Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]([O:48][C:49]([NH:51][CH2:52][C:53](O)=[O:54])=[O:50])([CH3:47])([CH3:46])[CH3:45].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)(Cl)Cl>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([C:53](=[O:54])[CH2:52][NH:51][C:49](=[O:50])[O:48][C:44]([CH3:45])([CH3:46])[CH3:47])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
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: ClC(Cl)Cl
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C(=O)CNC(=O)OC(C)(C)C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 1 (100 mg, 0.167 mmol) obtained in Example 1 was dissolved in chloroform (2 mL), and stirred at room temperature for 4 hours after adding N-(tert-butoxycarbonyl)glycine (Tokyo Chemical Industry Co., Ltd.; 55 mg, 0.250 mmol), diisopropylethylamine (0.146 mL, 0.833 mmol), and HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (Aldrich; 127 mg, 0.333 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3) to give tert-butyl 2-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)-2-oxoethylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[NH2:19])[CH:7]=1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=2[NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:32])[F:33])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1
Solvent: CCOCC
Product: O=S(=O)(Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Using the method of Example 17.4, 4-(3-chloro-5-pyridyloxy)-3-aminobenzotrifluoride (0.4 g) and 4-trifluoromethylbenzenesulfonyl chloride ((0.339 g ) were combined to provide, after trituration with ether, the title sulfonamide (0.198 g) which was obtained as a crystalline solid. mp 169-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([N:26]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:16]([O:15][CH3:14])[CH:17]=1)[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:8])=[O:5]
Reactant: COC(=O)c1ccc(NNC(=O)OC(C)(C)C)cc1OC
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(F)cccc2Cl)cc1OC
Yield: 89.6 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2-chloro-6-fluorobenzoyl isocyanate (Intermediate-8, 2.0 g, 6.75 mmol), tert-butyl 2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (Intermediate-14, 2.0 g, 10.10 mmol) and DCM (30 mL) to afford 3.0 g of desired product. 1H NMR (300 MHz, DMSO do): δ 1.42 (s, 9H), 3.76 (s, 6H), 6.99 (d, J=8.1 Hz, 1H), 7.11 (s, 1H), 7.2-7.50 (m, 4H), 9.88 (s, 1H), 11.32 (s, 1H); MS (m/z): 493.92 (M−H)−.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].[CH:27]([C:29]1[CH:47]=[CH:46][C:32]([O:33][CH2:34][C:35]([NH:38]C(=O)OC(C)(C)C)([CH3:37])[CH3:36])=[CH:31][CH:30]=1)=O>>[NH2:38][C:35]([CH3:36])([CH3:37])[CH2:34][O:33][C:32]1[CH:31]=[CH:30][C:29]([CH2:27][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C@@H:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:47][CH:46]=1
Reactant: CCNc1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Product: CC(C)(N)COc1ccc(CCCNc2ccccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 29 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylaminophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and tert-butyl [2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].Cl>C1COCC1.O>[I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(C(F)(F)F)ccc1I
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)ccc1I
Reaction time: 0.5 h

Procedure:
Borane-THF (1.0M solution in THF; 94 mL; 94 mmol) was added to a stirred solution of 2-iodo-5-(trifluoromethyl)benzoic acid (2.97 g; 9.4 mmol) in THF (300 mL) at 0° C. under N2. The reaction was heated at reflux for 90 min and then carefully quenched with 6N HCl until no further gas evolution. The reaction was diluted with H2O (250 mL) and extracted with EtOAc (3×250 mL). The combined extracts were washed with brine (300 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid. LCMS=285.0 (M−17)+. 1H NMR (CDCl3, 500 MHz): δ 7.97 (d, J=8.3 Hz, 1 H), 7.79 (s, 1 H), 7.28 (d, J=8.4 Hz, 1 H), 4.75 (s, 2 H). An alternative procedure is as follows: To a solution of 2-Iodo-5-(trifluoromethyl)benzaldehyde (EXAMPLE 80, Step A, 9 g) in THF (100 mL) and water (10 mL) at 0° C. was added NaBH4 (0.5 g). The reaction was stirred 30 minutes. To the reaction mixture was added dilute aqueous HCl (cautiously). The mixture was extracted with ether and the ether layer was washed with water, then brine. The ether layer was then dried over anhydrous MgSO4, filtered and concentrated. The material is chromatographed on SiO2 using a step gradient of 1:3 CH2Cl2/hexanes, then 1:1 CH2Cl2/hexanes, then 100% CH2Cl2 to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid.
Reaction SMILES: [Na].[NH2:2][C:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=2)[N:4]=1.C(#N)C=C[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[NH2:2][C:3]1[CH2:7][CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=2)[N:4]=1
Reactant: N#CC=Cc1ccccc1
Reactant: NC1=NN(c2ccc(Cl)cn2)CC1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccc(Cl)cn2)C(c2ccccc2)C1

