Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6]([S:26]([C:29]2[S:33][C:32]([NH:34]C(=O)C)=[N:31][N:30]=2)(=[O:28])=[O:27])[CH2:5]1)#[C:2][CH3:3].Cl.O1CCOCC1>CO>[NH2:34][C:32]1[S:33][C:29]([S:26]([N:6]2[CH2:7][CH2:8][N:9]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:25])([C:17]([F:19])([F:20])[F:18])[C:21]([F:23])([F:24])[F:22])=[CH:14][CH:15]=3)[CH:4]([C:1]#[C:2][CH3:3])[CH2:5]2)(=[O:27])=[O:28])=[N:30][N:31]=1
Reactant: CC#CC1CN(S(=O)(=O)c2nnc(NC(C)=O)s2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC#CC1CN(S(=O)(=O)c2nnc(N)s2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 100 °C
Yield: 46.7 %

Procedure:
A 20-mL microwave vial was charged with N-(5-((3-(1-propyn-1-yl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinyl)sulfonyl)-1,3,4-thiadiazol-2-yl)acetamide (370 mg, 0.647 mmol), MeOH (2 mL), 1N aq. HCl (3 mL, 3.00 mmol) and 4N HCl in dioxane (3 mL, 12.00 mmol). The reaction vessel was sealed and the mixture heated to 100° C. for 4 h. The reaction was concentrated onto silica and purified via column chromatography on silica gel (0 to 10% MeOH in CH2Cl2) to give 2-(4-(4-((5-amino-1,3,4-thiadiazol-2-yl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (160 mg) as a mixture of two isomers.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(O)C>[CH2:5]([N:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH:2]=[CH2:1])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C(=Cc1ccccc1)CNCc1ccccc1
Reactant: C=CCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CCN(CC=Cc1ccccc1)Cc1ccccc1
Yield: 78 %

Procedure:
11.0 g (90 mmol) of allyl bromide were added to 10.0 g (44.8 mmol) of N-cinnamylbenzylamine in 60 ml of ethanol, and then 5.0 g (50.0 mmol) of triethylamine were added while stirring. The mixture was refluxed for 4 h. Concentration under water pump vacuum was followed by partition of the contents of the flask between methylene chloride and water, rendition alkaline with dilute sodium hydroxide solution and extraction twice more with methylene chloride. The combined organic phases were washed with dilute sodium hydroxide solution, dried and concentrated. The crude product (12.5 g) was purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 98/2). 9.2 g (80%) of product (oil) were obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[Cl:8][CH2:9][C:10]([C:12]1[CH:25]=[CH:24][C:23]2[O:22][C:21]3[C:16](=[CH:17][C:18]([C:26](=[O:29])[CH2:27]Cl)=[CH:19][CH:20]=3)[CH2:15][C:14]=2[CH:13]=1)=[O:11].[I-].[K+]>O1CCCC1>[ClH:8].[ClH:8].[N:1]1([CH2:9][C:10]([C:12]2[CH:25]=[CH:24][C:23]3[O:22][C:21]4[C:16](=[CH:17][C:18]([C:26](=[O:29])[CH2:27][N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCl)c1ccc2c(c1)Cc1cc(C(=O)CCl)ccc1O2
Reactant: O=C1CCCCN1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(CN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CN3CCCCC3)ccc1O2
Reaction time: 168 h

