Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:24]([NH:31][C:9]1[C:10]([F:16])=[C:11]([F:15])[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O

Procedure:
A mixture of ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (28.2 g) prepared in Referential Example 1 (2), benzylamine (9.8 ml), anhydrous potassium carbonate (23.6 g), and acetonitrile (140 ml) was heated at 100°-110° C. for 1 hour to give ethyl 5-benzylamino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (21.4 g), which was recrystallized from ethanol, m.p. 134°-135° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>CCO>[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: O=Cc1cccc(OCC2CO2)c1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: O=Cc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Yield: 63 %

Procedure:
A solution of 3-(oxiran-2-ylmethoxy)benzaldehyde (1.0 g, 5.61 mmol) and 1,2,3,4-tetrahydroisoquinoline (1.49 g, 11.22 mmol) in EtOH (20 mL) was heated at 110° C. for 3 h. The solvent was then removed by concentration and the residue dissolved in ethyl acetate, washed with water and the separated organic layer dried and concentrated. The crude product was purified by column chromatography. (1.1 g, yield 63%.) MS (ESI+) e/z: 312.3 [M+1]+.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[NH2:21][C:22]1([CH2:28][C:29]([NH:31][CH3:32])=[O:30])[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]1>>[F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([NH:21][C:22]3([CH2:28][C:29]([NH:31][CH3:32])=[O:30])[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]3)=[O:14])=[N:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1
Reactant: CNC(=O)CC1(N)CS(=O)(=O)C1
Product: CNC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(C3(F)CCC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-fluorocyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 285a) and 2-(3-amino-1,1-dioxo-thietan-3-yl)-N-methyl-acetamide (example 282a) as starting materials and isolated (15 mg, 19%); MS (ESI, m/z): 468.3 (M+H+).
Reaction SMILES: O[C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.COCCN(S(F)(F)[F:32])CCOC.C1(C)C=CC=CC=1.[Cl-].[NH4+]>C(#N)C>[F:32][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)cc2)[C@H](O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)cc2)[C@H](F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of (3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (15.5 g, 61.4 mmol, intermediate D) in 270 mL of acteonitrile was chilled to 0° C. To the stirred solution was added bis(2-methoxyethyl)aminosulfur trifluoride 50% solution in toluene (Deoxo-fluor, 58.4 mL, 159 mmol) dropwise via addition funnel over 65 min. After the addition, the reaction mixture was stirred for 30 min at 0° C. and then allowed to come to rt and stirred for an additional 2 h. A saturated ammonium chloride solution (150 mL) was then added, and the mixture was extracted with two 150 mL portions of DCM. The organic layers were combined, dried over sodium sulfate, and concentrated to afford the crude product. The product was purified by silica gel chromatography (1.5 kg of silica) eluting with a gradient of 0-15% acetone in hexanes to afford 11.9 g (75%) of the desired (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate. LC/MS RT (conditions B)=3.295 min, (M+H with loss of t-butyl and elimination of fluorine)+=220.0. 1H NMR (400 MHz, chloroform-d) δ 7.15 (d, J=8.6 Hz, 2H), 6.83 (dt, J=8.6, 2.0 Hz, 2H), 4.59-4.48 (m, 1H), 4.47-4.37 (m, 1H), 4.23-4.12 (m, 1H), 2.88-2.68 (m, 3H), 1.96-1.84 (m, 1H), 1.80-1.66 (m, 1H), 1.51 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[CH3:24][O:25][C:26](=[O:30])[CH2:27][C:28]#[N:29].[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:24][O:25][C:26](=[O:30])[CH2:27][C:28]1[N:29]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)[C:3]2[C:2](=[CH:19][C:18]([O:20][CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[N:1]=1
Reactant: COC(=O)CC#N
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COC(=O)Cc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (6.3 g) and cyanoacetic acid methyl ester (23 ml), powdered aluminum chloride (5.3 g) was added, followed by stirring at 100° C. for 2.5 hours. The reaction mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1, v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline-2-acetic acid methyl ester (4.4 g, 55%), which was then recrystallized from isopropyl ether to yield a colorless needle crystal having a melting point of 152° to 153° C.
