Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[N:15]=[CH:16][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH2:30][C:31]([O:33]CC)=[O:32])=[N:22]2)=[N:18][CH:19]=1)=[O:12].O.[OH-].[Li+]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[N:15]=[CH:16][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH2:30][C:31]([OH:33])=[O:32])=[N:22]2)=[N:18][CH:19]=1)=[O:12]
Reactant: CCOC(=O)Cc1nn(Cc2cnc(NC(=O)c3ccc4ccccc4c3)cn2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1nn(Cc2cnc(NC(=O)c3ccc4ccccc4c3)cn2)c2ccccc12
Yield: 29.7 %

Procedure:
Ethyl 2-[1-[[5-(2-naphthamido)pyrazin-2-yl]methyl]-1H-indazol-3-yl]acetate (0.466 g, 1.0 mmol) was dissolved in 20 mL tetrahydrofuran, and in an ice bath, was added 10 mL aqueous solution dissolving lithium hydroxide monohydrate (0.18 g, 4.3 mmol). It was reacted at room temperature for 3 h, rotate evaporated to dryness to remove the solvent, purified by preparative liquid phase (methanol:water=50%) to obtain a white solid 130 mg, at a yield of 29.7%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([CH3:39])[N:33]([CH:40]1[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])[C:32]2=[O:48]>CN(C=O)C>[O:47]=[C:41]1[CH:40]([N:33]2[C:32](=[O:48])[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([CH2:28][NH:27][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=4)[CH:30]=3)[N:35]=[C:34]2[CH3:39])[CH2:45][CH2:44][C:43](=[O:46])[NH:42]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(CNC(=O)c3ccc(C(F)(F)F)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a stirred solution of 4-trifluoromethyl-benzoic acid (0.30 g, 1.6 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′ carbonyldiimidazole (0.29 g, 1.8 mmol), and the mixture was stirred for one hour. Then 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.54 g, 1.6 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethyl-benzamide as an off-white solid (500 mg, 67% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.33 min (99.1%); mp, 221-223° C.; 1HNMR (DMSO-d6) 2.14-2.20 (m, 1H, CHH), 2.56-2.88 (m, 6H, CHCH2, CH3), 4.62 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.59-8.11 (m, 7H, Ar), 9.40 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.90, 23.41, 30.60, 42.41, 56.53, 120.03, 123.90 (q, JC-F=253 Hz), 123.95, 125.36 (d, JC-F=3 Hz), 125.45 (d, JC-F=3 Hz), 126.65, 128.14, 131.23 (d, JC-F=31 Hz), 134.11, 137.83, 145.87, 154.64, 160.42, 165.12, 169.45, 172.59. LCMS MH=473; Anal Calcd For C23H19N4O4F3: C, 58.48; H, 4.05; N, 11.86; F, 12.06. Found: C, 58.36; H, 3.96; N, 11.75; F, 11.84.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH3:30])=[O:18].Br[C:32]1[S:33][C:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])=[CH:35][CH:36]=1>>[CH2:40]([S:37]([C:34]1[S:33][C:32]([C:6]2[CH:5]=[CH:4][C:3]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])=[O:18])=[C:2]([F:1])[CH:7]=2)=[CH:36][CH:35]=1)(=[O:39])=[O:38])[CH3:41]
Reactant: CCS(=O)(=O)c1ccc(Br)s1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCC[C@H]3C)c(F)c2)s1
Yield: 35 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone (458 mg, 1.1 mmol) and 2-Bromo-5-ethanesulfonyl-thiophene (255 mg, 1.0 mmol) to give 165 mg (35% yield). MS (ES+) 465.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][OH:28])[O:24][C:23]2=[O:29])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][O:28][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[O:24][C:23]2=[O:29])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(N3CC(CO)OC3=O)cc2F)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CN(c3cc(F)c(N4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)C(=O)O2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
The [3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methanol (24.2 g, 59 mmol) was dissolved in pyridine (110 mL) and then cooled to 0° C. (ice bath). Freshly recrystalized p-toluenesulfonyl chloride (13.4 g, 70 mmol) of was added and the reaction was allowed to stir at 0° C. for 2.5 hours under N2. The flask was then stoppered and stored in the refrigeratior (5° C.) overnight. The reaction mixture became a pale pink slurry. TLC revealed that some alcohol still remained. The reaction mixture was treated with additional p-toluenesulfonyl chloride (1.12 g, 5.85 mmol), catalytic 4-(dimethylamino)pyridine, and 20 mL of dry CH2Cl2 to facilitate stirring. After 4 hours at 0° C., the reaction was found to be complete by TLC (5% MeOH/CH2Cl3, UV short wave). The mixture was added to 750 mL ice water and the precipitated product isolated via suction filtration, washing it with both water (1 L) and ether (500 mL). After drying in vacuo, 29.921 g (90%) of the title compound was obtained as white solid with mp 150.5°-151.5° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: OCCN1CCOCC1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Nc1nc(OCCN2CCOCC2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, N-(2-hydroxyethyl)morpholine and DBU in THF. ES-MS m/e (%): 417 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Si]([N:11]=[C:12]=[O:13])(C)C>C(O)(C)C>[N:1]1([C:12]([NH2:11])=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=C=O
Reactant: C1COCCN1
Solvent: CC(C)O
Product: NC(=O)N1CCOCC1
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To a stirred solution of morpholine (1.3 mL, 15 mmol) in isopropanol (30 mL) at rt was added trimethylsilylisocyanate (2.8 mL, 21 mmol) and the resulting solution stirred overnight before the volatiles were removed in vacuo to give morpholine-4-carboxylic acid amide (2.0 g, quant.) as a solid; 1H-NMR (300 MHz, d6-DMSO) 6.00 (2H, s), 3.51-3.54 (4H, s), 3.23-3.26 (4H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH:13]([Br:15])[CH3:14].O>CN(C)C=O>[Br:15][CH:13]([CH3:14])[CH2:12][CH2:11][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Br)CCBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Br)CCOc1cccnc1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (1.00 g, 10.52 mmol) in N,N-dimethylformamide (DMF) (10 mL) was slowly added to a cold (0° C.), stirring slurry of sodium hydride (0.50 g of an 60% dispersion in mineral oil, 12.63 mmol) in DMF (5 mL). After stirring 30 min, 1,3-dibromobutane (2.50 g, 11.57 mmol) was slowly added drop-wise. The resulting mixture was stirred at 0-4° C. for 16 h. Cold water (10 mL) was added, and the mixture was extracted with ether (3×100 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to give 2.23 g (92.5%) of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[C:10]=1[CH3:11].C([O-])(O)=O.[Na+].CCOC(C)=O.[CH3:23][N:24](C=O)C>>[CH3:11][C:10]1[C:6]2[NH:7][CH:8]=[N:9][C:5]=2[CH:4]=[CH:3][C:2]=1[C:23]#[N:24]
Reactant: CN(C)C=O
Reactant: Cc1c(Br)ccc2nc[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c(C#N)ccc2nc[nH]c12
Temperature: 150 °C
Reaction time: 5 h