Procedure:
To a solution of 200 ml. of piperidone in 500 ml. of tetrahydrofuran were added 33.5 g (0.1 mole) of 2,7-bis(2-chloroacetyl)xanthene and 2 g of potassium iodide with warming. The reaction mixture was allowed to stand for 7 days, filtered and the filtrate evaporated to dryness, leaving a residue which was treated with dilute acid and filtered. The filtrate was made alkaline, and the resulting oily product was extracted with methylene chloride. The methylene chloride solution was acidified with ethereal HCl which gave an oily product that was recrystallized from methanol-diethyl ether then vacuum dried to give the desired product. M.P. 260°-262°C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N:13]([CH2:18][CH3:19])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][N:10]2[N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]([C:23](=[O:26])[NH:24][CH3:25])=[C:9]2[CH:8]=1)(=O)=O.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1([NH:45][C:46](=[O:62])[C:47]2[CH:52]=[CH:51][CH:50]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)[CH2:44][CH2:43]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[CH2:18]([N:13]([C:12]1[C:7]([C:51]2[CH:50]=[CH:49][CH:48]=[C:47]([C:46](=[O:62])[NH:45][C:42]3([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)[CH2:43][CH2:44]3)[CH:52]=2)=[CH:8][C:9]2[N:10]([N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]=2[C:23]([NH:24][CH3:25])=[O:26])[CH:11]=1)[S:14]([CH3:17])(=[O:15])=[O:16])[CH3:19]
Reactant: CC1(C)OB(c2cccc(C(=O)NC3(c4ccccn4)CC3)c2)OC1(C)C
Reactant: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OS(=O)(=O)C(F)(F)F)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)NC2(c3ccccn3)CC2)c1)S(C)(=O)=O

Procedure:
6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (0.1 g, 0.17 mmol, 1 eq), N-(1-(pyridin-2-yl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.0.65 g, 0.18 mmol, 1.1 eq), tetrakistriphenylphosphine palladium (0.0058 g, 0.0051 mmol, 0.03 eq) and cesium carbonate (0.165 g, 0.51 mmol, 3 eq) were dissolved in 1,4-dioxane (10 ml) and water (2 ml) and the reaction was heated at 90° C. for 14 hours. The solution was filtered through ciliate. Water was added to the filtrate which was then extracted with ethyl acetate. The organic layer was concentrated and the residue obtained purified by Preparative HPLC. Yield: 22 mg (26%) 1HNMR (400 MHz, CD3OD): δ 1.05 (t, J=8 Hz, 3H), 1.65-1.66 (m, 2H), 1.78-1.82 (m, 2H), 2.89 (s, 3H), 3.20 (s, 3H), 3.62 (br s, 2H), 7.28-7.30 (t, J=7.76 Hz, 2H), 7.57 (br s, 1H), 7.67 (t, J=7.72 Hz, 1H), 7.75 (d, J=8.20 Hz, 1H), 7.86-7.88 (m, 3H), 7.96 (s, 1H), 8.02 (d, J=2.09 Hz, 1H), 8.18 (br, 1H), 8.23 (s, 1H), 8.55 (d, J=5.32 Hz, 1H), 8.98 (s, 1H). LCMS: (ES+) m/z=627.2 (M+H); Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm); Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH; Mphase B: 98% MeCN—2% H2O-10 mM NH4COOH; Flow: 1 mL/Min; RT min: 1.768;
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH2:20])=[N:18][OH:19])[CH:12]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35](O)=O)=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]>>[CH3:9][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:20]=[C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH3:22])=[C:30]([C:38]([F:39])([F:41])[F:40])[CH:31]=3)[O:19][N:18]=2)[CH:12]=1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21].[CH3:9][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:20]=[C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH3:22])=[C:30]([C:38]([F:39])([F:41])[F:40])[CH:31]=3)[O:19][N:18]=2)[CH:12]=1)[CH2:7][C:6]([OH:5])=[O:21]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Product: Cc1ccccc1-c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)O)c3)no2)cc1C(F)(F)F
Product: Cc1ccccc1-c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1C(F)(F)F

Procedure:
Tert-butyl N-methyl-N-(3-{5-[2′-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycinate was prepared following the general procedure 7 starting from Intermediate 21 and Intermediate 5. It was hydrolyzed following procedure 8, affording the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.55 (s, 1H), 8.50 (d, J=8.0 Hz, 1H), 8.36 (s, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.78-7.63 (m, 2H), 7.42-7.12 (m, 3H), 7.17 (d, J=7.4 Hz, 1H), 4.51 (s, 2H), 4.12 (s, 2H), 2.81 (s, 3H), 2.02 (s, 3H). HPLC (Method A); Rt 4.20 min (Purity: 99.48%). CHN analysis: [C26H22O3F3N3—HCl] Calculated: C, 60.29%, H, 4.48%, N, 8.11%. Found: C, 60.08%, H, 4.42%, N, 7.91%.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[C:10](C(O)=O)[C:9]=2[O:21][CH3:22])=[O:7])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[O:21][CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: COc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 81.5 %

