Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[CH:21]=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)[CH:9]=[C:8]([C:22]([O:24]C)=[O:23])[C:7]=2[C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2].C(N1C2C=C(C3C=C4C=CNC4=NC=3)C=C(C(OC)=O)C=2C=N1)(C)C.O[Li].O>>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[CH:21]=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]=2[C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1c(C)nn2C(C)C
Agent: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1cnn2C(C)C
Agent: [Li]O
Solvent: O
Product: Cc1nn(C(C)C)c2cc(-c3cnc4[nH]ccc4c3)cc(C(=O)O)c12

Procedure:
The title compound was prepared from methyl 1-isopropyl-3-methyl-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-4-carboxylate, 1 (50 mg, 0.14 mmol) and LiOH.H2O (20 mg, 0.43 mmol) in the same manner as described for example 80 (step b). The product was collected as an off-white solid (60 mg) and used in the next step without any further purification. LCMS (ES+) m/z: 335.15.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([O:9][CH2:10][CH:11]=O)[CH2:6][CH:7]=[CH2:8])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.[NH2:19][OH:20]>C(O)C.O>[CH:1]1([CH2:4][CH:5]([O:9][CH2:10]/[CH:11]=[N:19]/[OH:20])[CH2:6][CH:7]=[CH2:8])[CH2:3][CH2:2]1
Reactant: NO
Reactant: C=CCC(CC1CC1)OCC=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCC(CC1CC1)OC/C=N/O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
[(1-Cyclopropylpent-4-en-2-yl)oxy]acetaldehyde (C67) (17 g from the previous step, ≦83 mmol) was dissolved in a 2:1 mixture of ethanol and water (450 mL). Sodium acetate (41 g, 500 mmol) was added; after the reaction mixture had been stirred for 15 minutes, hydroxylamine hydrochloride (98%, 21 g, 300 mmol) was added. The reaction mixture was heated to 60° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol and extracted with dichloromethane (3×140 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 22° C. Silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) provided the product as a colorless oil. By 1H NMR analysis, this material consisted of a roughly 1:1 mixture of E and Z oxime isomers. Yield: 10 g, 55 mmol, 49.6% over two steps.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[CH3:24][C:25]1[O:29][C:28]([C:30]2([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[CH2:37][CH2:38][O:39]S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:24][C:25]1[O:29][C:28]([C:30]2([CH3:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[N:27][C:26]=1[CH2:37][CH2:38][O:39][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH2:6][CH3:7])[C:4]([OH:23])=[O:3])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Product: CCC(Cc1ccc(OCCc2nc(C3(C)CCCCC3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
The title compound was prepared from 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the method of Example 46. 1H NMR (400 MHz, CDCl3) δ 7.29 (dd, 2H, J=8.60 Hz, J=7.43 Hz), 7.07-7.03 (m, 1H), 7.02-6.96 (m, 4H), 6.72 (d, 2H, J=8.60 Hz), 4.10 (t, 2H, J=6.25 Hz), 2.38 (s, 2H), 2.95 (t, 2H, J=6.25 Hz), 2.29 (s, 3H), 2.15-2.01 (m, 4H), 1.56-1.36 (m, 8H), 1.30 (s, 3H), 0.91 (t, 3H, J=7.43 Hz); MS (ES+) calcd for C30H38NO5: Found m/e 492.3 (M+1, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)=[C:12]([N+:25]([O-])=O)[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.Cl.[Pd]>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[C:13]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)=[C:12]([NH2:25])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc([N+](=O)[O-])c(OCC2CC2)c(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)c1cc(N)c(OCC2CC2)c(C(F)(F)F)c1
Reaction time: 4 h
Yield: 51.3 %

