Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][O:12][C:10](=[O:11])[C:9]2=[CH2:14])=[CH:4][CH:3]=1.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C.C(OCC)C>[CH2:15]([S:22][CH2:14][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13][O:12][C:10]1=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C1C(=O)OCC1c1ccc(Cl)cc1
Reactant: SCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C1OCC(c2ccc(Cl)cc2)C1CSCc1ccccc1
Reaction time: 6 h
Yield: 81 %

Procedure:
To a solution of 700 mg of β-(p-chlorophenyl)-α-methylene-γ-butyrolactone in 10 ml of toluene were added 0.51 ml of benzylmercaptan and one drop of triethylamine and the resulting mixture was kept at room temperature for 6 hours. After completion of the reaction, the reaction mixture was diluted with 100 ml of ethyl ether, washed with 10% aqueous sodium hydroxide and saturated saline, dried over magnesium sulfate and the solvent was distilled off. The crude product thus obtained was purified by a column chromatography to give 900 mg (yield 81%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]3[CH2:28][C:29](O)=[O:30])[CH2:17][CH2:16]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.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>CN(C=O)C>[O:30]=[C:29]1[CH2:28][C@@H:23]2[C@H:22]([CH2:27][CH2:26][CH2:25][CH2:24]2)[N:21]1[CH:18]1[CH2:17][CH2:16][N:15]([C:2]2([CH3:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:6][CH2:7]2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3CC(=O)O)CC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CC1