Procedure:
5-(p-Chlorobenzoyl)-3-hydroxycarbonyl-4-methoxy-1-methylpyrrole-2-acetic acid (prepared from Example 1, Step E) is dissolved in 5 ml of trifluoroacetic acid (TFA) and heated to reflux under nitrogen. After about 45 minutes the reaction is substantially complete. It is cooled and concentrated in vacuo. The resultant residue is treated with 10 ml of water, and the precipitate is filtered, and dried to afford 925 mg (81.5%) of 5-(p-chlorobenzoyl)-4-methoxy-1-methylpyrrole-2-acetic acid, m.p. 142°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([Cl:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:15]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Cl)cc1
Reactant: C#CCN1CCN(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CC(C)NC(C)C
Solvent: CO
Product: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(Cl)cc2)C3=O)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.061 mL, 0.4 mmol), 5-bromo-7-chloro-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.11 g, 0.3 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropylamine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.090 g, 70%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.31 (s, 3H), 2.32-2.74 (m, 8H), 3.54 (s, 2H), 4.18 (s, 2H), 4.74 (s, 2H), 7.22-7.36 (m, 5H), 7.44 (s, 1H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([B-](F)(F)F)[CH:10]=[CH2:11].[K+].Cl[C:18]1[C:23]2[O:24][CH:25]([CH3:29])[C:26](=[O:28])[NH:27][C:22]=2[CH:21]=[C:20]([CH:30]=[O:31])[CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O>[CH2:11]([C:18]1[C:23]2[O:24][CH:25]([CH3:29])[C:26](=[O:28])[NH:27][C:22]=2[CH:21]=[C:20]([CH:30]=[O:31])[CH:19]=1)[CH:10]=[CH2:9]
Reactant: C=CC[B-](F)(F)F
Reactant: CC1Oc2c(Cl)cc(C=O)cc2NC1=O
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCc1cc(C=O)cc2c1OC(C)C(=O)N2
Temperature: 115 °C
Reaction time: 48 h
Yield: 3.4 %

Procedure:
To a solution of potassium phosphate, tribasic (0.564 g, 2.66 mmol), potassium allyltrifluoroborate (0.197 g, 1.330 mmol), and 8-chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 15 (0.2 g, 0.886 mmol) in toluene (Ratio: 5.00, 20 mL) and water (Ratio: 1.000, 4.0 mL) was added PdOAc2 (0.015 g, 0.066 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.062 g, 0.133 mmol) at 23° C. The reaction was stirred at 115° C. for 48 hr. The reaction mixture was poured into water (2 mL) and extracted with Et2O (3×5 mL). The organic layer was dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The resulting crude material was reconstituted in DCM (0.25 mL) and purified via medium pressure chromatography using a gradient eluant of 1-5% MeOH:DCM. The appropriate fractions were combined and solvent was removed via rotary evaporation. The impure material was reconstituted in DMSO (1.0 mL) and purified via preparative mass trigger LCMS using a gradient eluant of 45-70% ACN:0.05% TFA (aq). The collected fractions were combined and the solvent was removed via rotary evaporation to provide the title compound as an off-white solid (0.007 g, 0.030 mmol, 3.41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=6.82 Hz, 3H) 3.38-3.42 (m, 2H) 4.82 (q, J=6.82 Hz, 1H) 5.06-5.12 (m, 2H) 5.91-6.01 (m, 1H) 7.28 (d, J=2.02 Hz, 1H) 7.42 (d, J=2.02 Hz, 1H) 9.82 (s, 1H) 10.93 (s, 1H). ESI-MS: m/z 232.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[N:3]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncnc(NCCc3ccc(S(N)(=O)=O)cc3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][C:24]2[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:14][N:13]=1.N.O>CCOC(C)=O>[CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][CH2:23][C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[CH:14][N:13]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1CC[C@H](N)CC1
Reactant: Cc1ccc(CCc2cnc(Cl)c3ccccc23)cn1
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(CCc2cnc(N[C@H]3CC[C@H](C(C)C)CC3)c3ccccc23)cn1