Procedure:
A mixture of 2-(4-cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (1.85 g, 4.59 mmol) and Pd/C (1.85 g) in ethanol and 1 N HCl (4.60 mL) was hydrogenated under 36 psi H2 in a Parr apparatus. After 4 h, the reaction mixture was filtered through Celite 521®. The filtrate was concentrated under reduced pressure to give a yellow oil. The residue was treated with an aqueous solution of sodium carbonate (3 g in 100 mL of water) and the resulting solution was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a brown oil, which was purified by silica-gel flash chromatography eluting with a gradient of heptane/ethyl acetate (from 10:1 to 2:1) to give 2-(3-amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (0.88 g, 51%) as a light pink oil: 1H NMR (300 MHz, CDCl3): δ 6.83 (s, 1H), 6.80 (s, 1 H), 4.04 (m, 2 H), 3.85 (s, 2 H), 3.66 (d, 2 H, J=6.9 Hz), 3.45 (t, 1 H, J=7.8 Hz), 1.84 (m, 1 H), 1.49 (m, 1 H), 1.39 (m, 1 H), 1.22 (m, 1 H), 1.14 (t, 3 H, J=7.2 Hz), 0.82 (m, 6 H), 0.56 (d, 2 H, J=7.5 Hz), 0.27 (d, 2 H, J=4.5 Hz); 13C NMR (75 MHz, CDCl3): δ 173.61, 142.71, 141.25, 135.51, 123.75 (q, J=30 Hz), 123.52 (q, J=271 Hz), 118.46, 115.52 (q, J=5 Hz), 77.88, 60.70, 49.03, 42.53, 25.86, 22.40, 22.31, 14.07, 10.98, 3.19.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[C:19]([F:31])[C:20]([S:22]([NH:25][C:26]5[S:30][N:29]=[CH:28][N:27]=5)(=[O:24])=[O:23])=[CH:21][C:16]=4[O:15][C:14]3=[O:32])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C.Cl[C:50]([O:52][CH3:53])=[O:51]>CO.O.CS(C)=O>[S:30]1[C:26]([NH:25][S:22]([C:20]2[C:19]([F:31])=[CH:18][C:17]3[N:13]([CH2:12][C:9]4[CH:8]=[CH:7][CH:6]=[C:5]5[C:10]=4[CH2:11][CH:2]([NH:1][C:50](=[O:51])[O:52][CH3:53])[CH2:3][CH2:4]5)[C:14](=[O:32])[O:15][C:16]=3[CH:21]=2)(=[O:24])=[O:23])=[N:27][CH:28]=[N:29]1
Reactant: NC1CCc2cccc(Cn3c(=O)oc4cc(S(=O)(=O)Nc5ncns5)c(F)cc43)c2C1
Reactant: COC(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)NC1CCc2cccc(Cn3c(=O)oc4cc(S(=O)(=O)Nc5ncns5)c(F)cc43)c2C1
Temperature: 25 °C

Procedure:
To a vial was added a single enantiomer (R or S) of 3-((7-amino-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (20-4) (19 mg, 0.037 mmol), then NMP (0.6 ml), DIPEA (30 μL, 0.172 mmol), and finally METHYL CHLOROFORMATE (12.30 μL, 0.159 mmol). The reaction mixture was then capped (not under N2) & stirred at room temperature. Followed by LC/MS. After 10 min at room temperature the reaction mixture was diluted with MeOH/drops of H2O/DMSO, then purified (without workup) by reverse phase chromatography (5-95% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions concentrated (GENEVAC), then dissolved in MeOH/DCM & concentrated to yield methyl (8-((6-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (23-1). HRMS [M+H] calculated; 534.0912, observed; 534.0918. 1H NMR (499 MHz, DMSO): δ 8.48 (s, 1H); 7.79 (d, J=5.5 Hz, 1H); 7.33-7.23 (m, 2H); 7.08-7.03 (m, 2H); 6.88-6.82 (m, 1H); 5.75 (s, 1H); 5.03-4.91 (m, 2H); 3.81-3.71 (m, 2H); 3.55 (s, 3H); 3.06-2.99 (m, 1H); 2.87-2.80 (m, 2H); 1.95-1.88 (m, 1H); 1.68-1.57 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[C:7]=1/[CH:8]=[N:9]/[NH:10][CH2:11][CH2:12][OH:13].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[N:10]([CH2:11][CH2:12][OH:13])[N:9]=[CH:8][C:7]=12
Reactant: OCCN/N=C/c1c(Br)cncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCn1ncc2c(Br)cncc21
Yield: 108.8 %

Procedure:
In analogy to GP2, 520 mg of 2-{N′-[1-(3,5-Dibromo-pyridin-4-yl)-meth-(E)-ylidene]-hydrazino}-ethanol (Intermediate 1.2, 1.61 mmol, 1 eq) were dissolved in 14 mL dry THF, treated at rt with 155 mg 50-60% sodium hydride (3.54 mmol, 2.2 eq) and subsequently refluxed for 90 min. The reaction mixture was quenched with water, extracted with ethyl acetate, the combined organic layers dried and concentrated in vacuo to yield 424 mg of a crude product, which was optionally further purified by trituration or flash column chromatography.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+].[F:16][C:17](Br)([F:19])[F:18]>CN(C)C=O>[F:16][C:17]([F:19])([F:18])[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Sc1ccccc1-c1ccccc1
Reactant: FC(F)(F)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)Sc1ccccc1-c1ccccc1
Temperature: 0 °C
Yield: 87.9 %