Procedure:
A solution of 2-[(1R,2S)-2-[[1-[4-methyl-1-[(2-methylpropan-2-yl)oxycarbonyl]-4-piperidyl]-4-piperidyl]amino]cyclohexyl]acetic acid, diisopropylethylamine (0.5 mL, 3.36 mmol) and HATU (0.7 g, 1.84 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction quenched with water and concentrated in vacuo. The residue was diluted in ethylacetate (100 mL) and washed with 1N NaOH (10 mL). The organic phase was separated and aqueous phase was extracted with ethylacetate (2×30 mL). The combined organic phases were dried and concentrated in vacuo to provide the title compound. MS (M+1): 420.38.
Reaction SMILES: [P:1]([O:44]C(C)(C)C)([O:39]C(C)(C)C)([O:3][CH2:4][C@@H:5]([NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([NH2:28])=[N:26][CH:25]=[C:24]([C@H:29]3[CH2:34][CH2:33][C@H:32]([OH:35])[C@@H:31]([F:36])[CH2:30]3)[N:23]=2)=[CH:18][C:17]=1[F:37])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[CH:7]=1)=[O:2].Cl.O1CCOCC1>CO>[P:1]([OH:39])([OH:44])([O:3][CH2:4][C@@H:5]([NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([NH2:28])=[N:26][CH:25]=[C:24]([C@H:29]3[CH2:34][CH2:33][C@H:32]([OH:35])[C@@H:31]([F:36])[CH2:30]3)[N:23]=2)=[CH:18][C:17]=1[F:37])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[CH:7]=1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OC[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(I)c1)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)N[C@H](COP(=O)(O)O)c2cc(F)cc(I)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
(S)-2-(4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate (4600 mg, 5.72 mmol) was fully dissolved in MeOH (Volume: 70 mL). Then HCl 4M in Dioxane (14.29 mL, 57.2 mmol) was added and stirred at room temperature for 3 hours, followed by LCMS. The solvent was concentrated mostly off. Then MeOH (Volume: 70 mL) was added and the solvent was concentrated off to residue, additional MeOH (Volume: 70 mL) was added and the residue concentrated to constant mass. The product was dissolved in 90 ml of 1:1 ACN/water and lyophilized to give 3.99 grams of the desired product as HCl salt. (94% yield). LCMS (m/z): 692.9 (MH+), 0.63 min. 1H NMR (<cd3od>) d: 7.84-7.93 (m, 1H), 7.75 (s, 1H), 7.60-7.71 (m, 3H), 7.45-7.51 (m, 1H), 7.26 (dt, J=9.7, 1.6 Hz, 1H), 5.40 (t, J=5.9 Hz, 1H), 4.31-4.50 (m, 1H), 4.22-4.30 (m, 2H), 3.64 (tdd, J=11.7, 8.6, 5.1 Hz, 1H), 2.82-2.98 (m, 1H), 2.32 (ddt, J=11.7, 5.8, 2.8 Hz, 1H), 2.01-2.15 (m, 1H), 1.89-1.97 (m, 1H), 1.75-1.89 (m, 1H), 1.58-1.72 (m, 1H), 1.42-1.55 (m, 1H). 31P NMR (<cd3od>) d: 0.00 (s, 1P).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30]C(OC(C)(C)C)=O)[CH2:12][C@@H:11]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:46][Mg]Br.[O:49]1[CH2:53][CH2:52]CC1.[Cl-].[NH4+].O>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30][C:53]([OH:49])([CH3:52])[CH3:46])[CH2:12][C@@H:11]([O:38][Si:39]([C:42]([CH3:44])([CH3:45])[CH3:43])([CH3:40])[CH3:41])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)COCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(O)COCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(tert-butoxycarbonylmethoxymethyl)androsta-5,7,16-triene (175 mg, 0.266 mmol) in tetrahydrofuran (4 ml), was added dropwise a 0.93M methylmagnesium bromide/tetrahydrofuran solution (3 ml, 2.79 mmol) at external temperature of −30° C., followed by stirring at the same temperature for 1 hour and 30 min. At the same temperature, a saturated aqueous ammonium chloride solution was added to the reaction solution, which was then warmed to room temperature and stirred for 10 min. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was purified by preparative thin layer chromatography (3 sheets (each 0.5 mm thickness), hexane:ethyl acetate=20:1, developed twice, hexane:ethyl acetate=15:1, developed twice, and hexane:ethyl acetate 10:1, developed once) to give the titled compound (115.3 mg, 70%) as a colorless oil.
Reaction SMILES: C([O:6][CH2:7][CH:8]([OH:11])[CH2:9]Cl)(=O)C(C)=C.[C:12]1([C:18]2[NH:22][N:21]=[N:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na]>COCCO>[OH:11][CH:8]([CH2:7][OH:6])[CH2:9][N:22]1[C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][N:20]=[N:21]1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: C=C(C)C(=O)OCC(O)CCl
Agent: [Na]
Solvent: COCCO
Product: OCC(O)Cn1nnnc1-c1ccccc1
Temperature: 100 °C

Procedure:
A solution of 3-chloro-2-hydroxypropyl methacrylate (0.50 mole; 89.3 g. and 500 ppm 4-methoxyphenol as inhibitor) in 2-methoxyethanol (300 ml) was added to sodium 5-phenyltetrazole (1.0 mole; 168.2 g) dissolved in 2-methoxyethanol (800 ml) and heated at 100° C. for 14.5 hours. The product solution was quenched with H2O (150 ml), extracted with CH2Cl2 (3×500 ml), the extracts washed with H2O (500 ml) and concentrated to a semi-solid, m.p. 25°-115° C, gas evolution, 219° C.
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[SH:9][CH2:10][CH:11](O)[CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:4][C:3]1[O:5][CH:11]([CH3:12])[CH2:10][S:9][C:2]=1[CH2:6][CH2:7][Cl:8]
Reactant: CC(=O)C(Cl)CCCl
Reactant: CC(O)CS
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1=C(CCCl)SCC(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 0.1 mole (15.4 g.) 3,5-dichloro-2-pentanone, and 0.1 mole (9.2 g.) 1-mercapto-2-propanol was stirred in 100 ml toluene; 0.1 mole (10.4 g.) triethylamine was added dropwise. The mixture was stirred at room temperature overnight, then washed with dilute hydrochloric acid and reluxed with 0.5 g. PTSA, using a Dean-Stark trap to remove water for about 7 hours. The PTSA solution was washed with sodium bicarbonate, dried over magnesium sulfate and the solvent was removed. The product was distilled; bp 80°-82°/0.1 mm. Yield 47%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12](=O)[CH3:13])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9].[OH:15][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[CH2:17][NH2:18]>>[ClH:25].[F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:18][CH2:17][CH:16]([OH:15])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:13])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COc1c(F)cc(CC(C)=O)cc1F
Product: COc1c(F)cc(CC(C)NCC(O)c2cccc(Cl)c2)cc1F
Product: Cl

