Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:10]1=[O:26].CI.Cl[CH2:30]CCl>C(Cl)Cl.[Ag]=O>[CH3:30][O:1][CH2:2][C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18]2)[C:10]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(CO)C(=O)OC1)C2=O
Reactant: ClCCCl
Agent: O=[Ag]
Solvent: CI
Solvent: ClCCl
Product: COCC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 25 °C

Procedure:
tert-butyl 2-(4-(hydroxymethyl)-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.42 g, 1.15 mmol), silver oxide (0.292 g, 1.26 mmol) and methyl iodide (0.358 mL, 5.73 mmol) were taken up in DCM (5 mL) and stirred over night at room temperature under nitrogen. Additional silver oxide (0.292 g, 1.26 mmol) and methyl iodide (0.358 mL, 5.73 mmol) were added to the mixture with DCE (8 mL) and the resulting mixture was heated at 54° C. overnight. The reaction mixture was filtered through CELITE® to remove silver oxide, concentrated, and purified by silica gel column chromatography (40 g RediSep Gold column) using (20-80) % EtOAc/DCM as mobile phase to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)N1CCCC1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 4-bromobenzoyl chloride (3 g, 13.7 mmol)) in dichloromethane (25 mL) was cooled to 0° C. and treated with pyrrolidine (2.5 mL, 30.3 mmol) and triethylamine (2 mL, 14.4 mmol). The mixture was warmed to ambient temperature over 3 hours and concentrated. The residue was purified by flash chromatography on silica gel using 10-60% hexane/ethyl acetate to provide the title compound (3.1 g, 89%). MS (ESI) m/e 256 (M+H)+.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][N:14]([CH3:16])[CH3:15])=[CH:7]2.C([Li])CCC.CN([CH:25]=[O:26])C>C1COCC1>[CH3:15][N:14]([CH2:13][C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([CH:25]=[O:26])=[CH:12][CH:11]=2)[CH3:16]
Reactant: CN(C)Cc1cc2cc(Br)ccc2[nH]1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)Cc1cc2cc(C=O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of potassium hydride (suspension in mineral oil, 0.79 g, 5.90 mmol) in anhydrous THF (60 mL) was added a solution of (5-bromo-1H-indole-2-ylmethyl)-dimethyl amine (1.24 g, 4.90 mmol) in anhydrous THF (20 mL) was added dropwise at 0° C. over a period of 15 minutes under nitrogen. Stirring was continued for 30 minutes at 0° C., then cooled to −10° C. n-Butyl lithium (1.6 M solution in hexanes, 7.4 mL, 11.7 mmol) was added rapidly. Stirring was continued at −10° C. for 1 h. Then, anhydrous DMF (5.0 mL) was added, and the mixture was allowed to warm to room temperature over 2 h. The reaction mixture was carefully quenched with 1N aq. HCl (10 mL). The reaction mixture was diluted with ethyl acetate (150 mL). The organic phase was separated, washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. The solvent was evaporated to give 2-dimethylaminomethyl-1H-indole-5-carbaldehyde as an orange-colored gummy material. Yield: 0.91 g (crude). This product was used in next step without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Fc1cnc(Cl)nc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(F)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-fluoro-pyrimidine following a procedure analogous to that described in Example 19. LC (method 5): tR=2.14 min; Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3]N(N=O)/C(/N)=N/[N+]([O-])=O.[S:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:16])(=[O:15])[NH2:14]>O.CCOCC>[CH3:3][O:22][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([S:13](=[O:15])(=[O:16])[NH2:14])=[CH:25][CH:24]=1
Reactant: CN(N=O)/C(N)=N/[N+](=O)[O-]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of KOH (108 mg, 2.0 mmol) in water (1 mL) was added Et2O and cooled to 0° C. MNNG (292 mg, 1.99 mmol) was added and the resulting yellow solution was added to a suspension of 4-Sulfamoyl-benzoic acid in Et2O at room temperature and stirred overnight. The reaction was quenched with acetic acid and the resulting mixture was diluted with water. The mixture was then extracted with ethyl acetate and the combined organic extracts was washed with bine and dried over Na2SO4. Removal of solvent gave the crude product which was used in the next reaction without further purification. 1H NMR (400 MHz, MeOD) δ8.17 (d, 2H), 8.00 (d, 2H), 3.92 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH:3]1[C:13]([O:15][CH3:16])=[O:14].Br[CH2:18][CH2:19][CH2:20][Cl:21].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:21][CH2:20][CH2:19][CH2:18][C:3]1([C:13]([O:15][CH3:16])=[O:14])[C:2](=[O:1])[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4]1
Reactant: COC(=O)C1Oc2ccccc2CCC1=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1(CCCCl)Oc2ccccc2CCC1=O
Yield: 81.6 %

