Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23]/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1(/[CH:25]=[CH:24]/[CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrC/C=C/c1ccccc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C/C=C/c3ccccc3)CC1)O2

Procedure:
Compound 139 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, [(1E)-3-bromoprop-1-en-1-yl]benzene and conditions outlined in procedure V. LCMS: 418 [M+H]; Rt=1.05 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1[CH:16]=[C:15]([O:17]C)[C:14]([CH2:19][CH2:20][CH3:21])=[C:13]([O:22]C)[CH:12]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1[CH:12]=[C:13]([OH:22])[C:14]([CH2:19][CH2:20][CH3:21])=[C:15]([OH:17])[CH:16]=1
Reactant: CCCc1c(OC)cc(C=Cc2ccc(F)cc2F)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1c(O)cc(C=Cc2ccc(F)cc2F)cc1O
Yield: 44 %

Procedure:
This material was prepared from 1-(2,4-difluorophenyl)-2-(3,5-dimethoxy-4-1-propylphenyl)ethene and pyridine hydrochloride in 44% yield in the same way as described in Example 34. 1HNMR (CDCl3, ppm): δ 1.41 (d, J=7.1 Hz, 6H), 3.49 (qint, J=7.1 Hz, 1H), 4.78 (br, 2H), 6.54 (s, 2H), 6.69-7.02 (m, 3H), 7.13 (d, J=16 Hz, 1H), 7.41-7.75 (m, 1H).
Reaction SMILES: [C:1]1(=[O:13])[O:10][C:8](=O)[CH:7]2[CH2:11][CH2:12][C:2]1([C:4]2([CH3:6])[CH3:5])[CH3:3].[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22]C)=[O:20])=[CH:17][CH:16]=1.CC1(C)CC(=O)OC(=O)C1>>[CH3:3][C:2]12[C:4]([CH3:5])([CH3:6])[CH:7]([CH2:11][CH2:12]1)[C:8](=[O:10])[N:14]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:24][CH:25]=1)[C:1]2=[O:13]
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC1(C)CC(=O)OC(=O)C1
Product: COC(=O)c1ccc(N2C(=O)C3CCC(C)(C2=O)C3(C)C)cc1

Procedure:
The desired product was prepared by substituting methyl 4-aminobenzoate and (+/−)-camphoric anhydride for ethyl 4-aminobenzoate and 3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI) m/e 333 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C@@H:17]3[CH:22]4[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]4)[CH2:18]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[N:19]12[CH2:20][CH2:21][CH:22]([CH2:23][CH2:24]1)[C@@H:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[CH:15][CH:14]=1)[CH2:18]2
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)cc2)cc1
Yield: 48.9 %

Procedure:
The product of Example 6E (384 mg, 1.18 mmol) in methanol (5 mL) was treated with Pd/C (Aldrich, wt. 10%, 50 mg) under H2 according to the procedure of Example 5C to provide the title compound (170 mg, yield, 49%). 1H NMR (MeOH-d4, 300 MHz) δ 1.44-1.58 (m, 1H), 1.63-1.89 (m, 2H), 1.99-2.13 (m, 1H), 2.15-2.23 (m, 1H), 2.72-3.04 (m, 5H), 3.29-3.39 (m, 1H), 4.48-4.56 (m, 1H), 6.76 (dt, J=8.8, 2.5 Hz, 2H), 6.91 (dt, J=8.8, 2.4 Hz, 2H), 7.31 (dt, J=8.5, 2.5 Hz, 2H), 7.43 (dt,J=9.2, 2.8 Hz, 2H) ppm. MS (DCl/NH3) m/z 295 (M+H)+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=O.COCCO[AlH2-]OCCOC.[Na+].O.Cl>C1(C)C=CC=CC=1>[CH2:25]([CH:22]1[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C@H:8]3[CH2:9][CH2:10][C@H:5]([CH:3]=[O:2])[CH2:6][CH2:7]3)=[CH:16][CH:15]=2)[CH2:24][CH2:23]1)[CH2:26][CH3:27]
Reactant: CCCC1CCC(CCc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CCC(CCc2ccc([C@H]3CC[C@H](C=O)CC3)cc2)CC1
Temperature: -40 °C