Procedure:
Under a N2 atmosphere, 600 mg (4.25 mmol) of trans-4-isopropyl-cyclo-hexylamine [for preparation see Arzneim. Forsch. 19 (1969), 140] and 120 mg (0.424 mmol) of 1-chloro-4-[2-(6-methyl-pyridin-3-yl)-ethyl]-isoquinoline are heated to 140° C. in an ampulla for 10 h. The reaction mixture is suspended in EtOAc, and mixed with 0.25 ml of NH3 solution (25%) and water. The separated aqueous phase is extracted twice more with EtOAc, the organic phases washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/EtOAc 1:1) yields trans 1-(4-isopropyl-cyclohexylamino)-4-[2-(6-methyl-pyridin-3-yl)-ethyl]-isoquinoline; 1H NMR (DMSO-d6) δ8.27 (m, 2H), 7.88 (d, 1H), 7.65 (t, 1H), 7.60 (s, 1H), 7.54 (m, 1H), 7.45 (t, 1H), 7.14 (d, 1H), 6.84 (d, 1H), 3.88 (m, 1H), 3.00 (m, 2H), 2.84 (m, 2H), 2.40 (s, 3H), 2.00 (m, 2H), 1.71 (m, 2H), 1.5-1.0 (m, 6H), 0.86 (d, 6H).
Reaction SMILES: [CH:1]1([CH2:6][C:7](=[O:48])/[CH:8]=[CH:9]\[C@H:10]([CH3:47])[C@H:11]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C@@H:12]([CH3:38])/[CH:13]=[C:14](/[CH3:37])\[CH2:15][C@H:16]([CH3:36])[C@@H:17]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@H:18]([CH3:27])[C@@H:19]([OH:26])[C@@H:20]([CH3:25])/[CH:21]=[CH:22]\[CH:23]=[CH2:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)[C:51]([N:53]=C=O)=[O:52]>C(Cl)Cl>[NH2:53][C:51]([O:26][C@@H:19]([C@@H:20]([CH3:25])/[CH:21]=[CH:22]\[CH:23]=[CH2:24])[C@@H:18]([CH3:27])[C@H:17]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:30])[CH3:31])[C@@H:16]([CH3:36])[CH2:15]/[C:14](/[CH3:37])=[CH:13]\[C@H:12]([CH3:38])[C@@H:11]([O:39][Si:40]([C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:42])[CH3:41])[C@@H:10]([CH3:47])/[CH:9]=[CH:8]\[C:7](=[O:48])[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:52]
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)CC1CCCC1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)CC1CCCC1
Temperature: 23 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
A solution of (3Z,5S,6S,7S,8Z,11S,12R,13R,14S,15S,16Z)-1-cyclopentyl-6,12-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-14-hydroxy-5,7,9,11,13,15-hexamethyl-3,8,16,18-nonadecatetraen-2-one (420 mg, 0.60 mmol, 1 eq) in CH2Cl2 (10 mL) is treated with trichloroacetyl isocyanate (135 mg, 0.72 mmol, 1.2 eq) at 23° C. (20 minutes). The solution is concentrated, and the residue dissolved in CH3OH (10 mL). To this solution is added K2CO3 (0.2 g) and the mixture is stirred at 23° C. (3 hours). The reaction mixture is concentrated and the residue dissolved in Et2O (20 mL). The organic solution is washed with H2O (1×10 mL) and brine (1×20 mL). The aqueous layer is extracted with Et2O (3×10 mL) and the combined extracts are dried (Na2SO4) and concentrated. Chromatography (SiO2, 30–50% EtOAc-hexanes gradient elution) provides (3Z,5S,6S,7S,8Z,11S,12R,13R,14S,15S,16Z)-14-[(aminocarbonyl)oxy]-1-cyclopentyl-6,12-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5,7,9,11,13,15-hexamethyl-3,8,16,18-nonadecatetraen-2-one (420 mg, 94%).
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][CH2:18][CH:19]([NH2:32])[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[C@@H:13]([C:33]([O:35]C)=[O:34])[CH2:12]1>O1CCOCC1.CO.O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][CH2:18][CH:19]([NH2:32])[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[C@@H:13]([C:33]([OH:35])=[O:34])[CH2:12]1
Reactant: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(N)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2nccc(C(N)CC[C@@H]3CCN(CCSc4cccs4)C[C@@H]3C(=O)O)c2c1
Yield: 102.9 %