Procedure:
A mixture of 5.0 g of methyl 3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate, 7.1 g of 1-bromo-3-chloropropane, 1.5 g of potassium iodide, 6.3 g of potassium carbonate and 60 ml of acetonitrile is heated under refluxing for 4 hours. After cooling, the inorganic substances are filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with water and then extracted with ethyl acetate. The organic layer is washed with water, dried, and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=8:1→2:1), to give 5.5 g of methyl 2-(3-chloropropyl)-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as a colorless oil. Recrystallization from ethanol gives 4.4 g of colorless prisms: m.p. 75°-77° C.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[CH2:9][CH2:8][N:7](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:6][C:5]=2[N:4]=1.[ClH:39]>CO.O1CCOCC1>[ClH:39].[F:38][C:2]([F:1])([F:37])[C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[N:4]=1
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CNCC2

Procedure:
A solution of the product (145 mg) from Step A in 0.5 mL of methanol and 2.5 mL of 4.0M hydrogen chloride in dioxane was kept at room temperature for 3 h. The reaction mixture was concentrated under a stream of nitrogen, and the residue was triturated with ether. The resultant precipitate was collected and dried in vacuo to afford the title compound as a light red powder. LC/MS 275.1 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH:6]1[CH:8]([CH3:10])[CH3:9])=[O:4].[Li+].[OH-]>CO.O>[C:16]([O:15][C:13]([NH:12][CH2:11][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH:6]1[CH:8]([CH3:9])[CH3:10])=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isopropyl-cyclopropanecarboxylic acid methyl ester (10.9 g, 40.2 mmol) in MeOH (320 mL) was added a solution of LiOH (4.2 g, 100 mmol) in water (98 mL). The reaction mixture was heated to reflux for 3 hours and cooled to room temperature. Excess of solvent was removed and the residue was dissolved in water (100 mL). The aqueous solution was washed with ether, acidified to pH=3 with 2N HCl and extracted with EtOAc (2×150 mL). The combined organic phase was washed with brine, dried (Na2SO4) and evaporation of the solvent provided 1-(tert-butoxycarbonylamino-methyl)-2-isopropyl-cyclopropanecarboxylic acid (9.0 g, 87%) as a colorless oil: 1H NMR (300 MHz, CD3OD) δ 0.72 (m, 1H), 0.99 (d, J=6.2 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 1.28-1.36 (m, 3H), 1.42 (s, 9H), 3.23 (d, J=14.3 Hz, 1H), 3.54 (d, J=14.3 Hz, 1H); 13C NMR (75 MHz, CD3OD) δ 20.0, 23.0, 23.3, 28.8, 30.2, 37.6, 40.8, 80.2, 158.1, 178.5; MS (APCI) m/z258 [M+H]+.
Reaction SMILES: O=[C:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][C@@H:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:19]([OH:21])=[O:20].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>O1CCCC1>[S:23]=[C:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][C@@H:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:19]([OH:21])=[O:20]
Reactant: CCC1C[C@@H](CCc2ccc(Br)cc2)CN(C(=O)O)C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: CCC1C[C@@H](CCc2ccc(Br)cc2)CN(C(=O)O)C1=S
Temperature: 60 °C
Yield: 113.1 %

