Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:7]([CH:8]([O:11][Si](C)(C)C)[C:9]#N)=[C:6]([CH3:16])[N:5]=[C:4]2[S:17][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:3]=12.S(=O)(=O)(O)O.[OH-:29].[Na+].[C:31](OCC)(=[O:33])C>CO.O>[CH3:31][O:33][C:9](=[O:29])[CH:8]([C:7]1[C:2]([I:1])=[C:3]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:4]2=[N:5][C:6]=1[CH3:16])[OH:11]
Reactant: CCOC(C)=O
Reactant: Cc1nc2sc3c(c2c(I)c1C(C#N)O[Si](C)(C)C)CCCC3
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(O)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 70 °C
Reaction time: 36 h
Yield: 43 %

Procedure:
To a stirred suspension of 2-(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl)-2-trimethylsiloxyacetonitrile (Preparation 8, 168.0 g, 369.10 mMol) in methanol (2.5 L) was added concentrated sulphuric acid (410 mL, 7.38 Mol) at 5° C. The mixture was heated to 70° C. and stirred for 36 hours. After allowing the mixture to cool to room temperature, the mixture was diluted with water (1.0 L) and ethyl acetate (2.0 L), and then cooled to 5° C. The pH of the aqueous layer was adjusted to pH 8 by careful addition of 6 M aqueous sodium hydroxide solution. This resulted in the precipitation of solids. The solids were collected by filtration, and the filter-cake was washed with warm water (500 mL) and ethyl acetate (200 mL). The filtrate was saved for further manipulation. The filter-cake was suspended in methanol (500 mL) and stirred vigorously until the solid was free flowing. The solids were collected by filtration and the filter-cake was washed with methanol (2×200 mL) and diethylether (2×200 mL). The resulting solid was dried at 50° C. for 16 hours. This gave the title compound (66.5 g, 43%) as a white solid. The layers of the saved filtrates were separated and the organic layer was concentrated under reduced pressure. The resulting residue was triturated with methanol (100 mL), ethyl acetate (100 mL) and diethylether (100 mL). The resulting solid was collected by filtration and dried at 50° C. for 16 hours. This gave an additional portion of the title compound (38.3 g, 25%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[C:13]3[C:14]([O:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:15][O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:26][CH2:27][C:28]1([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([CH2:6][O:7][C:8]2[C:13]3[C:14]([O:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([CH2:26][CH2:27][C:28]5([C:34]([O:36][CH3:37])=[O:35])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[CH2:23][CH2:24]4)=[N:15][O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1(CC=O)CCOCC1
Reactant: c1cc(OCC2CCCC2)c2c(OCC3CCNCC3)noc2c1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CCN2CCC(COc3noc4cccc(OCC5CCCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclopentylmethoxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 22, Step 2) and methyl 4-(2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (WO 2004/043958) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25](S(C)(=O)=O)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].NCCC[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C1COCC1.CN(C)C(=O)C>[C:1]([O:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([CH2:9][CH2:8][CH2:7][NH:6][N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCCN1CCOCC1
Reactant: CC(C)(C)ONc1ccccc1NC(=O)c1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)ONc1ccccc1NC(=O)c1ccc(-c2ccnc(CCCNN3CCOCC3)n2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 193.7 %

Procedure:
N-(2-t-Butoxyaminophenyl)-4-(2-methylsulfonyl-pyrimidin-6-yl)benzamide (Method 21, 62.5 mg, 0.133 mmol) was dissolved in a mixture of THF (2 ml) and N,N-dimethylacetamide (2 ml) and N-(3-aminopropyl)morpholine (60 μl 0.411 mmol) added. The reaction mixture was heated to 50° C. and stirred for 2 hours. The reaction mixture was then cooled and solvents removed under reduced pressure. The resultant oil was purified by elution through silica with a 5% methanol in dichloromethane, to yield the title compound as a colourless solid (65 mg, 92%); NMR Spectrum: (DMSO-d6) 1.45 (s, 9H), 1.74 (m, 2H), 2.37 (m, 6H), 3.40 (br, 2H), 3.59 (m, 4H), 7.20 (m, 2H), 7.23 (d, 1H), 7.34 (t, 1H), 7.57 (d, 1H), 8.08 (d, 2H), 8.26 (d, 2H), 8.40 (m, 1H), 8.72 (s, 1H), 9.94 (s, 1H); Mass Spectrum: M+H+ 534.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][CH:12]1[CH2:16][O:15][C:14](=[S:17])[NH:13]1.C(N(CC)CC)C>C1COCC1>[S:17]=[C:14]1[NH:13][CH:12]([CH2:11][O:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][O:15]1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC1COC(=S)N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCC1COC(=S)N1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.2 %