Procedure:
In a 100 ml reaction vessel, to a solution of 6-bromo-7-methyl-1H-benzimidazole (500 mg) in DMF were added Zu(CN)2 (834 mg) and Pd (PPh)4 (547 mg) at room temperature, followed by stirring at 150° C. for 5 hours. The reaction solution was poured into a 1:1 mixed solvent of a saturated NaHCO3 solution and EtOAc, followed by stirring for 1 hour. The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. It was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=98:2 to 90:10) to obtain 7-methyl-1H-benzimidazole-6-carbonitrile (161.8 mg) as a brown solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([O-])=O.[K+].IC1[CH:14]=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:24])[F:23])[C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:18][C:17]=2[CH:31]=1>C1(C)C=CC=CC=1.CN(C=O)C.[Cu]I>[F:7][C:3]([F:8])([C:4]1[CH:14]=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:23])[F:24])[C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:18][C:17]=2[CH:31]=1)[C:2]([F:10])([F:9])[F:1]
Reactant: CCOC(=O)C1=Cc2cc(I)ccc2OC1C(F)(F)F
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(C(F)(F)C(F)(F)F)ccc2OC1C(F)(F)F
Temperature: 120 °C

Procedure:
Potassium pentafluoropropionate (0.476 g, 2.35 mmol) was dissolved in toluene (6 mL) and DMF (6 mL). The vessel was fitted with a distilling head, and CuI (0.471 g, 2.474 mmol) was added with stirring. The reaction was heated to 120° C., removing the toluene by distillation. Ethyl 6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 72, Step 3) (0.469 g, 1.178 mmol) was added and the reaction was heated to 150° C. for 2 hours. The reaction was allowed to cool to room temperature and was partitioned between diethyl ether and H2O. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel 60, eluant:hexanes-ethyl acetate, 8:1) yielding, upon concentration of the solution, the desired ester (0.096 g, 21%) as a tan solid mass of suitable purity to use without further purification: 1H NMR (acetone-d6/300 MHz) 8.04 (s, 1H), 7.91 (d, 1H, J=2.2 Hz), 7.74 (dd, 1H, J=8.7, 2.2 Hz), 6.00 (q, 1H, J=7.1 Hz), 4.42–4.24 (m, 2H), 1.34 (t, 3H, J=7.3 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5].[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:4]=1[NH:5][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)F)cc1Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 60 h