Procedure:
A mixture of 1.12 g (3.16 mmol) of (3RS, 5R)-2-oxo-3-ethylcarboxy-5-[2-(4-bromophenyl)ethyl]piperidine and 0.77 g (1.74 mmol) of phosphorus pentasulfide in 20 mL of tetrahydrofuran was heated at 60° C. until complete conversion was obtained (about 3 hours). The mixture was evaporated to a residue which was purified by chromatography on silica gel. The product was eluted with ethyl acetate-hexane 1:1, affording 0.729 g (61%) of (3RS, 5R)-2-thioxo-3-ethylcarboxy-5-[2-(4-bromophenyl)ethyl]piperidine (mixture of C-3 epimers)), mp 105°-115° C., 1H NMR (300 MHz, CDCl3) δ 9.47 (s, 1H), 7.41 (d, J=8.7 Hz,); 7.39 (d, J=8.2 Hz,), total 2H, 7.02 (d, J=8.7 Hz, 2H), 4.20 (m, 2H), 3.94 (m); 3.69 (m), total 1H, 3.45 (m, 1H), 2.99 (m, 1H), 2.60 (m, 2H), 2.13 (m, 2H), 1.5-1.87 (m, 3H), 1.31 (t, J=7.1 Hz); 1.26 (t, J=7.1 Hz), total 3H; IR (CHCl3) 2983, 1731, 1540, 1489, 1373, 1073, 1012 cm-1 ; MS (FD) m/z 371 (100), 369 (75); UV (EtOH) 219.8 nm (ε 13 174), 281.4 (13 557); Anal. Calcd for C16H20BrNO2S: C, 51.90; H, 5.44; N, 3.78. Found: C, 51.61; H, 5.38; N, 3.88.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH:23]=O)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:32][N:33]([CH3:43])[S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH2:23][N:40]3[CH2:41][CH2:42][N:37]([S:34](=[O:35])(=[O:36])[N:33]([CH3:32])[CH3:43])[CH2:38][CH2:39]3)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)Nc2ncc(C=O)s2)C2CCCCC2)CC1
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Agent: Cl
Product: CN(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCN(C(=O)OC(C)(C)C)CC3)s2)CC1

Procedure:
Prepared in 55% (338 mg) yield as described in general procedure (B) from 4-[1-cyclohexyl-3-(5-formyl-thiazol-2-yl)ureido]-piperidine-1-carboxylic acid tert-butyl ester (436 mg, 1.0 mmol) and piperazine-1-sulfonic acid dimethylamide hydrochloride (230 mg, 1.0 mmol).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.P(Br)(Br)[Br:20]>O1CCCC1>[Br:20][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCCC1CCCCC1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: BrCCCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 5-cyclohexylpentanol (1.74 g., 10.25 mmol) and pyridine (0.94 g., 11.1 mmol) at 0° under argon was added phosphorus tribromide (1.21 g., 4.5 mmol) dropwise. The reaction mixture became viscous, therefore 25 ml tetrahydrofuran was added. This mixture was stirred for 1.5 hours at room temperature, then partitioned between ethyl ether and 5% aqueous hydrochloric acid. The organic portion was washed with a 5% sodium bicarbonate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a dark yellow oil. Purification by flash chromatography (silica, hexane) yielded the desired alkyl halide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br.[Br:13][CH2:14][CH2:15][NH2:16].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:13][CH2:14][CH2:15][NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCBr
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCCBr)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a stirred mixture of 4-chlorobenzenesulfonyl chloride (5.0 g, 23.7 mmol) and 2-bromoethylamine hydrobromide (5.4 g, 26.3 mmol) in anhydrous methylene chloride (50 mL) at 0° C. was slowly added N,N-diisopropylethyl amine (8.6 mL, 52.1 mmol) and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was washed sequentially with water, 2N aqueous hydrochloric acid, saturated aqueous sodium carbonate, and saturated aqueous sodium chloride. The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo to afford a white solid (7 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, 2H, J=8.7 Hz), 7.52 (d, 2H, J=8.7 Hz), 4.96 (s, 1H), 3.50-3.30 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11](CCl)[CH:12]=[O:13].[OH-].[Na+].[CH2:18](O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:18]=[C:12]([OH:13])[CH:11]=[N:10]1
Reactant: O=CC(CCl)=NNc1ccc(Cl)cc1Cl
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cnn(-c2ccc(Cl)cc2Cl)c1
Yield: 87 %

