Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29]CC)=[O:28])[CH2:22]2)=[O:20])=[CH:13][C:12]=1[N+:32]([O-:34])=[O:33])([CH3:3])[CH3:2].[OH-].[K+].[OH-].[Na+]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([OH:29])=[O:28])[CH2:22]2)=[O:20])=[CH:13][C:12]=1[N+:32]([O-:34])=[O:33])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCCN(C(=O)/C=C/c2ccc(Sc3ccccc3C(C)C)c([N+](=O)[O-])c2)C1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccccc1Sc1ccc(/C=C/C(=O)N2CCCC(C(=O)O)C2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared by the procedures described in Example 155, substituting the ethyl ester from Example 137 with the ethyl ester from Example 225B, and KOH with NaOH, to give a light-yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 1.15 (d, J=6.9 Hz, 6H), 1.30-1.50 (m, 1H), 1.50-1.80 (m, 2H), 1.88-2.04 (m, 2H), 2.95-3.17 (m, 1H), 3.94-4.06 (m, 1H), 4.06-4.22 (m, 2H), 4.40-4.52 (m, 1H), 6.63 (d, J=8.7 Hz, 1H), 7.33-7.53 (m, 3H), 7.56-7.68 (m, 3H), 7.91 (dd, J=1.8, 8.4 Hz, 1H), 8.63 (d, J=8.4 Hz, 1H). MS (APCI+) (M+H)+ at m/z 455.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:27](=[O:28])[C:26]([C:29]([NH2:31])=[O:30])=[C:25]([OH:32])[C@:24]2([OH:33])[C@H:5]1[CH2:6][C@H:7]1[C:21]([C:22]2=[O:23])=[C:20]([OH:34])[C:10]2[C:11]([OH:19])=[C:12]([NH2:18])[CH:13]=[C:14]([N:15]([CH3:17])[CH3:16])[C:9]=2[CH2:8]1)[CH3:3].[C:35]([N:39]([C:51]([O:53][CH2:54][CH:55]([CH3:57])[CH3:56])=[O:52])[CH2:40][C:41](OC(OCC(C)C)=O)=[O:42])([CH3:38])([CH3:37])[CH3:36]>>[NH2:31][C:29]([C:26]1[C:25](=[O:32])[C@:24]2([OH:33])[C@@H:5]([CH2:6][C@H:7]3[C:21](=[C:22]2[OH:23])[C:20](=[O:34])[C:10]2[C:11]([OH:19])=[C:12]([NH:18][C:41](=[O:42])[CH2:40][N:39]([C:35]([CH3:36])([CH3:38])[CH3:37])[C:51](=[O:52])[O:53][CH2:54][CH:55]([CH3:56])[CH3:57])[CH:13]=[C:14]([N:15]([CH3:16])[CH3:17])[C:9]=2[CH2:8]3)[C@H:4]([N:2]([CH3:1])[CH3:3])[C:27]=1[OH:28])=[O:30]
Reactant: CC(C)COC(=O)OC(=O)CN(C(=O)OCC(C)C)C(C)(C)C
Reactant: CN(C)c1cc(N)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Product: CC(C)COC(=O)N(CC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2)C(C)(C)C

Procedure:
The title compound is prepared by the procedure of Example 42, using 1 equivalent of 9-amino-minocycline and 2 equivalents of isobutoxycarbonyl N-(tert-butyl)-N-(isobutoxycarbonyl)glycinate, Reference Example 119 to give the product of the example.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.O.[NH2:12][NH2:13]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:12][NH2:13])=[O:9])[CH2:3][CH2:2]1
Reactant: COC(=O)C1CCOCC1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a round-bottom flask was added a solution of methyl tetrahydro-2H-pyran-4-carboxylate (compound 137.1, 5.00 g, 31.2 mmol, 1.00 equiv, 90%) in methanol (50 mL). Hydrazine hydrate (5.20 g, 83.2 mmol, 3.00 equiv) was added and the resulting mixture was stiffed overnight at 40° C. in an oil bath. After cooling to ambient temperature, the mixture was concentrated in vacuo to yield 4.00 g (80%) of tetrahydro-2H-pyran-4-carbohydrazide as a white solid.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].S(=O)(=O)(O)O.[F:17][C:18](I)([F:20])[F:19].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:17][C:18]([F:20])([F:19])[C:7]1[NH:8][C:9]2[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]=2[N:6]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: Nc1nc2nc(C(F)(F)F)[nH]c2c(=O)[nH]1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