Procedure:
Vitride (3.3M in toluene, 19 mL, 62.7 mmol) was added with syringe to a flask filled with Argon gas, adjusted to 0° C., and morpholine (5.5 ml, 62.7 mmol) was added slowly dropwise with syringe. Then, toluene (31 ml) was added dropwise with syringe to produce vitride solution. 63 ml of a solution including 4-{4-[2-(4-propyl-cyclohexyl)-ethyl]-phenyl}-cyclohexane carboxylic acid methyl ester (2.3 g, 6.27 mmol) obtained in Example 5-2 in toluene a solution was added to another flask filled with argon gas, and vitride solution was added slowly dropwise at −70° C. for 30 minutes. Then, the solution was stirred with maintaining −30 to −50° C. for 6 hours and water was added very slowly dropwise to the flask. After reaction, 1M HCl was slowly added to the flask to neutralize the reaction solution. White precipitate was filtered under reduced pressure and the filtrate was extracted by toluene (20 ml×three times). The organic layer was collected, washed by distilled water (10 ml×two times), dried with anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane:ether=5:1, Rf=0.32) to produce 0.96 g (45%) of trans-4-{4-[2-(4-propyl-cyclohexyl)ethyl]phenyl}cyclohexane carbaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:17]([O:19][C:20](=[O:32])[C:21]([C:30]#[N:31])=[CH:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[CH3:18].[Cl-].[NH4+]>C1COCC1>[CH2:17]([O:19][C:20](=[O:32])[CH:21]([C:30]#[N:31])[CH:22]([C:23]1[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=1)[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH3:18]
Reactant: Fc1ccc(I)c(F)c1
Reactant: CCOC(=O)C(C#N)=Cc1ccc(Br)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C(c1ccc(Br)cc1)c1ccc(F)cc1F
Reaction time: 1 h

Procedure:
To a solution of 2,4-difluoro-1-iodo-benzene (12.0 g) in anhydrous THF (200 mL) was added a solution of isopropylmagnesium chloride lithium chloride complex (52.9 mL, 14% solution in THF) slowly over 10 min at room temperature. After stirring for 1 h, a solution of 3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester (10.0 g; example 74, step 1) in anhydrous THF (100 mL) was added and stirring continued at room temperature. After 1 h, a saturated aq. solution of ammonium chloride was added (100 mL), the phases separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate and the crude reaction product purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane/ethyl acetate (1:0 to 3:1) to provide the title compound as a light yellow oil. MS (ESI−): m/z=391.9 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[CH2:40]([O:42][C:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])[CH3:41]>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:48]3[CH2:49][CH2:50][CH:45]([C:43]([O:42][CH2:40][CH3:41])=[O:44])[CH2:46][CH2:47]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: CCOC(=O)C1CCN(c2nc3c(c(-c4ccccc4C)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)CC1
Yield: 99.5 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 4-(ethoxycarbonyl)piperidine (28.3 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-2-[4-(ethoxycarbonyl)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (97.0 mg, 100%).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:20][C:19]=1[F:27]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Product: CCC(=O)NC1CCCc2c(-c3ccc(Cl)c(F)c3)cncc21
Yield: 83 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 4-chloro-3-fluorophenylboronic acid to give the title compound as light brown foam in 83% yield. MS: 333.4 (M+H+, 1Cl).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].Cl.Cl.[CH2:26]([N:33]1[CH2:37][CH2:36][C:35]([CH3:39])([NH2:38])[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]1[CH2:37][CH2:36][C:35]([NH:38][C:21](=[O:22])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]2=[O:1])([CH3:39])[CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC1(N)CCN(Cc2ccccc2)C1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: Cl
Product: CC1(NC(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CCN(Cc2ccccc2)C1

Procedure:
The title compound was prepared as described in Example 28B reacting 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E) with 1-benzyl-3-methylpyrrolidin-3-amine dihydrochloride. (CAS 181114-76-1). 1H NMR (300 MHz, CDCl3) δ ppm 7.33 (m, 15H), 4.08 (d, J=14.67 Hz, 2H), 4.00 (m, 2H), 3.81 (m, 2H), 3.51 (m, 2H), 3.25 (m, J=2.38 Hz, 1H), 3.05 (d, J=13.88 Hz, 1H), 2.67 (m, 2H), 2.26 (m, 2H), 1.85 (m, 2H), 1.49 (s, 3H); MS (ESI+) m/z 482 (M+H)+.
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH:21]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[C:30]([Cl:39])[CH:29]=3)[N:24]=2)[CH3:22])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O.O>>[Cl:39][C:30]1[CH:29]=[C:28]([C:25]2[N:24]=[C:23]([C@H:21]([NH:20][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([CH:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[CH:19]=[CH:18][N:17]=3)[CH3:22])[O:27][N:26]=2)[CH:33]=[CH:32][C:31]=1[O:34][C:35]([F:36])([F:38])[F:37]
Reactant: CC(Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1nc(-c2ccc(OC(F)(F)F)c(Cl)c2)no1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(O)[C@H]1COC(=O)N1c1ccnc(N[C@H](C)c2nc(-c3ccc(OC(F)(F)F)c(Cl)c3)no2)n1
Yield: 66.3 %