Reaction SMILES: [F:1][C:2]([F:26])([C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>N1C=CC=CC=1>[S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:26])([F:1])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])(=[O:35])=[O:34]
Reactant: OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
2.76 ml of 7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecan-1-ol is dissolved in 20 ml of absolute pyridine, mixed at 0° C. with 2.48 g of p-toluenesulfonyl chloride and stirred for 3 hours under cold conditions. Then, the reaction mixture is stirred into water, extracted with dichloromethane, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Column-chromatographic purification on silica gel with a hexane-ethyl acetate gradient yields 4.33 g of 7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecyl tosylate as a clear oil.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][O:25][CH:26]1[CH2:29][NH:28][CH2:27]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:28]1[CH2:29][CH:26]([O:25][CH2:24][C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[CH2:27]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-(2-thienylmethoxy)azetidine hydrochloride (29 mg, 0.14 mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a brown solid. This solid was triturated in acetone and diethyl ether, filtered, washed with diethyl ether then dried to give the title compound (8 mg, 18%) as a pale brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1>>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[NH:14][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:13]
Reactant: Nc1nccs1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Product: Cn1cc(C(=O)Nc2nccs2)c2ccccc21

Procedure:
1-Methyl-1H-indole-3-carboxylic acid and 2-aminothiazole was coupled and purified according to the conditions described in General Procedure (B), Step C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][CH2:25][CH2:24][NH:23][C:22]=2[CH:27]=1)=[O:17]>ClCCl.N1C=CC=CC=1>[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][CH2:25][CH2:24][N:23]([S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:12][CH3:13])(=[O:10])=[O:9])[C:22]=2[CH:27]=1)=[O:17]
Reactant: COC(=O)c1ccc2c(c1)NCCO2
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-methoxy-benzenesulfonyl chloride (4.7 g, 19.7 mmol, 1.05 equiv.) in dichloromethane (60 mL) and pyridine (25 mL) was added a solution of 3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester (3.6 g, 18.8 mmol, 1 equiv.) in dichloro-methane (60 mL). The mixture was stirred at room temperature overnight then the solvent was removed. The residue was purified by flash chromatography to yield 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester as a pink solid, 7.12 g (95%), MS (ISP): m/e=398.0 (M+H+.); δH (300 MHz; CDCl3) 8.24 (1H, s), 8.07 (1H, s), 7.72 (1H, dd), 7.48 (1H, dd), 6.91 (1H, d), 6.89 (1H, d), 4.10 (2H, m), 3.91 (2H, m), 3.88 (3H, s), 3.63 (3H, s).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][O:17][CH:18]1[CH2:21][N:20]([CH2:22][CH2:23][NH:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N:30]=2)[CH2:19]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH3:16][O:17][CH:18]1[CH2:21][N:20]([CH2:22][CH2:23][NH:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N+:30]=2[O-:4])[CH2:19]1
Reactant: COC1CN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1CN(CCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)C1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
H2O2 (70%, 1.4 mL, ca. 28 mmol) was added dropwise to a stirred solution of TFAA (4.0 mL, 28 mmol) in DCM (30 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 34 (890 mg, 2.8 mmol) and TFA (1.1 mL, 14 mmol) in DCM (35 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 35 (390 mg, 42%) as a red solid: mp 152° C. (dec.); 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.30 (br s, 1H, NH), 4.04 (p, J=5.8 Hz, 1H, CHO), 3.67-3.72 (m, 2H, CH2N), 3.54 (dt, J=5.9, 5.5 Hz, 2H, CH2N), 3.25 (s, 3H, OCH3), 3.11 (dt, J=7.4, 0.9 Hz, 2H, H-6), 3.06 (dt, J=7.4, 1.1 Hz, 2H, H-8), 2.95-2.99 (m, 2H, CH2N), 2.78 (t, J=5.9 Hz, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7); 13C NMR δ 155.6, 149.4, 145.8, 138.0, 129.8, 115.8, 111.6, 69.9, 61.5 (2), 58.0, 56.0, 39.5, 33.4, 32.4, 25.6; MS (APCI) m/z 332 (MH+, 100%). Anal. calcd for C16H21N5O3.0.15CH2Cl2: C, 56.4; H, 6.2; N, 20.4. Found: C, 56.2; H, 6.1; N, 20.4%.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+]=[N-]>CO.C(O)(=O)C.[Pd]>[NH2:1][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(N)C1