Procedure:
A solution of benzoyl chloride (14.6 mL, 126.1 mmol) in dry THF (50 mL) was added to a solution of 4-hydroxymethyl-1,3-oxazolidine-2-thione (14.0 g, 105.1 mmol) in dry THF (250 mL) and triethylamine (17.5 mL, 126.1 mmol) at 0° C. After 12 hours of stirring at room temperature, triethylamine hydrochloride was filtered off, and the solvent was distilled out in vacuo. The residue was purified by silica gel column chromatography eluted with ethyl acetate/acetone (1/1=v/v), followed by recrystallization from a mixed solvent [n-hexane/ethyl acetate (3/1=v/v)] to afford benzoic acid 2-thioxo-oxazolidin-4-ylmethyl ester as a colorless solid (20.5 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23](O)=[O:24])=[CH:19][CH:18]=2)=[O:14])[CH:3]=1.Cl.CN.F[B-](F)(F)F.[N:36]1(OC(N(C)C)=[N+](C)C)[C:40]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(#N)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([NH:36][CH3:40])=[O:24])=[CH:26][CH:27]=2)=[O:14])[CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOc1nc(C(=O)NCc2ccc(OCC(=O)O)cc2)cc(N)c1C#N
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(C(=O)NCc2ccc(OCC(=O)NC)cc2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of Example 188B (19 mg, 0.05 mmol), methylamine HCl salt (7 mg, 0.1 mmol) in N,N-dimethylformamide (500 μL) was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (18 mg, 0.055 mmol), followed by N,N-diisopropylethylamine (44 μL). The reaction mixture was stirred at ambient temperature for 1 hr. It was diluted with 1 mL acetonitrile and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to provide the titled compound as white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.95 (t, J=6.4 Hz, 1H), 8.00-7.94 (m, 1H), 7.29 (bs, 2H), 7.23 (d, J=8.9 Hz, 2H), 7.07 (s, 1H), 6.91 (d, J=8.9 Hz, 2H), 4.49 (q, J=7.1 Hz, 2H), 4.42 (s, 2H), 4.40 (d, J=6.4 Hz, 2H), 2.65 (d, J=4.6 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H). MS (m/e) 384 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.N#N.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:13]([OH:18])[OH:14])[CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C=CCCCc1ccccc1Br
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCCCc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
This compound was prepared according to the procedure described by Watson, I.D.G.; Ritter, S.; Toste, F.D. J. Am.Chem.Soc. 2009, 131, 2056-2057. 1-Bromo-2-(pent-4-en-1-yl)benzene (480 mg, 2.132 mmol) was dissolved in a mixture of toluene (8 mL) and THF (2 mL). Then triisopropyl borate (0.490 mL, 2.132 mmol) was added. While under N2 atmosphere, the reaction mixture was cooled to −78° C. Using a manual syringe, n-butyllithium (0.853 mL, 2.132 mmol)(2.5 M in hexanes) was added dropwise over the course of 30 min. The resulting nearly colorless solution was stirred at −78° C. for 60 min and then at −20° C. for 15 min. The reaction was quenched with 10 mL of 2 N HCl and allowed to stir to warm to rt. The aqueous layer was extracted with ether. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. Biotage purification eluting with 5-50% EtOAc/hexanes gave the desired product (65 mg, 0.342 mmol, 16.04% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.27-8.18 (m, 1H), 7.51 (td, J=7.5, 1.4 Hz, 1H), 7.36-7.31 (m, 2H), 5.90-5.80 (m, 1H), 5.04-4.91 (m, 2H), 3.26-3.18 (m, 2H), 2.18 (q, J=6.9 Hz, 2H), 1.83 (dt, J=15.3, 7.7 Hz, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][O:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>CO.ClCCl>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][O:8][NH2:9]