Procedure:
(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (97 mg, 0.17 mmol) was treated with 90% TFA/water for 2 hours. Concentrate in vacuo and neutralized by passing through a column of MP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded 58 mg of (R)-3-(2-(((R)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-(1-hydroxyethyl)oxazolidin-2-one as a waxy off-white foam. Separated the diastereomers via chiral SFC chromatography on an AD-H column (75 g/min, 120 bar, 21×250 mm) eluting 25% IPA/CO2 (v/v) to give (R)-3-(2-(((R)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:31])[NH:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (Intermediate 4B; 406 mg, 0.953 mmol) in DMF (3 mL) was charged with potassium carbonate (348 mg, 2.52 mmol) and methyl iodide (0.089 mL, 1.430 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with water, filtered, and dried under vacuum to give 6-chloro-3-methoxy-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine, which was carried onto the next step without further purification. MS ESI calc'd. for C27H22ClN3O [M+1]+ 440. found 440.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])/[CH:5]=[CH:6]/[C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:8]=1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[N:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1cc(-c2ccccc2)n(-c2ccc(S(C)(=O)=O)cc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(-c2ccccc2)n(-c2ccc(S(C)(=O)=O)cc2)n1
Reaction time: 2 h

Procedure:
To a solution of 16 (0.17 g, 0.42 mmol) in 5 mL of EtOAc was added 10% palladium on carbon. The solution was filled with H2 and the reaction mixture was stirred for 2 hours. After the solution was filtered through Celite, the filtrate was concentrated in vacuo. Purification by column chromatography (3:7 EtOAc-hexanes) gave the title compound, 0.15 g (90%) as a white solid. mp 96.5-99.1° C. 1H NMR (300 MHz, DMSO-d6): δ 7.91 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H), 7.44-7.37 (m, 3H), 7.29-7.23 (m, 2H), 6.57 (s, 1H), 4.09 (q, J=7 Hz, 2H), 3.24 (s, 3H), 2.93 (t, J=7 Hz, 2H), 2.74 (t, J=7 Hz, 2H), 1.18 (t, J=7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>[Cu]>[C:4]([C:3]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:2]=1[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Cu]
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1C(=O)OC
Temperature: 220 °C
Yield: 45 %

Procedure:
A mixture of methyl 2-chloro-5-nitrobenzoate (66.5 g, 0.309 mol) and sand (200 g) is added to a 500 ml, three-necked round-bottom flask equipped with an overhead stirrer, condenser and a nitrogen inlet tube. After the mixture is heated to 220° C. under nitrogen with stirring, activated copper (50.0 g) is added gradually during 1 hour. The reaction mixture is stirred at 220° C. under nitrogen for another 3 hours, and the mixture is then extracted with boiling acetone, and filtered while hot to remove copper and sand. The acetone is thereafter removed from the filtrate under reduced pressure. The residue is recrystallized from methanol two times to yield 45 percent of yellow crystals: mp 176.5°-177.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:11]([O:18]COC)[CH:10]=[C:9]([O:22]COC)[C:8]=1[C:26](=[O:39])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35]COC)=[CH:31][CH:30]=1)=[O:4].Cl.CO.C(=O)([O-])O.[Na+]>CO>[OH:18][C:11]1[CH:10]=[C:9]([OH:22])[C:8]([C:26](=[O:39])[CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=2)=[C:7]([O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[C:12]=1[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: COCOc1ccc(CCC(=O)c2c(OCOC)cc(OCOC)c(CCC(C)C)c2OCC(=O)OC)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1c(CCC(C)C)c(O)cc(O)c1C(=O)CCc1ccc(O)cc1
Yield: 93 %

Procedure:
Then, 1.30 g of 1-[2-methoxycarbonylmethoxy-4,6-bis(methoxymethoxy)-3-isopentylphenyl]-3-(4-methoxymethoxyphenyl)-1-propanone was dissolved in 3 ml of methanol, and 10 ml of a hydrochloric acid/methanol reagent was added to the solution and the mixture was heated and refluxed for 40 minutes. The temperature of the reaction mixture was lowered to room temperature and the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 500 ml of ethyl acetate. The ethyl acetate layer was washed with water, shaken with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation. The obtained residue was recrystallized from chloroform to obtain 918 mg (yield=93.0%) of 1-(4,6-dihydroxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-hydroxyphenyl)-1-propanone in the form of a colorless prism.
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Na+].S(O[CH2:22][CH2:23][O:24][C@H:25]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@:31]3([OH:49])[CH2:32][CH2:33][C@@H:34]2[C:44]2[CH:48]=[CH:47][O:46][CH:45]=2)[CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[N:4]1([CH2:3][CH2:2][S:1][CH2:22][CH2:23][O:24][C@H:25]2[CH2:42][CH2:41][C@@:40]3([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]4[C@@H:39]3[CH2:38][CH2:37][C@@:35]3([CH3:36])[C@:31]4([OH:49])[CH2:32][CH2:33][C@@H:34]3[C:44]3[CH:48]=[CH:47][O:46][CH:45]=3)[CH2:26]2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Reactant: SCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H](OCCSCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Temperature: 25 °C