Yield: 69.4 %

Procedure:
A solution of the title compound of Example 3 (37.1 g, 164 mmol) in a mixture of MeOH (100 mL) and acetic acid (25 mL) was added 10% Pd-C (3.7 g) and the reaction mixture was hydrogenated (50 psi) for 24 h at rt in a Parr apparatus. Analysis of the reaction by TLC (solvent system A) and IR (to look for presence or absence of N3 str peak at 2100 cm-1) indicated the reaction to be complete. The solution was filtered through celite to remove catalyst and the filtrate was evaporated in vacuo to give the crude product as an oily residue. The residue was dissolved in 500 mL of 10% aqueous acetic acid and the solution was extracted with Et2O (3×200 mL). The combined ethereal extract was discarded and the aqueous solution was basified by addition of excess concentrated aqueous NH3 solution. The basified mixture was extracted with Et2O (3×200 mL) and the combined organic extract was dried (Na2SO4) and evaporated to give the title compound (22.8 g, 69%) as a pale yellow oil. The fumarate salt crystallized from 2-propanol: mp 197°-198° C., 1H-NMR (CDCl3) ∂ 3.93 (br s, 1H), 3.82 (dm, Jgem =13 Hz, 1H), 1.46 (s, 9H), 1.29-1.41 (complex m, 3H), 1.24 (m, 1H); CIMS (MH+ calcd for C10H20N2O2): 201. Found (MH+): 201; Anal. (calc'd for C10H20N2O2.0.5C4H4O4): C, H, N.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[C:25]4[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH2:29][C:24]=4[NH:23][N:22]=3)=[O:20])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.C(Cl)[Cl:42].Cl>CCOCC>[ClH:42].[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[C:25]4[CH2:26][NH:27][CH2:28][CH2:29][C:24]=4[NH:23][N:22]=3)=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:8]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)c2C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (53, 142 mg, 0.26 mmol) in 1:1 MeOH/CH2Cl2 (2 mL) was added HCl (2N in Et2O, 2 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL) and the resulting solids were collected by filtration to give (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride (54) as an off-white solid (127 mg, >99%): 1H NMR (500 MHz, DMSO-d6) δ 9.28 (br s, 2H), 8.02-7.98 (m, 2H), 7.96-7.92 (m, 1H), 5.30-5.09 (m, 1H), 4.78-4.55 (m, 1H), 4.28-4.14 (m, 2H), 3.43-3.28 (m, 2H, overlaps with H2O), 3.26-3.07 (m, 2H), 3.02-2.90 (m, 2H), 2.89-2.75 (m, 1H), 2.00-1.82 (m, 2H), 1.80-1.61 (m, 2H), missing N—H pyrazole; ESI MS m/z 447 [M+H]+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:12][C:13]1([CH2:20][CH3:21])[C:18](=[O:19])[CH:17]=[CH:16][CH2:15][CH2:14]1)([O:10][CH3:11])=[O:9]>C1COCC1.S(C)C>[C:8]([CH2:12][C:13]1([CH2:20][CH3:21])[CH2:14][CH2:15][CH:16]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:17][C:18]1=[O:19])([O:10][CH3:11])=[O:9]
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Solvent: CSC
Product: CCC1(CC(=O)OC)CCC(C2CCCC2)CC1=O
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
Following the procedure of Paquette et al., J. Am. Chem. Soc., 103, 1831 (1981) a solution of cyclopentylmagnesium bromide (222.5 mmol, 111.2 ml of 2M in Et2O), in 481 ml of dry THF under nitrogen was cooled to -78° C. and treated dropwise with a solution of 120.4 mmol (24.75 g) of CuBr.Me2S in 170 ml of Me2S. After 1.5 hours at -78° C., a solution of the enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexene-1-one prepared in Example 1, Step (c), (40.77 mmol, 8 g) in 80 ml of THF was added dropwise. After 1.5 hours, TLC indicated the consumption of enone and the reaction was quenched with 250 ml of 1M HCl (aq.) and extracted with 2×100 ml of CH2Cl2 and 2×100 ml of petroleum ether. Drying (Na2SO4) and flash chromatography afforded 8.027 g (30.13 mmol, 74%) of pale yellow oil containing a mixture of diastereomers. This material was combined with another batch to give 11.04 g and this was separated by preparative HPLC to afford 2.96 g of a less polar isomer and 4.3 g of a more polar isomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[CH2:14][O:15][C:16]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:45]([C:42]2[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=2)(=[O:47])=[O:46])[CH2:10][C@@H:9]1[CH2:14][O:15][C:16]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C(OC[C@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