Reactant: O=C1c2ccccc2C(=O)N1OC[C@H]1COCCO1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: NOC[C@H]1COCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
2L (4.30 g, 12.4 mmol) was dissolved in 90 mL of methanol/dichloromethane 1/9 ratio. Hydrazine hydrate (1.67 mL, 22.4 mmol) was added and the reaction was stirred at room temperature for 2 h at which time the deprotection was done. The precipitate byproduct was filtered, and the filtrate was concentrated down to an oil and then purified by flash column chromatography, using chloroform/methanol 99/1 ratio to yield (R)—O-((1,4-dioxan-2-yl)methyl)hydroxylamine (2M, 0.915 g, 61.4% yield over 2 steps). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.41 (t, J=10.86 Hz, 1H) 3.57-3.71 (m, 4H) 3.71-3.82 (m, 3H) 3.83-3.92 (m, 1H) 5.55 (br. s., 2H).
Reaction SMILES: [C:1]1([C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:17]3[C:22]=2[CH:21]=[C:20]([O:23][C:24](=[O:26])[CH3:25])[CH:19]=[CH:18]3)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:37]1(C(Cl)=O)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44]C=2)[CH:40]=[CH:39][CH:38]=1.C(OC1C=CC=C2C=1C=CC(OC(=O)C)=C2)CCCC>C(Cl)Cl>[C:1]1([C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:17]3[C:22]=2[CH:21]=[C:20]([O:23][C:24]([C:25]2[C:46]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:42]=[CH:43][CH:44]=2)=[O:26])[CH:19]=[CH:18]3)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCCCCOc1ccc(C(=O)c2cccc3ccccc23)c2cc(OC(C)=O)ccc12
Agent: CCCCCOc1cccc2cc(OC(C)=O)ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCOc1ccc(C(=O)c2cccc3ccccc23)c2cc(OC(=O)c3cccc4ccccc34)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Acetic acid 8-(naphthalene-1-carbonyl)-5-pentyloxynaphthalen-2-yl ester: To a stirred suspension of anhydrous aluminium chloride (4.42 g, 33.09 mmol) in anhydrous DCM (290 mL) at 0° C. under nitrogen is added dropwise a solution of naphthoyl chloride (3.7 mL, 24.8 mmol) in anhydrous DCM (35 mL). After 15 min, a solution of acetic acid 5-pentyloxynaphthalen-2-yl ester (4.5 g, 16.54 mmol) in anhydrous DCM (70 mL) is added, and the reaction mixture is allowed to warm to room temperature and stir for 20 h. The mixture is washed with saturated sodium hydrogen carbonate solution, the phases separated and the DCM removed under reduced pressure. The residue is taken up in diethyl ether and washed with water, dried (MgSO4) and the solvent removed under reduced pressure. Purification by chromatography on silica gel (1–3% ethyl acetate in cyclohexane) affords the desired product (4.8 g, 68%) and naphthalene-1-carboxylic acid 8-(naphthalene-1-carbonyl)-5-pentyloxynaphthalen-2-yl ester (2.1 g), arising from naphthoyl replacement of the acetyl group.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[C:12]=1[N:20]=[C:21]=[S:22])([CH3:10])[CH3:9].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:18])[CH3:19])[C:12]=1[N:20]1[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:21]1=[S:22])([CH3:9])[CH3:10]
Reactant: CCNCC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2c(C(C)C)cccc2C(C)C)C1=S
Yield: 27 %