Procedure:
To an ice cooled solution of 2-Methoxy-5-trifluoromethylaniline (311 mmol, 59.4 g) in 500 ml dry dimethylformamide is added sodiumhydride (438 mmol, 17.5 g 60%) followed by slow addition of 2-chloro-5-trifluoromethyl-nitrobenzene (311 mmol, 47.4 ml) and the mixture is stirred for 60 hours. More sodiumhydride (10 g 60%) is added and after stirring for additional two hours is another portion of 2-chloro-5-trifluoromethyl-nitrobenzene (5 ml) and sodiumhydride (2 g 60%) added. Upon completion is the reaction mixture poured into water and a black precipitate is formed. The crude product is filtered of and is washed with 1M HCl and petroleum ether yielding the title compound as grey crystals, M.p. 86°-88° C.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH3:36])[CH:28]=3)[C:24]([CH3:37])=[CH:23][N:22]=2)=[C:13]([O:38][CH3:39])[CH:12]=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:24]([CH3:37])=[CH:23][N:22]=3)=[C:13]([O:38][CH3:39])[CH:12]=2)[CH2:6]1
Reactant: CN(C)C1CNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 71.6 %

Procedure:
N,N-dimethylazetidin-3-amine (Intermediate 26, 113 mg, 0.65 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)-pyrimidin-2-amine (Intermediate 79, 250 mg, 0.61 mmol) and DIPEA (0.374 mL, 2.15 mmol) in 2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at 140° C. for 1 h. The cooled mixture was purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (213 mg, 71%) as an orange foam; 1H NMR: 2.13 (6H, s), 2.37 (3H, s), 3.09-3.16 (1H, m), 3.72 (2H, dd), 3.89 (3H, s), 3.93 (3H, s), 4-4.08 (2H, m), 6.27 (1H, s), 7.04 (1H, t), 7.20-7.26 (1H, m), 7.49 (1H, d), 7.90 (1H, s), 8.03 (1H, s), 8.23 (1H, s), 8.35 (1H, d), 8.46 (1H, s); m/z: ES+ MH+ 488.63.
Reaction SMILES: O[CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].[K+].[Br-].[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>Cl(O)(=O)(=O)=O>[C:21]([O:24][C:11]1[S:12][C:4]2[CH:3]([N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[CH2:2][C:7]([CH3:9])([CH3:8])[O:6][C:5]=2[CH:10]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Agent: [Br-]
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)Oc1cc2c(s1)C(N1CCCC1=O)CC(C)(C)O2
Temperature: 0 °C

Procedure:
A solution of 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (2.0 g, 7.48 mmol) and perchloric acid (70%, 10 drops) in acetic anhydride (20 mL) were stirred for 1 h at 0°-5° C. The solution was poured into ice water (100 mL). The product was extracted into dichloromethane, washed with water (4×), and evaporated in vacuo. The resultant oil was purified by flash chromatography, using 1% methanol in dichloromethane as the eluant, then crystallized from hexanes to give the product, 2.12 g (92%), as a colorless solid: mp 92°-93° C.; IR (KBr): 1745 and 1684 cm-1 ; MS: 310 (MH+); 1H NMR (CDCl3): δ1.37(s, 3H), 1.38(s, 3H), 1.98(m, 2H), 2.10(s, 3H), 2.37(m, 2H), 3.24(m, 1 H), 3.40(m, 1H), 5.15(d, J=9.1 Hz, 1H), 5.44(d, J=9.1 Hz, 1H), 6.58(d, J=5.4 Hz, 1H) and 7.13(d, J=5.4 Hz, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc3ccccc3c2)cc1
Temperature: 120 °C
Yield: 95.2 %