Procedure:
N-[2-(3,5-difluoro-4-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride, m.p. 120°-140° C. was prepared from 1-(3,5-difluoro-4-methoxyphenyl)propan-2-one (500 mg) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (430 mg) as a 44:56 mixture of diastereoisomers, by an analogous procedure to that described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2C3C(=C(Br)C=CC=3)C=[CH:24][C:23]=2OC)[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.N[C@@H]1C(=O)N(CC2C3[C:61](=[CH:62][CH:63]=[CH:64]C=3)[N:60]([C:67]3[CH:74]=[CH:73][CH:72]=[CH:71][C:68]=3[C:69]#[N:70])[N:59]=2)C2C=CC=CC=2NC1.N(C(OC(C)(C)C)=O)(C)[C@H](C(O)=O)C>>[C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:23]3[C:61](=[CH:62][CH:63]=[CH:64][CH:24]=3)[N:60]([C:67]3[CH:74]=[CH:73][CH:72]=[CH:71][C:68]=3[C:69]#[N:70])[N:59]=2)[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: N#Cc1ccccc1-n1nc(CN2C(=O)[C@@H](N)CNc3ccccc32)c2ccccc21
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Agent: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)N[C@H]1CNc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Yield: 72.8 %

Procedure:
In a similar manner to that described for the preparation of {(S)-1-[(S)-1-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 12), 2-[3-((S)-3-amino-2-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-ylmethyl)-indazol-1-yl]-benzonitrile trifluoroacetate (step 1 above) (680 mg, 1.30 mmol) and Boc-N-Me-Ala-OH (290.88 mg, 1.43 mmol) were converted to the title compound (570 mg, 72.8%) obtained as white solid. LC-MS: 594 (M+H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].C([O:41][C:42]([N:44]1[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=O)(C)(C)C.[C:51](OC(=O)C)(=O)C>>[C:42]([N:44]1[CH2:50][CH2:49][CH2:48][N:47]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]3[C:8](=[O:27])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:46][CH2:45]1)(=[O:41])[CH3:51]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1c2c(-c3ccc(F)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: CC(=O)N1CCCN(c2cc(-c3ccc(F)cc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 35 %