Procedure:
A 0.5 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 14.36 g. of 5-chloro-2-hydrazinopyridine (prepared as described in Example 3) is added followed by 12.92 g. of cinnamonitrile. The reaction mixture is refluxed for 16 hours. The solvent is removed in vacuo and water is added to the residue to separate a solid. The solid is collected by filtration and dissolved in dichloromethane. The solution is dried over anhydrous sodium sulfate and filtered through a hydrous magnesium silicate. The filtrate is concentrated while adding hexane to separate crystals. The material is recrystallized from ethyl acetate to give 11.68 g. of a light yellow crystalline material. The material is dried in vacuo to give the product of the Example as yellow crystals, m.p. 142°-147° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[ClH:14].[C:15]1([CH3:27])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C.Cl>O1CCOCC1>[ClH:14].[C:15]1([CH3:27])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=2)[CH2:25][CH2:26]1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: Cc1ccccc1N1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccccc1N1CCN(Cc2ccc(CC(=O)O)cc2)CC1
Yield: 52.7 %

Procedure:
Using 2.2 g of methyl 4-bromomethylphenylacetate, 1.9 g of 1-(2-tolyl)piperazine hydrochloride, 2.5 ml of triethylamine, and 80 ml of dioxane, the reaction procedure of Example 2 was otherwise repeated and the reaction product was converted to the hydrochloride using 2N-hydrochloric acid and recrystallized from ethanol-ether to provide 1.7 g of the title compound melting at 249° C.-252° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH3:21])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1.[CH3:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH3:21])[N:5]([C:26](=[O:27])[CH2:25][CH2:24][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](C)NCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@@H](C)C(=O)OC

Procedure:
Reaction of 2.0 g of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-alanine methyl ester, 1.23 ml of triethylamine and 0.92 ml of n-butyryl chloride yields N-butyryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-alanine methyl ester. (TLC: N2) Rf : 0.5.
Reaction SMILES: C[Si](C)(C)[N:3]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[Si](C)(C)C.[CH3:15][N:16]([CH2:18][CH2:19][NH:20][C:21]([CH3:26])=[CH:22][C:23](=O)[CH3:24])[CH3:17].FC(F)(F)C(F)(F)C(O)=O.CC(C)([O-])C.[Na+]>O1CCCC1>[CH3:11][N:10]([CH2:9][CH2:8][NH:3][C:23](=[CH:22][C:21](=[N:20][CH2:19][CH2:18][N:16]([CH3:15])[CH3:17])[CH3:26])[CH3:24])[CH3:12]
Reactant: CN(C)CCN([Si](C)(C)C)[Si](C)(C)C
Reactant: CC(=O)C=C(C)NCCN(C)C
Agent: CC(C)(C)[O-]
Agent: O=C(O)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=CC(C)=NCCN(C)C)NCCN(C)C
Reaction time: 1 h