0.15 g (1.0 mmol) of guanine was weighed and placed in a 500 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 197 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethylguanine (19F-NMR yield: 46%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 8-Trifluoromethylguanine was obtained as a white solid (0.019 g, yield: 9%) by column chromatography.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[CH3:7][C:8]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]3[O:30][C:31]([NH:34][C:35]4[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=4[F:43])=[N:32][N:33]=3)=[O:28])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)([CH3:13])[C:9]([O:11]C)=[O:10].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:13][C:8]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27]([C:29]3[O:30][C:31]([NH:34][C:35]4[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=4[F:43])=[N:32][N:33]=3)=[O:28])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)([CH3:7])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Agent: C[Si](C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Potassium trimethylsilanolate (970 mg, 7.6 mmol) was added in one portion in a stirred solution of methyl 2-methyl-2-(trans-4-{4-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)propanoate (Example 623, 390 mg, 0.76 mmol) in THF (10 mL) and the reaction mixture was heated in the microwave at 90° C. for 20 min, then 100° C. for 1 h and finally at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to leave a yellow solid and then a 1M aqueous solution of citric acid (40 mL) was added and the mixture was stirred for 30 mins. The mixture was filtered to leave a solid. The solid was washed with H2O (20 mL) and purified by recrystallisation, using ethanol as solvent, to give the title compound (219 mg, 57%) as a white solid; 1H NMR δ 1.06 (6H, s), 1.12-1.27 (2H, m), 1.37-1.5 (2H, m), 1.58-1.75 (3H, m), 1.8-1.9 (2H, m), 2.39-2.5 (1H, m), 7.22 (2H, m), 7.65 (2H, m), 7.68-7.78 (1H, m), 8.14-8.24 (1H, m), 11.0 (1H, s), 11.13 (1H, s), 12.1 (1H, s); MS m/e MH+ 502.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][NH2:35])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([NH:35][CH2:34][C:31]3[CH:32]=[C:33]4[C:28]([CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:29][CH:30]=3)=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Reactant: NCc1ccc2cccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc4cccnc4c3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (17 mg, 0.055 mmol) in N,N-dimethylformamide (0.5 mL) were added quinolin-7-ylmethanamine (34 mg, 0.22 mmol) (WO 2008/130481), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (80 mg, 0.21 mmol) and N,N-diisopropylethylamine (80 μL, 0.46 mmol). The reaction mixture was stirred at 50° C. for 16 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC to afford the titile compound.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].[H][H].[1HH]>CO>[CH3:3][CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:1]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: [1HH]
Solvent: CO
Product: COC(=O)CC(C)C(=O)OC
Reaction time: 0.25 h

Procedure:
4.73 mg (0.0126 mmol) of [Rh(NBD)2]BF4 and 8.55 mg (0.0133 mmol) of B2a are placed in a flask provided with a magnetic stirrer and blanketed with argon by repeatedly evacuating the flask and flushing it with argon. 5 ml of degassed methanol are then added and the mixture is stirred for 15 minutes. 0.4 g (2.53 mmol) of dimethyl itaconate and 5 ml of degassed methanol are subsequently introduced into a 10 ml Schlenk flask filled with an argon atmosphere. Stirring is continued until a homogeneous solution is formed. The solution is injected by means of a steel capillary into a 180 ml glass reactor filled with argon. Finally, 1.05 bar of hydrogen are introduced in three flushing cycles (argon 1 bar/hydrogen 1 bar). The hydrogenation is started by switching on the stirrer and is carried out at 25° C. The course of the reaction is followed via the hydrogen consumption (pressure decrease in the hydrogen reservoir). After a reaction time of 20 hours, the conversion is found to be complete. The enantiomeric purity of dimethyl 2-methyl succinate is 94.6% of (R).