Procedure:
A mixture of the crude N-ethyl glycine (18.4 g), 2,6-diisopropylphenyl-isothiocyanate (21.9 g), triethyl amine (20.2 g) and chloroform (300 mL) was heated at reflux for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1N HCl (2×300 mL), then evaporated to dryness. Purification was achieved through crystallization from ethanol. The title compound (8.2 g) was obtained as a light yellow solid, m.p. 159°-161° C. Anal. Calcd. for. C17H24N2OS: C, 67.07; H, 7.94; N, 9.20. Found: C, 66.92; H, 8.03; N, 9.13. Mass spectrum (PBEI, M.+) m/z 304.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Product: CC(C)(C)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Yield: 66.8 %

Procedure:
Using the procedure in Example 118A, 3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-amine (996 mg, 3.67 mmol) and phenyl chloroformate (1.40 mL, 11.0 mmol) were reacted to give phenyl 3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-ylcarbamate (957 mg, 2.45 mmol, 66%). 1H NMR (300 MHz, DMSO-d6) δ 10.05 (br s, 1H), 7.56-7.08 (m, 8H), 6.77 (s, 1H), 6.33 (s, 1H), 1.33 (s, 9H), 1.28 (s, 9H); LC-MS (ESI) m/z 392 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].C(O[C:41]([N:43]([CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)C)=O)(C)(C)C>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:47]3[CH2:48][CH2:49][CH:45]([NH:43][CH3:41])[CH2:46]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CNC1CCN(c2cc(-c3ccccc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)C1
Yield: 50.1 %

Procedure:
In a similar manner to Example 11, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (40.0 mg) was reacted with 3-(N-(t-butoxycarbonyl)-N-methylamino)pyrrolidine (38.9 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-9-[3-(methylamino)pyrrolidine-1-yl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (22.5 mg, 50%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]2=[O:24])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:26]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:57][C@@H:58]([CH2:88]O)[CH2:59][N:60]1[CH:64]=[CH:63][C:62]([NH:65]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:61]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][C:13]2=[O:24])[C:9]([NH:65][C:62]2[CH:63]=[CH:64][N:60]([CH2:59][C:58]([OH:57])([CH3:88])[CH3:26])[N:61]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2)=CC1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3)=CC2=O)n1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-(2-oxo-4-phenoxy-2,5-dihydro-pyrrol-1-yl)-propionic acid (80 mg, 0.2 mmol) in dichloromethane (8 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (137 mg, 0.7 mmol) and N,N-diisopropylethylamine (155 mg, 1.2 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (110 mg, 0.7 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 37 mg, 0.2 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(2-oxo-4-phenoxy-2,5-dihydro-pyrrol-1-yl)-propionamide (21 mg, 19%) as an off-white gummy solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.83-1.08 (m, 2H), 1.13 (s, 6H), 1.24 (s, 3H), 1.58-2.06 (m, 8H), 3.77 (br. s., 1H), 3.91 (s, 2H), 4.08 (d, J=18.1 Hz, 1H), 4.32 (d, J=18.1 Hz, 1H), 4.87-4.96 (m, 1H), 4.96 (s, 1H), 6.67 (s, 1H), 7.15 (d, J=7.8 Hz, 2H), 7.20-7.31 (m, 1H), 7.39 (t, J=7.8 Hz, 2H), 9.01 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25](O)=[O:26])=[O:14])[N:4]=1.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:25]([C:17]1[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=2[S:20][C:16]=1[NH:15][C:13](=[O:14])[CH2:12][N:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:3]([C:2]([F:29])([F:28])[F:1])=[N:4]1)=[O:26]
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1sc2c(c1C(=O)O)CCCC2
Reactant: CN(C)CCN
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2

Procedure:
2-[2-(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (50 mg, 0.117 mmol) was dissolved in a solution of DCM (2 mL) and DMF (0.4 mL). O-(7-azabenzotriazol-1-yl)-N,N′,N′,N′-tetramethyluronium hexafluorophosphate (54 mg, 0.141 mmol) was added, followed by N,N-dimethylethylenediamine (15.5 μL, 0.141 mmol) and N,N-diisopropylethylamine (24.6 μL, 0.141 mmol). The resultant mixture was stirred at RT overnight. The solvent was removed under reduced pressure, and the residue obtained purified by preparative reverse phase HPLC, to afford the title compound, a colourless oil, as the TFA salt (52 mg, 0.084 mmol, 72%).
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[C:21](=[O:25])[CH2:22][CH2:23][CH3:24]>CCO>[CH2:23]([CH:22]([C:21](=[O:25])[C:14]1[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[CH3:12])[C:3](=[O:5])[C:2]([O:9][CH2:10][CH3:11])=[O:8])[CH3:24]
Reactant: CCCC(=O)c1c(C)cc(C)cc1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C(CC)C(=O)c1c(C)cc(C)cc1C
Temperature: 50 °C
Yield: 53.2 %