Procedure:
28.2 g (200 mmol) of β-naphthol and 30.4 g (220 mmol) of potassium carbonate were mixed in 80 ml of dimethylformamide, 27.8 g (220 mmol) of benzyl chloride were added dropwise, and the mixture was heated at 120° C. for 2 hours. The residue formed was filtered off, and the filtrate was admixed with water to the onset of cloudiness. Filtration of the cold mixture and drying of the solid gave 44.6 g (95%) of β-naphthyl benzyl ether; melting point: 101° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[CH3:15].[H-].[Na+].[CH3:18]I>CN(C=O)C>[CH3:18][O:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[CH3:15]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of racemic (cis)-tert-butyl 4-hydroxy-3-methylpiperidine-1-carboxylate (310 mg, 1.44 mmol) (CAS#955028-93-0; prepared as described in US 20070249589)] in DMF (5 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 75 mg, 1.87 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and MeI (0.13 mL, 2.02 mmol) was added. After 2 h the reaction was quenched with saturated aqueous NH4Cl. The aqueous phase was washed three times with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (0-100% EtOAc/heptanes) to provide racemic (cis)-tert-butyl 4-methoxy-3-methylpiperidine-1-carboxylate. 1H NMR (400 MHz, CDCl3) δ ppm 3.36-3.50 (m, 6 H), 3.34 (dt, J=6.6, 3.3 Hz, 1 H), 3.22-3.29 (m, 1 H), 1.78-1.96 (m, 2 H), 1.49 (s, 9 H), 0.95 (d, J=6.8 Hz, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=O)=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:32]([N:35]1[CH2:40][CH2:39][NH:38][CH:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36]1)(=[O:34])=[O:33])[CH:26]=[CH:25]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2[S:14][C:15]([C:17]([N:38]3[CH2:39][CH2:40][N:35]([S:32]([C:27]4[CH:26]=[CH:25][C:24]5[C:29](=[CH:30][CH:31]=[C:22]([Cl:21])[CH:23]=5)[CH:28]=4)(=[O:34])=[O:33])[CH2:36][CH:37]3[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:19])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Reactant: CC(C)(C)OC(=O)C1Cc2nc(C(=O)O)sc2CN1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (30 ml), 6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (WO94/21599) (742 mg), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-ethoxycarbonylpiperazine hydrochloride (WO96/10022) (1.00 g) and benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP®) (1.50 g) were dissolved. Triethylamine (0.40 ml) was added to the resulting solution, followed by stirring overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue. The resulting mixture was washed with water and saturated aqueous NaCl solution and then, dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane ethyl acetate=4:1), whereby the title compound (505 mg, 30%) was obtained.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:17](O)[CH2:18][OH:19]>>[ClH:1].[OH:19][CH2:18][CH2:17][O:13][C:12](=[O:14])[C@H:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:16][CH:15]=1)[NH2:11]
Reactant: OCCO
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCO
Temperature: 82.5 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
Dry hydrogen chloride (68.3 g) was dissolved in ethylene glycol (994 mL) at <20° C. and then solid 4-nitro-(S)-phenylalanine (198.7 g) added with stirring. The mixture was heated to 80-85° C. and held at this temperature for 2 h. After a LC completion check, the preparation was allowed to drift to 60° C. and seeded with authentic product. Once crystallisation had initiated, the resulting suspension was cooled further to 20° C. and stirred out overnight. The 4-nitro(S)-phenylalanine hydroxyethyl ester hydrochloride was collected by filtration, washed in situ with dimethoxyethane (795 mL), and then dried in vacuo at 40-45° C. to constant weight (white powder m.p. 195-197° C., 187.0 g, 73.9% yield). 1H NMR (D6-DMSO): δ3.27 (2H, ddd); 3.42 (2H, m); 4.01 (2H, m); 4.27 (1H, t); 4.88 (1H, b,s); 7.52 (2H, d); 8.11 (2H, d); 8.76 (3H, b,s) ppm. Mass Spectrum: ESI+ (m/z+1) 255.0
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH3:1][CH:2]([S:4]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([CH:22]=[O:23])=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)(=[O:6])=[O:5])[CH3:3]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=Cc1ccc(OCCc2ccc(O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 72.9 %

Procedure:
3.77 g (13 mmole) 2-propanesulfonyl chloride dissolved in dichloromethane was slowly added to a solution of 3.2 g (13 mmole) 4-[2-(4-hydroxyphenyl)ethoxy]benzaldehyde and 2.63 g (26 mmole) triethylamine in 80 ml dichloromethane at 0° C. The temperature was slowly allowed to rise to room temperature and when the starting material was consumed the reaction mixture was poured on to ice. The phases were separated and the organic phase was washed with sodium carbonate, dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography on silica gel using dichloromethane as eluent to give 3.3 g (yield 72.8%) of 4-[2-(4-formylphenoxy)ethyl]phenyl 2-propanesulfonate.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:49]1[CH2:53][CH2:52][CH2:51][C@H:50]1[CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C=O)C>[F:17][C:10]1[CH:9]=[C:8]([C:6]2[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:16]=[CH:15][C:11]=1[C:12]([N:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1)=[O:14]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: N#Cc1ccc(-c2ccc(C(=O)O)c(F)c2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2ccc(C(=O)N3CCCC3CN3CCCC3)c(F)c2)s1
Yield: 9.2 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 6 mL DMF using 4-(5-Cyano-thiophen-2-yl)-2-fluoro-benzoic acid (248 mg, 1.0 mmol), EDC-HCl (287 mg, 1.5 mmol), HOBt (203 mg, 1.5 mmol), DIEA (0.43 mL, 2.5 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (131 mg, 0.85 mmol) to give the title compound (30 mg, 10% yield). MS (ES+) 384.2 (M+H)+