Procedure:
To a solution of 0.28 g of 1-(2-mercaptoethyl)pyrrolidine in 20 ml of dimethylformamide, 0.086 g of sodium hydride (60% dispersion in mineral oil) were added under nitrogen atmosphere, and the mixture stirred at room temperature for half an hr; a DMF solution of 1.0 g of 3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as described in Ex. 7, was added and the mixture was stirred for another 4 hrs; the reaction mixture was quenched with water and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-cromatography (SiO2) using methylene chloride/methanol 95/5 as eluant and 0.90 g of the title compound (I-ai) as a white amorphous solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]#[N:15].C(OP(=S)(OCC)[SH:20])C>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([NH2:15])=[S:20]
Reactant: CCOP(=S)(S)OCC
Reactant: N#CCCN1C(=O)c2ccccc2C1=O
Solvent: O
Product: NC(=S)CCN1C(=O)c2ccccc2C1=O
Yield: 91 %

Procedure:
A suspension of 3-(1,3-dioxoisoindolin-2-yl)-propionitrile (2 g, 9.99 mmol) and dithiophosphoric acid O,O′-diethyl ester (2.05 g, 1.74 mL, 11.0 mmol) in water (4 mL) was irradiated at 80° C. for 10 min. The obtained suspension was diluted with water (5 mL), filtered, washed with water and dried in vacuo to give the product as light yellow solid (2.13 g, 9.09 mmol, 91.0%) which was used without further purification for the next step. MS: M=235.1 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.[N:39]1([C:47](=O)[CH2:48]Cl)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[N:39]1([CH2:47][CH2:48][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[CH:20]3[CH2:29][CH2:28][C:27]4[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=4[CH2:21]3)=[CH:37][CH:38]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(CCl)N1CCCCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCCCCCC3)cc2)c1
Yield: 64.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 1-azocan-1-yl-2-chloroethanone (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (21 mg) was obtained.
Reaction SMILES: [C:1]([C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:17]([O:20][CH2:21][CH3:22])(=[O:19])C>O>[C:1]([C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12])([C:4]([C:7]([F:10])([F:8])[F:9])([F:6])[F:5])([F:3])[F:2].[NH2:13][C:17]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(C)=O
Agent: O=C(NCCO)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Product: CCOC(N)=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A 500 mL round bottom flask equipped with a magnetic stirrer and fitted with a condenser was charged with C3F7CONHC2H4OH (30.0 grams), ethyl acetate (53.0 grams) and N3300 (22.6 grams). Upon dissolution, the mixture was heated to 80° C., DBTDL (one drop) was added, and heating was continued for 16 hours. The reaction was monitored by FTIR analysis, which showed the disappearance of the —NCO band at approximately 2289 wavenumbers. A solution of Witconate DS-10 (2.6 grams) in DI water (200.0 grams) was slowly added to the solution in the 500 mL flask with vigorous stirring, keeping the temperature between 65° C. and 73° C. during addition. Upon completion of addition, the solution was sonicated with a Cole-Parmer ultrasonic homogenizer (model CPX 600, available from Cole-Parmer, Vernon Hills, Ill.) for 8 minutes. The ethyl acetate was removed using a rotary evaporator, yielding C3F7CONHC2H4OH/N3300 Urethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:17]=O)=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1.[Cl-].[OH:20][NH3+:21].Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH:17]=[N:21][OH:20])=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1
Reactant: [NH3+]O
Reactant: COc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Product: COc1cc2c(cc1C=NO)C(C)(C)CCC2(C)C
Yield: 97.6 %

Procedure:
5 g (20 millimoles) of 5,6,7,8-tetrah-ydro-3-methoxy-5,5,8,8-tetramethyl-2-naphthaldehyde and 2.1 g (30 millimoles) of hydroxylammonium chloride in 32.5 ml of dry pyridine were refluxed for 2 hours. The mixture was then allowed to cool, poured onto water and acidified with concentrated hydrochloric acid, and the precipitate which had separated out was filtered off under suction and dried to give 5.1 g of 5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethyl-2-naphthaldoxime of melting point 182°-183° C.