Reaction SMILES: C[Sn](C)(C)[N:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:6][N:5]=[N:4]1.[C:23]1([C:29](Cl)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[C:23]1([C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:3]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:6][N:5]=[N:4]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2[Sn](C)(C)C)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-trimethylstannyl 5 (4'-methylbiphenyl-2-yl)tetrazole (Example 10, 0.4 g) and anhydrous pyridine (10 mL) was treated with triphenylmethyl chloride (0.3 g) and stirred at room temperature under a nitrogen atmosphere for 48 hours. The resulting solution was evaporated and the residue was partitioned between dichloromethane and saturated aqueous CuSO4. The organic layer was dried over MgSO4 and evaporated. The residual solid was triturated with diisopropyl ether and collected by filtration to give the title compound, mp 163°-165° C. (decomp., gas evol.).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([N:8]([CH2:12][CH2:13][Cl:14])[CH2:9][CH2:10][Cl:11])=[CH:6][CH:5]=1)([O-])=O.Cl>C(OCC)(=O)C.CO.[Pd]>[ClH:11].[Cl:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][Cl:14])[C:7]1[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(N(CCCl)CCCl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(N(CCCl)CCCl)cc1
Yield: 160 %

Procedure:
4-Nitro-[N,N-bis(2-chloroethyl)]aniline (5.0 g; 19.0 mmol) was dissolved in a mixed solvent of 50 ml of ethyl acetate and 25 ml of methanol, followed by the addition of 5.0 ml of 4N hydrochloric acid. Using 10% Pd/C, the reactant was subjected to hydrogenation under normal pressure at room temperature. The Pd/C was filtered off and the solvent was distilled out. The residue was crystallized from ethanol-ethyl ether, whereby 4.1 g (15.2 mmol) of the title compound was obtained (yield: 80%).
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:37])[C:9]1[S:10][C:11]([S:35][CH3:36])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH:24]=3)[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH3:36][S:35][C:11]1[S:10][C:9]([C:8]([NH2:37])=[NH:7])=[CH:13][C:12]=1[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])[CH:24]=2)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(C(=O)C(F)(F)F)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2cccc(C(=O)C(F)(F)F)c2)c1
Yield: 80 %

Procedure:
(Imino-{5-methylsulfanyl-4-[3′-(2,2,2-trifluoro-acetyl)-biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (30 mg, 0.051 mmol, as prepared in Example 29, step a) was treated with trifluoroacetic acid (50% in DCM) for 1 hr at rt. The reaction mixture was concentrated in vacuo and the residue obtained was purified using C18-HPLC (20–60% CH3CN in H2O (0.1% TFA) over 25 min) to give 20 mg (80%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz) δ 8.35 (s, 1H), 8.33 (t, 1H, J=1.7 Hz), 7.98–8.07 (m, 2H), 7.90–7.93 (m, 1H), 7.68–7.78 (m, 3H), 7.60 (t, 1H, J=7.8 Hz), 2.77 (s, 3H). 19F-NMR (CDCl3; 400 MHz) δ −84.99 (s). ESI-MS (m/z): Calcd. for C20H15F3N2O3S3: 485.5 (M+H); found: 485.3, 503.3 (M+H2O), 517.3 (M+CH3OH).