Procedure:
3.48 g (0.015 moles) of N,N-Bis(trimethylsilyl)-2-(N′,N′-dimethylamino)ethylamine were mixed with 1.7 g (0.01 moles) of 4-(2-(N,N-dimethylamino)ethylamino)-3-penten-2-one. To this mixture was added 1.64 g (0.0125 moles) of pentafluoropropionic acid dropwise over 5 minutes with rapid stirring. The mixture darkened and became warm, eventually forming two immiscible layers, and was allowed to stir for 1 hour. 0.98 g (0.0125 moles) of sodium t-butoxide dissolved in 5 ml of tetrahydrofuran was then added dropwise over a five minute period. The mixture warmed and became one liquid phase, which was yellow. The solvent was then removed by vacuum distillation at room temperature, and the product then vacuum distilled out of the resulting residue as a clear liquid by heating >150° C. Yield of MeC(NCH2CH2NMe2)CHC(HNCH2CH2NMe2)Me=2.05 g (85% of theoretical).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH:60]1[CH2:65][CH2:64][CH:63]([N:66]2[C:74]3[C:69](=[N:70][CH:71]=[CH:72][CH:73]=3)[NH:68][C:67]2=[O:75])[CH2:62][CH2:61]1>CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:60]4[CH2:61][CH2:62][CH:63]([N:66]5[C:74]6[C:69](=[N:70][CH:71]=[CH:72][CH:73]=6)[NH:68][C:67]5=[O:75])[CH2:64][CH2:65]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
(S)-2-(1,4-Dichloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (110 mg, 0.268 mmol) was dissolved in N,N-dimethylformamide (2.0 ml). N,N-Diisopropylethylamine (150 μl, 0.861 mmol) was added to the mixture followed successively by TBTU (92 mg, 0.287 mmol) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (92 mg, 0.316 mmol). Reaction stirred at room temperature for 5 hours. Reaction was quenched with 50% acetonitrile-water. Material was purified by prep HPLC (water-acetonitrile-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 70% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.89 (s, 1H) 11.55 (s, 1H) 7.90 (dd, J=5.19, 1.22 Hz, 1 H) 7.64 (dd, J=70.19, 7.93 Hz, 1H) 7.35 (s, 1H) 6.99 (dd, J=7.78, 5.34 Hz, 0.4H) 6.90 (dd, J=7.93, 5.19 Hz, 0.6H) 5.44 (d, J=4.88 Hz, 2H) 4.35-4.62 (m, 3H) 3.95-4.32 (m, 3H) 3.15-3.28 (m, 2H) 2.85-3.12 (m, 2H) 2.61-2.76 (m, 1H) 2.20-2.47 (m, 2H) 1.93-2.12 (m, 1H) 1.64-1.87 (m, 2H). High resolution MS m/e (M+H)+=610.1328.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(N(CC)CC)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>[CH3:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CC(C)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-iodoisopropylbenzene (12.3 g, 50 mmol, Lancaster Chemical Co.) in triethylamine (150 mL) was added trimethylsilylacetylene (5.89 g, 60 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.70 g, 1 mmol, Aldrich), and copper(I) iodide (1.5 g). The reaction was stirred at room temperature for 18 hours, diluted with hexanes and filtered. The filtrate was evaporated under reduced pressure to give crude 1-(4-(2-propyl)phenyl)-2-trimethylsilyl acetylene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18](=[O:22])[CH:19]=[N+]=[N-])[CH3:16]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][O:11][CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCCl
Product: CCOC(=O)COC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 65.4 %

Procedure:
To a solution of N-t-butyloxycarbonyl-(S)-prolinol (5.0 g, 25 mmol) in 1,2-dichloroethane (500 ml) rhodium(II)acetate (180 mg) was added and the mixture is was heated to 80° C. Ethyldiazoacetate (3.9 ml, 37 mmol) in 1,2-dichloroethane (180 ml) was added over a period of 90 min and the mixture was heated at 80° C. for 3 hours. Then another portion of ethyldiazoacetate (1.3 ml, 12 mmol) in 1,2-dichloroethane (40 ml) was added and the mixture was refluxed for 6 hours. The mixture was cooled to room temperature and washed with saturated sodium bicarbonate (2×100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (300 g) with petrol ether/ethyl acetate 4:1 as eluent to give 4.7 g of (2S)-2-(((ethoxycarbonyl)methoxy)methyl)pyrrolidin-1-carboxylic acid tert-butylester. The obtained product was taken up in 50 ml of 1 M lithium hydroxide in water/methanol 1:3 and stirred at room temperature overnight. The mixture was concentrated in vacuo, water (20 mL) was added and washed with ether (20 mL). The aqueous phase was acidified to pH 4 with 1 M aqueous hydrogen chloride and extracted with ethyl acetate (200 ml), dried over magnesium sulfate and concentrated in vacuo to give 3.6 g of (2S)-2-(((carboxy)methoxy)methyl)pyrrolidin-1-carboxylic acid tert-butylester.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH:10]=[CH:9]4)[C@H:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH2:33]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH:10]=[CH:9]4)[C@H:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:5][C:4]=2[CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O