Procedure:
A reaction tube in a photoreaction apparatus was charged with 50 ml of dimethylformamide (DMF) and 5.59 g (30 mmol) of 2-mercaptobiphenyl, and with ice cooling and stirring, 1.2 g (30 mmol) of sodium hydride (60% in oil) was added. When foaming ceased, trifluoromethyl bromide was introduced into the reaction solution. The atmosphere within the reaction system was replaced by gaseous trifluoromethyl bromide, and while irradiating light from a high-pressure mercury lamp, about 2 equivalents of trifluoromethyl bromide was passed into the reaction system over about 2 hours. Ice water (150 ml) was added to the resulting brown reaction solution, and it was extracted with pentane. The organic layer was washed with water and then with saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 6.71 g (87.9%) of 2-(trifluoromethylthio)biphenyl as an oil. It was purified by silica gel column chromatography. The properties of the product were as shown below.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=O)[CH2:13][CH2:12][N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OCC)(=O)C>O1CCCC1>[CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[CH2:30])[CH2:13][CH2:12][N:11]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:10][C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc2N(Cc2ccccc2)C(=O)C1
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)CC(=O)N(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
μ-Chloro-μ-methylene-[bis(cyclopentadienyl)titanium]dimethylaluminium (0.5M in toluene/15 ml, 7.5 mmol) was added to a solution of 1-benzyl-4-tert-butyloxycarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (2.95 g, 7.5 mmol) in tetrahydrofuran (23 ml) at -5° C. The resultant suspension was stirred at -5° C. for 15 minutes then allowed to warm to room temperature. Stirring was continued for a further 30 minutes followed by the addition of ethyl acetate (50 ml) and the mixture was washed with 0.2M sodium hydroxide solution (1.5 ml), and dried (MgSO4). The mixture was filtered through a pad of celite and evaporated to dryness. The crude product was purified by chromatography on silica gel with ethyl acetate-hexane (1:3) as eluant. (981 mg, 33%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[OH:18][CH2:17][CH2:16][N:15]([CH2:14][CH2:13][OH:12])[CH2:19][CH2:20][CH2:21][NH:22][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCCN(CCO)CCO
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: OCCN(CCO)CCCNc1ccc2ccccc2n1

Procedure:
A mixture of 5.05 g. of 2-chloroquinoline, 5.5 g. of bis(2-hydroxyethyl)aminopropylamine and 3.0 g. of sodium carbonate is heated in 20 ml. of refluxing isopropanol for 24 hours. The reaction mixture is then filtered, solvent removed in vacuo and the residue chromatographed over silica gel to obtain an oil of 2-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:4]>C([O-])(O)=O.[Na+].CO>[C:3]([CH:5]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:6]([OH:8])=[O:7])#[N:4]
Reactant: COc1ccc(C=C(C#N)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C#N)C(=O)O)cc1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (30.2 g) is added portionwise over a period of 2 hours to a stirred mixture of α-cyano-4-methoxycinnamic acid (52.5 g) in aqueous saturated NaHCO3 (200 ml) and methanol (600 ml) cooled to about 15° C. The reaction mixture is allowed to warm to RT, stirred at RT for 30 min and concentrated in vacuo. The residue is partitioned between water and ether and the aqeuous layer acidified and extracted with ether. The ether extract is washed, dried over Na2SO4, filtered and the filtrate evaporated in vacuo producing a liquid which is crystallized from toluene yielding the desired product as a solid, M.P. 94°-95° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16](SC)=[N:17][CH:18]=[N:19]3)[CH2:9][C@@H:8]1[C:26]([O:28][CH3:29])=[O:27])=[O:6])[CH:2]=[CH2:3].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35]>CC#N.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[C:32]([O:31][CH3:30])[CH:33]=2)=[N:17][CH:18]=[N:19]3)[CH2:9][C@@H:8]1[C:26]([O:28][CH3:29])=[O:27])=[O:6])[CH:2]=[CH2:3]
Reactant: COc1cccc(N)c1
Reactant: C=CCOC(=O)[C@@H]1CCN(Cc2cccc3ncnc(SC)c23)C[C@@H]1C(=O)OC
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: C=CCOC(=O)[C@@H]1CCN(Cc2cccc3ncnc(Nc4cccc(OC)c4)c23)C[C@@H]1C(=O)OC
Temperature: 70 °C