Procedure:
1 cm3 of 5N aqueous sodium hydroxide solution is added with stirring, at a temperature in the region of 20° C., to a solution of 0.05 g of methyl (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-(R,S)-amino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 2 cm3 of dioxane and 2 cm3 of methanol, and then the combined mixture is brought to reflux and refluxed for 20 hours. The mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is dissolved in 6 cm3 of distilled water The aqueous phase is washed with 2 cm3 of methylene chloride and then evaporated to dryness. The residue is taken up in 2 cm3 of isopropanol and the insoluble material is washed with 2 cm3 of isopropanol and then dried to give 0.05 g of (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-(R,S)-amino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylic acid, sodium salt.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][OH:22])[CH3:17])=[CH:12][CH:11]=3)=[CH:4][C:3]=2[O:2]1.O[C:24]1[CH:56]=[CH:55][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]2=[O:54])=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][O:22][C:24]4[CH:56]=[CH:55][C:27]([CH2:28][CH:29]5[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[C:30]5=[O:54])=[CH:26][CH:25]=4)[CH3:17])=[CH:14][CH:15]=3)=[CH:4][C:3]=2[O:2]1
Reactant: CC(=NOCCO)c1ccc(-c2ccc3c(c2)OCO3)cc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccc3c(c2)OCO3)cc1
Yield: 77 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 600 mg of 2-[1-(3',4'-methylenedioxybiphenyl-4-yl)ethylideneaminooxy]ethanol (prepared as described in Preparation 30), 907 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 550 mg of triphenylphosphine and 365 mg of diethyl azodicarboxylate, 1.12 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:16]([OH:18])=O)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]([NH:28][C:16]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14]2)=[O:18])[CH3:27])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC(=O)CC1
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCC(=O)CC1)c1ccc(F)cc1

Procedure:
1-(tert-Butoxycarbonylamino)-4-oxocyclohexanecarboxylic acid (750 mg) was coupled with (R)-1-(4-fluorophenyl)ethanamine using the HATU procedure as described in Example 1. The crude was chromatographed with gradient elution 15-80% ethyl acetate in heptane to yield the title compound (900 mg). MS MH+ 379.3
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:17]([OH:30])=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=2)[C:8]([OH:15])=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[P:31](Cl)(Cl)Cl.[CH2:35]([NH:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH3:38].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:22]([C:20]1[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]2[O:30][P:31]([N:39]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:35][CH2:36][CH2:37][CH3:38])[O:15][C:8]3[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=3[C:16]=2[CH:21]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCCNCCCC
Reactant: ClP(Cl)Cl
Reactant: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)p1oc2c(C(C)(C)C)cc(C(C)(C)C)cc2c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
170 g (0.414 mol) of 4,4',6,6'-tetra-tert-butyl-2,2'-biphenol in 150 ml of toluene is heated to 80°-90° C. in a nitrogen atmosphere, and 40 ml (0.458 mol) of phosphorus trichloride is added dropwise in the course of 2 hours. The reaction mixture is stirred at reflux temperature for 4 hours and, towards the end of the reaction, nitrogen gas is again introduced. There is then added dropwise at reflux temperature, during 11/2 hours, a solution of 53.5 g (0.414 mol) of dibutylamine and 41.9 g (0.414 mol) of triethylamine in 80 ml of toluene. After 15 hours, the reaction mixture is allowed to cool to room temperature, and the triethylamine hydrochloride which has precipitated is filtered off. The toluene is afterwards evaporated off, and the N-(2,4,8,10-tetra-tert-butyl-dibenz[d,f][1,3,2]dioxaphosphepin-6-yl)-dibutylamine obtained has a melting point of 140° C.