Procedure:
27.0 g of 3-chloropyruvaldehyde 2,4-dichlorophenylhydrazone is suspended in 100 ml of ethanol. To the suspension is added at room temperature 12 g of sodium hydroxide dissolved in 10 ml of water. After stirring the mixture for 2 hours ethanol is distilled off, and water is added to the resultant residue to dissolve it. Insolubles are removed by filtration, and the filtrate is neutralized with glacial acetic acid. The precipitate is recovered by filtration, washed with water and dried. Recrystallization from toluene results in 17.3 g of the subject compound in the yield of 87%.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>CN(C=O)C.O>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: c1nc[nH]n1
Reactant: N#Cc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1-n1cncn1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
To a solution of 2,5-dichlorobenzonitrile (10 g, 58.1 mmol) in DMF (100 ml) is added cesium carbonate (22.7 g, 69.8 mmol) and 1,2,4-triazole (4.8 g, 69.8 mmol) and the reaction mixture is stirred at 65° C. for 5.5 h, at 75° C. for 16 h, at 85° C. for 7 h. More 1,2,4-triazole (5 g) is added and the reaction mixture is stirred at 85° C. for 18 h and at 100° C. for 4 h. After cooling to room temperature, the mixture is diluted with water and extracted with EtOAc 3 times. The combined organic layer is washed with aqueous LiCl, dried on sodium sulfate, concentrated in vacuo to give 5-Chloro-2-[1,2,4]triazol-1-yl-benzonitrile as a white solid which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: C1COCCN1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N2CCOCC2)s1
Yield: 52 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using morpholine instead of rac-2-amino-1-butanol, to the title compound (98 mg, 52%) which was obtained as a colourless gum after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=376.3 [M+H]+.
Reaction SMILES: COC1C=CC(C[O:8][C@@H:9]2[C@@H:17]([CH:18]=[CH2:19])[O:16][C@H:15]3[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]3)[C@H:10]2[O:23]CC2C=CC(OC)=CC=2)=CC=1.C(O)(C(F)(F)F)=O.[NH4+].[OH-]>ClCCl>[CH3:22][N:20]([CH3:21])[C:13]1[S:14][C@H:15]2[O:16][C@H:17]([CH:18]=[CH2:19])[C@@H:9]([OH:8])[C@H:10]([OH:23])[C@H:11]2[N:12]=1
Reactant: C=C[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](O)[C@@H]1O
Reaction time: 0.17 h
Yield: 32.2 %