Procedure:
A solution of 2.85 g of 3-hydroxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one in 57 ml of acetone is mixed with 3.25 g of cesium carbonate and 1.14 ml of benzyl bromide, and the mixture is refluxed for 1 hour. The reaction mixture is concentrated by evaporation, the residue is mixed with water, shaken out with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate. 3.12 g of 3-benzyloxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one is obtained as foam.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C(N(CC)CC)C>[C:22]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)(=[O:25])[CH:23]=[CH2:24]
Reactant: C=CC(=O)Cl
Reactant: c1ccc(C2CNc3ccccc32)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CC(c2ccccc2)c2ccccc21
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A mixture comprising 4.0 g of 3-phenylindoline, 40 ml of benzene, 5 ml of triethylamine and 4.0 g of acryloylchloride was stirred at 10°-15° C. for 15 minutes. The mixture was then washed with water, the benzene solution dried and the solvent removed. 4.1 G of resin which was crystallized from ether to give 2.3 g of the desired N-acryloyl-3-phenylindoline which was found to have a melting point of 77°-8° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:30][CH2:27][CH:28]=[CH2:29])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: C=CCN
Solvent: CC#N
Product: C=CCNCC1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), prop-2-en-1-amine (0.5 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. MS m/z (rel. intensity, 70 eV) 283 (M+, 4), 79 (4), 71 (6), 70 (bp), 68 (4).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:13]([CH:15]1CCC(=O)CC1)[CH3:14]>C(OC(=O)C)(=O)C>[CH3:14][C:13]1([CH3:15])[O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[O:4]1
Reactant: CCC1CCC(=O)CC1
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)OC(=O)CC(=O)O1
Temperature: 25 °C
Yield: 124.9 %

Procedure:
Malonic acid (5.2 g, 0.05 mol) and concentrated sulfuric acid (0.5 ml) were added to acetic anhydride (10 ml), and therein the source compound was dissolved thoroughly while stirring at room temperature. Thereto, 4-ethylcyclohexanone (6.31 g, 0.05 mol) was slowly added dropwise while cooling in an ice bath. The stirring of the admixture was continued in an ice bath, and colorless crystals separated out as the reaction progressed. These crystals were filtered off, washed with distilled water, and dried. Thus, 9.0 g of a meldrum's acid derivative was obtained as colorless crystals (in a 85.1% yield). The thus obtained meldrum's acid derivative (4.25 g, 0.02 mol) and N,N′-1,3-pentadiene-1-yl-5-ylidenedianiline hydrochloride (5.70 g, 0.02 mol) were dissolved in methanol (50 ml), and thereto triethylamine (3.04 g, 0.03 mol) was added. The stirring of the resulting admixture was continued at room temperature to result in deposition of violet crystals. Then, these crystals were filtered off, and washed with methanol. Thus, 5.61 g of violet crystals corresponding to Compound (3-I) was obtained (in a 76.3% yield). These violet crystals (4.40 g, 12.0 mmol) and the Compound (1-I) obtained in the foregoing Synthesis (1.71 g, 6.0 mmol) were dissolved in dimethylformamide (20 ml), and thereto triethylamine (1.82 g, 18 mmol) was added dropwise. The resulting admixture was stirred for 4 hours at 50° C. Thereafter, the reaction solution obtained was admixed with distilled water, and extracted with ethyl acetate. The organic layer thus extracted was purified by column chromatography (dichloromethane/methanol=6/1) on silica gel to give 2.0 g of violet powder corresponding to Compound (3-II) (in a 39.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)C=1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:30](=[O:31])[CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:5][C:4]=1[O:10][CH2:11][C:12]1[C:19]2[C:20](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:21]=[CH:22][CH:13]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(N)cc1OCCc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1ccc(NC(=O)C(c2ccccc2)c2ccccc2)cc1OCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[4-methoxy-3-(naphthylmethoxy)phenyl]-2,2-diphenylethanamide (Exemplary Compound 49) was prepared using the same experimental conditions used to prepare Example 52 (Scheme X). From 4-methoxy-3-(2-naphthylethoxy)phenylamine (350 mg, 1.25 mmol) and diphenylacetyl chloride (290 mg, 1.25 mmol) in 10 mL of dimethyl acetamide containing triethylamine (1 mL, 7.17 mmol) stirred at room temperature for 16 h., was obtained 375 mg of product in (64%) yield as a white solid after recrystallization from ethyl acetate/hexane: mp 170-172° C. 1H NMR (400 MHz, Me2SO-d6) δ3.69 (s, 3H); 5.13 (s, 1H); 5.46 (s, 2H); 6.93 (d, 1H, J=8.7); 7.20-7.37 (m, 10H); 7.50-7.65 (m, 5H); 7.94-8.09 (m, 3H); 10.28 (s, 1H). Anal. Calcd for C32H27NO3: C, 81.16; H, 5.75; N, 2.96. Found: C, 80.95; H, 5.76; N, 3.03.