Procedure:
Sodium (1.0 g, 42.1 mmol, spheres) was cautiously added to 25 mL of absolute EtOH with stirring. After the sodium had dissolved, diethyl oxalate (6.0 g, 42.1 mmol) was added dropwise to the resulting solution at 0° C., followed by addition of a solution of 2',4',6'-trimethylbutyrophenone (8 g, 42.1 mmol) in 5 mL of absolute EtOH. The reaction mixture was slowly warmed to 50° C. and stirred overnight. The solvent was then evaporated. The resulting residue was washed with hexane, diluted with water, acidified with 1 N HCl, and then extracted with ether. The extracts were washed with brine, dried over Na2SO4 and concentrated to give 6.5 g of an oil which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](O)=O.N[C@@H](CCCC)[C:12]([OH:14])=O.[NH2:19][C@H](CCCCC)C(O)=O.N[C@H](CCCCCC)C(O)=O.NC(CCCCCC)C(O)=O>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][C:12](=[O:14])[NH2:19]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CCCCC[C@@H](N)C(=O)O
Reactant: CCCC[C@H](N)C(=O)O
Agent: CCCCCCC(N)C(=O)O
Agent: CCCCCC[C@@H](N)C(=O)O
Product: NC(=O)CC[C@H](N)C(=O)O

Procedure:
In a similar manner using the dimethyl esters of (S)-aspartic acid, (S)-2-aminohexanoic acid, (R)-2-aminoheptanoic acid, (R)-2-aminooctanoic acid, (RS)-2-aminooctanoic acid, and the methyl ester of (S)-glutamine in place of (S)-glutamic acid dimethyl ester, there were obtained 2-[4-(2(R)-carboxypyrrolidine-1-sulfonyl)benzoylamino]butane-(S)-dioic acid, MS: calc. 414, obs. 415 (M+H), 2-[4-(2(R)-carboxypyrrolidine-1-sulfonyl)benzoylamino]hexane-(S)-dioic acid, MS: calc. 442, obs. 443 (M+H), 2-[4-(2(R)-carboxypyrrolidine-1-sulfonyl)benzoylamino]heptane-(S)-dioic acid, MS: calc. 456, obs. 457 (M+H), 2-[4-(2(R)-carboxypyrrolidine-1-sulfonyl)benzoylamino]octane-(R)-dioic acid, MS: calc. 470, obs. 471 (M+H), 2-[4-(2(R)-carboxypyrrolidine-1-sulfonyl)benzoylamino]octane-(RS)-dioic acid, MS: calc. 470, obs. 471 (M+H), and 4-aminocarbonyl-2-[4-(2(R)-carboxypyrrolidine-1-sulfonyl)benzoylamino]-(S)-butanoic acid, MS: calc. 427, obs. 428 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[N:32][NH:33][CH:34]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:16][CH:17]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Product: CN1CCC(c2ccc(Cl)cc2)(c2ccc(-c3cn[nH]c3)cc2)CC1

Procedure:
4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-1-methyl-piperidine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 12.90 [M+H]+352. 1H NMR (Me-d3-OD) δ 2.41-2.53 (2H, m), 2.82 (3H, d), 2.97-3.12 (4H, m), 3.56-3.59 (2H, m), 7.28 (2H, s), 7.34 (1H, m), 7.42 (1H, d), 7.49 (1H, d), 7.54 (1H, d), 7.61 (1H, d), 7.75 (1H, d), 8.52 (2H, d).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=O.[NH2:13][C:14]([NH2:16])=[O:15].[OH-].[Na+]>CC(O)=O>[NH:13]1[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8](=[O:10])[NH:16][C:14]1=[O:15]
Reactant: NC(N)=O
Reactant: CCOC(=O)C1CCCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1[nH]c2c(c(=O)[nH]1)CCCC2
Temperature: 180 °C
Reaction time: 4.5 h
Yield: 38.6 %

Procedure:
A mixture of ethyl 2-oxocyclohexanecarboxylate (66 g, 0.39 mol) and urea (68 g, 1.1 mol) was heated at 175-185° C. and stirred for 4-5 h. After cooled to 70° C., adjusted pH=13-14 by NaOH (a.q.), and then the mixture was stirred at 70° C. for 2 h. After cooled to r.t, the mixture was adjusted pH=6-7 by AcOH, and then extracted with DCM for several times. The combined organic layer was dried and evaporated to give the title compound (25 g, 39% yield) as brown solid which was set to do next step without any purification. MS: m/z 167.3 [M+H]+.