Procedure:
To a mixture of 15B (453 mg, 1.05 mmol), 3-methoxyaniline (142.5 mg, 1.16 mmol) in CH3CN (25 ml) was added AgNO3 (197 mg, 1.16 mmol). The mixture was heated at 70° C. for 30 min. After cooling to room temperature, the solid was removed by filtration through a pad of Celite and the filtrate was concentrated in vacuo. The residue was taken into with water, treated with saturated NaHCO3 and extracted with EtOAc (×3). The combined extracts were dried over anhydrous Na2SO4. Concentration in vacuo gave 644 mg of crude 15C as an oil, which was used in next step without further purification. The compound has an analytical HPLC retention time=2.259 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=506+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([C@@H:21]([NH:20][C:16]([CH:9]2[CH2:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18])[CH3:22])=[CH:24][CH:25]=1)=[O:28]
Reactant: CC1(C)CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2CC(C)(C)CCN2C(=O)OC(C)(C)C)cc1
Yield: 44.2 %

Procedure:
The title compound (D59) (230 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 1-(tert-butoxycarbonyl)-4,4-dimethylpiperidine-2-carboxylic acid (320 mg; described in J. Med. Chem. 1997, 40, 2491-2501) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (295 mg). Reaction time: 18 hrs
Reaction SMILES: [CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].S(Cl)(Cl)=O.[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][NH:34][CH3:35].O>C(Cl)Cl.N1C=CC=CC=1>[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][N:34]([CH3:35])[C:23]([C@H:20]1[CH2:19][CH2:18][C@H:17]([CH2:16][N:2]([CH3:1])[S:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:15])[F:14])=[CH:8][CH:7]=2)(=[O:5])=[O:4])[CH2:22][CH2:21]1)=[O:25]
Reactant: CN(C[C@H]1CC[C@H](C(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CNCCN(C)C
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)CCN(C)C(=O)[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 200 mg (0.53 mmol) trans-4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexanecarboxylic acid and 125 mg (1.05 mmol, 2 eq) of thionyl chloride in 1 mL of dry CH2Cl2 were heated at 50° C. for 1 h, then evaporated and dissolved in 1 mL of CH2Cl2. This solution was added to 269 mg (2.54 mmol, 5 eq) of N,N,N′-trimethylethylenediamine in 1 mL of pyridine at 0° C. and stirred for 2 h at RT. Subsequently the reaction mixture was poured on a mixture of ice and water and extracted with 3 portions of 15 mL of CH2Cl2. The combined organic phases were washed with H2O, diluted HCl, saturated aqueous NaHCO3 solution and brine, then dried over anhydrous Na2SO4 and finally evaporated. The residue was chromatographed on silicagel with CH2Cl2:MeOH:25% NH4OH (9:1:0.1) as eluent. 195 mg (79.8%) of trans-4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexanecarboxylic acid (2-dimethylamino-ethyl)-methyl-amide were obtained as colorless amorphous solid, MS: 464 (MH+).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH3:4].N=C=N.[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([N:41]([CH3:52])[C:42]([NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])[CH:36]=2)=[CH:31][CH:30]=1)[C:25]([OH:27])=[O:26])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([N:41]([CH3:52])[C:42]([NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])[CH:36]=2)=[CH:31][CH:30]=1)[C:25]([O:27][CH2:1][CH2:2][CH2:3][CH3:4])=[O:26])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Reactant: CCCCO
Agent: CN(C)c1ccncc1
Agent: N=C=N
Solvent: ClCCl
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)OCCCC)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
4.7 mg (63.3 μmol) of n-butanol, 5.7 mg (8.5 μmol) of PS-DMAP resin and 68 mg (94.0 μmol) of PS-carbodiimide are added successively to a solution containing 25 mg (42.3 μmol) of (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionic acid (Example 2) in 0.6 ml of DCM. After stirring for 16 h at ambient temperature and then 5 h at 40° C., the reaction medium is filtered and the solvents are evaporated off. The reaction crude is purified by chromatography on a column of silica and eluted with a heptane/ethyl acetate mixture. 5.5 mg of butyl (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionate are obtained with a 20% yield.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:18][C@@H:5]2[C@@:6]([CH2:16][F:17])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[NH:7][O:8][C@@H:4]2[CH2:3]1>CCCCCCC.C(O)C>[F:19][C:2]1([F:1])[CH2:18][C@H:5]2[C@:6]([CH2:16][F:17])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[NH:7][O:8][C@H:4]2[CH2:3]1
Reactant: FC[C@]1(c2ccccc2F)NO[C@@H]2CC(F)(F)C[C@@H]21
Solvent: CCO
Solvent: CCCCCCC
Product: FC[C@@]1(c2ccccc2F)NO[C@H]2CC(F)(F)C[C@H]21