Reaction SMILES: O.[OH-].[Li+].[N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3([C:17]4[N:21]5[N:22]=[C:23]([C:26]6[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=6)[CH:24]=[N:25][C:20]5=[N:19][CH:18]=4)[CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.O.Cl>C1COCC1.CO>[N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3([C:17]4[N:21]5[N:22]=[C:23]([C:26]6[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=6)[CH:24]=[N:25][C:20]5=[N:19][CH:18]=4)[CH2:15][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide monohydrate (14 mg, 0.34 mmol) was added to a solution of methyl 4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate (30.0 mg, 0.07 mmol) in THF (0.3 mL), methanol (0.3 mL), and water (0.2 mL). The mixture was stirred at RT for 2 h and adjusted to pH 2 with conc. HCl. The volatiles were removed under reduced pressure and the residue was dried to provide the crude product which was directly used in the next step without further purification. LCMS: (M+H)=408.1.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:6]([N:8]1[CH2:28][CH2:27][CH2:26][C@H:9]1[C:10]([NH:12][CH2:13][C:14](OC1C=CC([N+]([O-])=O)=CC=1)=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH2:36][C@H:37]([C:48]([NH:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:49])[CH2:38][CH:39]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:40](=[O:42])[OH:41].Cl.C(N(CC)CC)C>CN(C)C=O>[NH:1]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C@H:2]([C:6]([N:8]1[CH2:28][CH2:27][CH2:26][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:36][C@H:37]([C:48]([NH:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:49])[CH2:38][CH:39]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[C:40](=[O:41])[OH:42])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CNC(=O)[C@@H](N)CC(OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)[C@H](CC(OC(C)(C)C)C(=O)O)NC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of XV (1.66 g, 3.38 mmol) in dimethyl formamide (5 ml) were added XVII (1.05 g, 3.38 mmol) and triethylamine (0.57 ml, 4.06 mmol) in dimethyl formamide (5 ml) and the mixture was stirred for 2 days at room temperature. The reaction mixture was evaporated and the residue, dissolved in ethyl acetate, was washed with 10% citric acid solution, 4% sodium bicarbonate solution, water and dried over sodium sulfate. The solution was evaporated to dryness. An oil obtained gave a single spot on TLC; yield 1.64 g (77%), Rf1 0.57.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)C(C)=Cc1ccc(O)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Cc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of the alkene (515) (0.481 g, 2.0 mmol) in ethyl acetate (20 mL) was added Pd/C (48 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight under a hydrogen balloon at room temperature, then filtered through a pad of celite and concentrated in vacuo to provide the intermediate ethyl 3-(3-chloro-4-hydroxyphenyl)-2-methylpropanoate (516A) (0.470 g, 96.9%) as a white solid. LC-MS ESI m/z: found 243.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22](O)=[S:23])=[N:14]1.C(N(CC)CC)C.C1(P([N:46]=[N+:47]=[N-:48])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([N:46]=[N+:47]=[N-:48])=[S:23])=[N:14]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC(=S)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=S)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(F)(F)F
Temperature: 5 °C
Yield: 90.9 %

Procedure:
1-(2,6-Dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole-3-carboxylic acid (5.6 g) was dissolved in dry N,N-dimethylformamide (50 ml) and triethylamine (1.33 g) added. After cooling to 5° C., a solution of diphenylphosphorylazide (3.63 g) in N,N-dimethylformamide (20 ml) was added. When the solution had reached ambient temperature, it was heated to 35° C. for 21/2 hours. After evaporation in vacuo at a temperature kept below 40° C., a solution of sodium chloride (5 g) in water (100 ml) was added, and the suspension extracted with ether (3×100 ml). The combined extracts were washed with water (50 ml), dried over anhydrous magnesium sulphate and evaporated to give 1-(2,6-dichloro-4-trifluoromethylphenyl)4-trifluoromethylthiopyrazole-3-carboxylic acid azide (5.4 g). A solution of this in dry toluene (200 ml) was heated under reflux with stirring for 1.5 hours, tert-butanol (35 ml) was added, and reflux continued for 4 hours. After evaporation in vacuo the residue was purified by chromatography eluting with dichloromethane to give the title compound (3.3 g) as an off-white solid, m.p. 122°-125° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1.[NH:32]1[CH2:37][CH2:36][CH:35]([O:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34][CH2:33]1.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[C:43]([O:42][C:40]([CH2:39][O:38][CH:35]1[CH2:34][CH2:33][N:32]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:37][CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COC1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.90 g (13.27 mmol) sodium triacetoxyborohydride were added batchwise to a mixture of 2.58 g (11.06 mmol) benzyl 4-oxo-piperidine-1-carboxylate and 2.80 g (12.36 mmol) tert-butyl (piperidin-4-yloxy)-acetate in 30 mL THF and the reaction mixture was stirred overnight at RT. It was combined with 50 mL 1 M NaOH, the mixture was stirred for 1 h at RT, combined with EtOAc, the organic phase was separated off and dried over Na2SO4. After elimination of the desiccant and solvent the residue was purified by chromatography (Alox, DCM/MeOH 100:1).