(2R,4R)-1-(tert-Butyloxycarbonyl)-2-(4,4'-Dimethoxytrityl) oxymethyl-4-hydroxypyrrolidine 38 (8.09 g, 20.27 mmol) was dissolved in dry pyridine/CH2Cl2 (2:1, 200 ml) and chilled in an ice bath under argon atmosphere. To this cold solution was added TEA (3.03 g, 30 mmol) followed by p-toluenesulphonyl chloride (5.7 g, 30 mmol). The reaction mixture was allowed to stir at 0° C. for 3 h and below 30° C. for 8 h. The reaction mixture was evaporated to dryness, partitioned between EtOAc (200 ml) and 5% NaHCO3 solution (100 ml), and extracted in EtOAc. The EtOAc extract was washed with water (100 ml) and brine (100 ml), dried and evaporated to dryness. The crude product was purified by flash chromatography over silica gel using hexane→EtOAc as the eluent. The pure fractions were pooled together and evaporated to give 12.2 g (89%) of an orange oil. 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 2.40 (s, 3H, CH3), 3.40-3.62 (m, 3H), 3.74 (s, 6H, 2.OCH3), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H), 6.82 (d, 4H, Ph), and 7.26-8.00 (m, 13H, Ph).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:28]>[N+](CC)(CC)(CC)CC.[Cl-].C(#N)C>[Cl:28][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCC(=O)OCc1nccc(O)n1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CCCCCC(=O)OCc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 300 mg (1.33 mMol) hexanoic acid 4-hydroxy-pyrimidin-2-ylmethyl ester, 487 mg (2.94 mMol) Et4NCl and 373 μl (2.94 mMol) N,N-dimethylaniline in 15 ml of acetonitrile, 1.22 ml (13.3 mMol) POCl3 are added. After stirring for 24 h at rt, the solution is concentrated in vacuo. The residue is re-dissolved in EtOAc and sat. NaHCO3, the aq. layer separated off and extracted twice with EtOAc. The organic phases are dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/ether 199:1→9:1→3:2) gives the title compound as an oil: MS: [M+1]+=243/245; TLC(CH2Cl2): Rf=0.26.
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:29]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[N:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[N:10]=1)(C)(C)C.C(OC(=O)CN(C(OC(C)(C)C)=O)C1C=CC=C(C(CC2C=CC(C3C=CC=CN=3)=CC=2)NS(C2C=NC=CC=2)(=O)=O)N=1)(C)(C)C>>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([S:29]([CH:15]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[N:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[C:11]2[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:45])=[O:5])[CH:14]=[CH:13][CH:12]=2)(=[O:30])=[O:31])[CH:33]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-n3cncn3)cc2)S(=O)(=O)c2cccnc2)n1
Agent: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Product: O=C(O)CNc1cccc(C(NCc2ccc(-n3cncn3)cc2)S(=O)(=O)c2cccnc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Reaction was carried out in the same manlier as in Example 19-(b) except for using tert-butyl[tert-butoxycarbonyl(6-{(pyridin-3-ylsulfonyl)[4-(1,2,4-triazol-1-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate (936 mg, 1.47 mmol) obtained in Example 20-(a) in place of tert-butyl[tert-butoxycarbonyl(6-{[4-(pyridin-2-yl)benzyl]-(pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The concentrate was adjusted to pH 4.5 with a 6N aqueous sodium hydroxide solution, and a precipitated solid was collected by filtration. Acetone (1.3 ml) was added to the crude product, followed by stirring at 50° C. for 1 hour, and then at room temperature for 1 hour. A precipitated solid was collected by filtration, and then dried under reduced pressure to afford the title compound (618 mg) as a white solid. (Yield: 88%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:31])C(Cl)(Cl)Cl)[C:22](=O)[C:21]2=[O:33])=[CH:16][CH:15]=1)([O-:13])=[O:12]>CO.C(O)(=O)C>[OH:31][C:26]1[C:23]2[CH2:24][CH2:25][N:20]([C:17]3[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=3)[C:21](=[O:33])[C:22]=2[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1C(=O)N(c2ccc([N+](=O)[O-])cc2)CCC1C(=O)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-n2nc(O)c3c2C(=O)N(c2ccc([N+](=O)[O-])cc2)CC3)cc1

Procedure:
Condensation of 4-methoxyphenylhydrazine with 1-(4-nitro-phenyl)-4-(2,2,2-trichloro-acetyl)-piperidine-2,3-dione in refluxing methanol-acetic acid media afforded 3-hydroxy-1-(4-methoxy-phenyl)-6-(4-nitro-phenyl)-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one. Treatment of this intermediate with NaH and isopropyliodide afforded the corresponding 3-isopropoxy pyrazolo intermediate which was subjected to the same experimental protocol as described for Example 3 to afford the title compound. ESI mass spectrum 460 (M+H)+.