Procedure:
A solution of above crude product 40 (220 mg, purity 57% by LC-MS) in dichloromethane (10 mL) was treated with TFA (1 mL) for 4 hours at room temperature. The solution was adjusted to pH at 8 with NH4OH, and then condensed to give a crude product, which was purified by Prep-HPLC with the following conditions (Agilent 1200 prep HPLC: Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, WATER with 0.03% NH4OH and CH3CN (10% CH3CN up to 45% in 10 min; Detector, UV 220 nm) to provide compound 43 (Example 7) as a white solid (35.7 mg). (ES, m/z): 245.0. 1H NMR (300 MHz, D2O) δ 6.20-6.22 (d, J=6.3 Hz, 1H), 5.79-5.87 (m, 1H), 5.30-5.38 (m, 2H), 3.98-4.08 (m, 2H), 3.87-3.91 (t, J=6.0 Hz, 1H), 3.46-3.52 (m, 1H), 2.93 (s, 6H).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:32])=[C:25]([C:28]([NH:30][CH3:31])=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:33])[CH:12]=[C:11]([CH3:34])[N:10]=1)C1C=CC=CC=1.[CH3:35]O>[Pd]>[CH3:33][C:13]1[CH:12]=[C:11]([CH3:34])[NH:10][C:9](=[O:8])[C:14]=1[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[C:24]([CH3:32])=[C:25]([C:28]([N:30]([CH3:31])[CH3:35])=[O:29])[CH:26]=[CH:27][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: CO
Reactant: CNC(=O)c1ccc2c(c1C)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CCO2
Agent: [Pd]
Product: Cc1cc(C)c(CN2CCOc3ccc(C(=O)N(C)C)c(C)c3C2=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-N,6-dimethyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide (130 g, 0.17 g, 0.36 mmol) and Pd/C (93 mg) in MeOH (15 mL) was stirred at room temperature under an H2 balloon for 2 hours. The reaction mixture was concentrated under vacuum to give the title compound (Example 130, 130 mg, 94%) as a white solid. 1H NMR (400 MHz, chloroform-d): δ 11.34 (s, 1H), 7.18-7.16 (d, 1H), 6.88-6.86 (d, 1H), 5.97 (s, 1H), 4.90-4.86 (d, 2H), 4.12 (s, 1H), 3.93 (s, 1H), 3.53 (s, 2H), 3.13 (s, 3H), 2.85 (s, 3H), 2.36-2.35 (d, 6H), 2.27 (s, 3H); MS 256.8 [M+H].
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][S:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)(=[O:19])=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]([C:38]2[C:39]([CH3:46])=[C:40]([CH:44]=O)[NH:41][C:42]=2[CH3:43])=[O:37])[CH2:32]1>N1CCCCC1.C(O)C>[OH:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]([C:38]2[C:39]([CH3:46])=[C:40](/[CH:44]=[C:23]3\[C:24](=[O:29])[NH:25][C:26]4[C:22]\3=[CH:21][C:20]([S:17]([CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:19])=[O:18])=[CH:28][CH:27]=4)[NH:41][C:42]=2[CH3:43])=[O:37])[CH2:32]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CC[C@@H](O)C1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3OCCN3CCOCC3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4OCCN4CCOCC4)cc32)c(C)c1C(=O)N1CC[C@@H](O)C1
Yield: 69.3 %

Procedure:
5-[2-(2-Morpholin-4-yl-ethoxy)-phenylmethanesulfonyl]-1,3-dihydro-indol-2-one (42 mg, 0.1 mmol) was condensed with 4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (24 mg, 0.1 mmol) and piperidine (1 drop) in ethanol (1.5 mL) at rt for 48 hours. The solvent was removed and the residue was purified on a silica gel column to give 44 mg (69%) of the titled compound.
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][C@H:42]1[CH2:46][CH2:45][CH2:44][C@@H:43]1[OH:47]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:41][C@H:42]4[CH2:46][CH2:45][CH2:44][C@@H:43]4[OH:47])=[O:40])=[CH:11][CH:12]=3)[CH:21]=2)[CH:27]=1
Reactant: N[C@H]1CCC[C@@H]1O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)N[C@H]3CCC[C@@H]3O)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1

Procedure:
Method as described for example 58 using intermediate 32 (100 mg, 0.18 mmol) and (1S,2S)-2-aminocyclopentanol (27 mg, 0.267 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound. (50 mg, 49%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[CH2:24]([NH:40][C:41]1[CH:42]=[C:43]([C:46](Cl)=[O:47])[S:44][CH:45]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CCOCC>[CH2:24]([NH:40][C:41]1[CH:42]=[C:43]([C:46]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:47])[S:44][CH:45]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: C1CCNCC1
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)Cl)c1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)N2CCCCC2)c1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 4-hexadecylamino-2-thiophenecarbonyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with water and dried. The solvent is removed in vacuo and the solid is recrystallized from ether to yield the product as a white solid.