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([OH:21])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][C:6]=1[Cl:22])[CH2:2][CH2:3][CH3:4].C1([C@H](N)C)C2C(=CC=CC=2)C=CC=1>>[CH2:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([OH:21])=[O:20])[C@@H:11]([C:15]([F:16])([F:17])[F:18])[O:12]2)=[CH:7][C:6]=1[Cl:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Agent: C[C@@H](N)c1cccc2ccccc12
Product: CCCCc1cc2c(cc1Cl)C=C(C(=O)O)[C@@H](C(F)(F)F)O2

Procedure:
A racemic mixture of the compound prepared in Example 9a, Step 5 was resolved by chiral separation using Chiralpak AD-spring column eluting with iPA/heptane/TFA=5/95/0.1 and detecting at 254 nm to give a S-enantiomer as peak 2 with retention time 7.83 min. ESHRMS m/z 333.0519 (M−H, C15H13ClF3O3 Calc'd 333.0500). 1HNMR (DMSO-d6/400 MHz), 13.13 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.00 (s, 1H), 5.89 (q, 1H, J=7.1 Hz), 2.62 (t, 2H, J=7.5 Hz), 1.50 (m, 2H), 1.30 (m, 2H), 0.860 (t, 3H, J=7.3 Hz): 19FNMR (d6-benzene; 6 eq of (R)-(+)-1-(1-naphthyl)ethylamine) d −77.82 (d, 3F, J=6.8 Hz, R-enantiomer), −77.78 (d, 3F, J=6.8 Hz, S-enantiomer).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:28])[CH2:6][C:7]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)([OH:22])[CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18](=[O:21])(=[O:20])[NH2:19])[CH:13]=1.COC(=O)CC(=O)CC(C1CCCC1)(O)CCC#CC1C=C(C)C(O)=CC=1C>>[CH:23]1([C:7]2([CH2:8][CH2:9][C:10]#[C:11][C:12]3[CH:13]=[C:14]([S:18]([NH2:19])(=[O:20])=[O:21])[CH:15]=[CH:16][CH:17]=3)[CH2:6][C:5](=[O:28])[CH2:4][C:3](=[O:2])[O:22]2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)CC(=O)CC(O)(CCC#Cc1cccc(S(N)(=O)=O)c1)C1CCCC1
Agent: COC(=O)CC(=O)CC(O)(CCC#Cc1cc(C)c(O)cc1C)C1CCCC1
Product: NS(=O)(=O)c1cccc(C#CCCC2(C3CCCC3)CC(=O)CC(=O)O2)c1

Procedure:
The desired product was prepared analogously to example F(1), substituting 5-cyclopentyl-5-hydroxy-3-oxo-9-(3-sulfamoyl-phenyl)-non-8-ynoic acid methyl ester (80 mg, 0.19 mmol) from Step 2 below in place of 5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoic acid methyl ester. Yield: 17 mg, 23%. 1H NMR (CDCl3) δ: 1.43-1.74 (m, 8H), 1.93-2.05 (m, 2H), 2.20 (p, J=8.59 Hz, 1H), 2.52 (t, J=7.45 Hz, 2H), 2.70 (d, J=16.17 Hz, 1H), 2.80 (d, J=16.17 Hz, 1H), 3.39 (s, 2H), 4.82 (s, 2H), 7.38 (t, J=7.83 Hz, 1H), 7.50 (d, J=8.84 Hz, 1H), 7.76 (d, J=7.83 Hz, 1H), 7.90 (t, J=1.52 Hz, 1H). MS (ESI): 388 (M−H).