Procedure:
Intermediate XXII-1: The racemate of (3S,3aR,6aR)-5,5-difluoro-3-fluoromethyl-3-(2-fluoro-phenyl)-hexahydro-cyclopenta[d]isoxazole was resolved on a chiral high-performance liquid chromatography (HPLC) column (Chiralpak AD) using n-heptane/ethanol (85:15) to give (3R,3aS,6aS)-5,5-difluoro-3-fluoromethyl-3-(2-fluoro-phenyl)-hexahydro-cyclopenta[d]isoxazole as the faster eluting enantiomer and the desired (3S,3aR,6aR)-5,5-difluoro-3-fluoromethyl-3-(2-fluoro-phenyl)-hexahydro-cyclopenta[d]isoxazole as the slower eluting enantiomer. MS: m/z=276.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:4][C:5]([CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])([C:14]([O-:16])=[O:15])[CH:6]([S:10]([OH:13])(=[O:12])=[O:11])[C:7]([O-:9])=[O:8])[CH3:2].[Na+].[Na+].[N+]([O-])([O-])=O.[Ag+:35]>C(OCC)C>[CH2:1]([CH:3]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:4][C:5]([CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])([C:14]([O-:16])=[O:15])[CH:6]([S:10]([OH:13])(=[O:11])=[O:12])[C:7]([O-:9])=[O:8])[CH3:2].[Ag+2:35]
Reactant: [Ag+]
Agent: CCCCC(CC)CC(CC(CC)CCCC)(C(=O)[O-])C(C(=O)[O-])S(=O)(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: [Ag+2]

Procedure:
Sodium bis(2-ethylhexyl)sulfosuccinate (NaAOT) is obtained from Fisher. 10 g NaAOT is dissolved in 100 mL diethylether and combined with an equal volume of 0.1 M aqueous AgNO3 in a separatory flask. The mixture is shaken and the aqueous phase was decanted. Two additional 100 mL volumes of 0.1 M AgNO3 are similarly ion exchanged with the ether solution. The ether solution is then washed twice with deionized water. The aqueous phase is decanted and the ether phase is reduced to a paste using rotary evaporation. The remaining paste is dried in a vacuum oven at 25-50° C., and a yield in excess of 90% is obtained.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C@:25]([OH:29])([C:27]#[CH:28])[CH3:26])[N:21]=1>N1CCCCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:29][C@:25]([C:22]1[N:21]=[C:20]([CH3:19])[O:24][N:23]=1)([CH3:26])[C:27]#[C:28][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2CCO3)no1
Temperature: 60 °C
Yield: 49.9 %

Procedure:
A mixture of 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide (100 mg, 0.28 mmol), (R)-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-but-3-yn-2-ol (70 mg, 0.46 mmol), and copper(I) iodide (10 mg, 0.05 mmol) in piperidine (1.5 ml) was sonicated under a stream of argon for 15 minutes. After the addition of tetrakis(triphenylphosphine)palladium (0) (40 mg, 0.035 mmol) the mixture was heated at 60° C. for 3 hours before the being concentrated. The residue was taken up in ethyl acetate (100 ml) and pre-absorbed onto a small amount of silica. Purification by FCC (silica, 0-10% methanol in dichloromethane) gave a solid residue, which was re-crystallised from heptane/dichloromethane (˜10 ml, 2/1). Filtration and drying of the crystalline material under high vacuum provided 53 mg (40%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.83 (3H, s), 2.61 (3H, s), 3.17 (2H, t, J=5.80 Hz), 4.49 (2H, t, 0.1=5.80 Hz), 6.71 (1H, s), 6.74 (1H, s), 7.22 (1H, d, J=8.39 Hz), 7.35 (1H, s), 7.38 (1H, dd, J=8.32, 2.06 Hz), 7.81 (1H, s), 8.03 (1H, d, J=1.98 Hz); M+1=380.