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2ccccc2Oc2ccccc21
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 3.0 grams of 10H-dibenz[b,f][1,4]oxazepin-11-one in 50 ml of dry dimethylformamide was added 0.82 grams of a 50% dispersion of sodium hydride in mineral oil. The resulting mixture was stirred for one hour and 3.7 grams of 1-bromopropane was then added slowly. The reaction mixture was stirred for 3 hours and the excess sodium hydride decomposed by the addition of ice. After further dilution with water the product was extracted with ether, dried (anhydrous sodium sulfate) and concentrated. The resulting oil was purified on a silica gel column (ethyl acetate/hexane, 1:4) to provide 3.1 grams (87% of theory) of 10-propyl-10H-dibenz[b,f][1.4]oxazepin-11-one as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1.[N:20]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[O:12]([C:8]1[CH:7]=[C:6]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:19])[NH2:20])[CH:11]=[CH:10][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=N[O-]
Reactant: COC(=O)CNc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CN(N)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 25.5 %

Procedure:
N-(3-Phenoxyphenyl)glycine methyl ester (Intermediate 48; 10 g, 0.0389 mol) was dissolved in a mixture of glacial acetic acid (60 ml) and water (7 ml) and the solution was cooled to between 0° and 5° C. A solution of sodium nitrite (2.8 g, 0.0408 mol) in water (8.5 ml) was added to this over 15 min at the same low temperature. The solution was stirred for 1 h before being cooled to between 0° and -10° C. Zinc powder (9.9 g, 0.1517 mol) was gradually added at this temperature and the reaction was then stirred at 0° to 5° C. for 4 h. It was then poured into water (300 ml) and extracted with ethyl acetate (3×150 ml). The organic extract was washed with 8% sodium bicarbonate solution until effervescence had ceased. It was then dried and evaporated to give a dark brown oil. This was purified by FCC on deactivated silica (200 g) eluting with hexane-chloroform (2:1) to give the title compound as a brown oil (2.7 g, 25%).
Reaction SMILES: [OH:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=[CH:4][C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@H:6]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=[CH:4][C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@H:6]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(=[O:28])[CH3:27]
Reactant: CCCCCC(O)C=C[C@@H]1CCC(=O)[C@H]1C/C=C\CCCC(=O)OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC(C=C[C@@H]1CCC(=O)[C@H]1C/C=C\CCCC(=O)OC)OC(C)=O
Temperature: 0 °C

Procedure:
A solution of the compound of formula I, methyl trans,cis-7-[2-(3-hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoate (5 g), described in Example 161, in 50 ml of pyridine and 50 ml of acetic anhydride is stirred at room temperature for 4 hr. The solution is diluted with ice-water and extracted with ether. The ether is washed with 10% H2SO4, water 10% Na2CO3 and water, dried (Na2SO4) and evaporated to give the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1)(=[O:25])[CH3:24]
Reactant: Nc1ccc(N2CCCCC2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(4-aminophenyl)piperidine dihydrochloride (2.49 g) and triethylamine (5.6 g) in dichloroform (30 ml) was ice-cooled and to this was added dropwise acetyl chloride (1.42 ml). After stirred at room temperature for 30 minutes, water (10 ml) was added to the mixture and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and then the residue was recrystallized from ethyl ether to obtain N(4-acetylaminophenyl)piperidine (2 g) as colorless crystals, m.p. 150°-152° C.