Procedure:
In a similar manner to Example 6, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine(compound of Reference Example 16; 80.0 mg) was reacted with 1-(t-butoxycarbonyl)homopiperazine (75.1 mg) and acetic anhydride (70 μL) to obtain 9-(4-acetylhomopiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl)-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (33.4 mg, 35%).
Reaction SMILES: [CH2:1]([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.CON(C)[C:17]([C:19]1(OC)[CH2:21][CH2:20]1)=[O:18].C(OCC)(=O)C>C(OCC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]([C:19]2([CH3:1])[CH2:21][CH2:20]2)=[O:18])=[CH:8][CH:9]=1
Reactant: Clc1ccc(Br)cc1
Reactant: [Li]CCCC
Reactant: CON(C)C(=O)C1(OC)CC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
22 ml (0.036 mol) of a 1.6 molar n-butyl-lithium solution are added at -78° C. with stirring to a mixture of 6.9 g (0.036 mol) of 4-bromochlorobenzene and 70 ml of diethyl ether. The reaction mixture is warmed to 0° C. and stirred at this temperature for 15 minutes. After cooling to -78° C. again, a solution of 4.8 g (0.03 mol) of N-methoxy-N-methyl-1-methoxycyclopropane-carboxamide in 20 ml of diethyl ether is added rapidly. The mixture is then subsequently stirred at -78° C., at 0° C. and at room temperature, in each case for one hour. 20 ml of ethyl acetate are then added to the reaction mixture, which is stirred for 5 minutes and then poured into ice-water. The resulting mixture is extracted three times with ethyl acetate, and the combined organic phases are dried over sodium sulphate and then concentrated by stripping off the solvent under reduced pressure. 6.1 g (97% of theory) of 1-methycyclopropyl 4-chlorophenyl ketone are obtained in this manner and are reacted further without prior purification.
Reaction SMILES: [C:1]1([S:7](Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C@:13]1(O)[C:18](=[CH2:19])[CH2:17][C@H:16]2[C@H:20]3[C:30](=[CH:31][CH2:32][C@:14]12[CH3:15])[C@:28]1([CH3:29])[C:23](=[CH:24][C:25](=[O:33])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)(=[O:12])[CH3:11].C(N(CC)CC)C.O>C(Cl)Cl>[C:1]1([S:7]([CH2:19][C:18]2[CH2:17][C@@H:16]3[C@:14]([CH3:15])([CH2:32][CH:31]=[C:30]4[C@H:20]3[CH2:21][CH2:22][C:23]3[C@:28]4([CH3:29])[CH2:27][CH2:26][C:25](=[O:33])[CH:24]=3)[C:13]=2[C:10](=[O:12])[CH3:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)c1ccccc1
Reactant: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@]1(O)C(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)C1=C(CS(=O)c2ccccc2)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C

Procedure:
A solution of phenylsulfinylchloride (2.5N, 1.4 ml) in methylene chloride was added dropwise over a period of 1.5 hrs to a solution of 17-acetyl-17β-hydroxy-16-methyleneandrost-4,9(11)-dien-3-one (VA, Example 12, 1 g) in methylene chloride (10 ml) containing triethylamine (0.82 ml) previously cooled equal to 31 55°. Water was added to the reaction mixture, the organic phase separated, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to a partially crystalline substance. Crystallization from toluene gives the title compound, m.p. 160°-163°; NMR (CDCl3) 0.87, 1.36, 2.11, 4.03, 5.50 and 5.75 δ.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH:7]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=1Br)([CH3:9])[CH3:8].[C:23](OCC)(=O)C>CN(C)C=O.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:8][CH:7]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=1[CH:23]=[CH:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH3:9]
Reactant: CCOC(C)=O
Reactant: C=CC(=O)OC
Reactant: CC(C)c1cc(C(C)C)c(Br)c(C(C)C)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC=Cc1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of methyl acrylate (15.9 mL, 176 mmol) and bis(triphenylphosphine)palladium (II) chloride (0.99 g, 1.4 mmol) in 125 mL dimethylformamide and 125 mL triethylamine was heated to reflux for 1 hour and then 2,4,6-triisopropylbromobenzene (10.0 g, 35 mmol) was added. Reflux was continued for 6 hours and then stirred at room temperature for 16 hours. Partitioned the reaction between water and diethyl ether. The ether layer was dried with MgSO4, filtered, and concentrated to give a brown oil. Chromatography (SiO2, eluant=5% ethyl acetate in hexanes) gave 3.80 g of 3-[2,4,6-tris(1-methylethyl)phenyl]-2-propenyl carboxylic acid, methyl ester as an off-white solid, mp 61°-63° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1.O>CN(C=O)C>[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH2:30]1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: OCC1CCCNC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCC(CO)C4)cc3)c2)cc1
Reaction time: 72 h
Yield: 65.7 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4—(chloromethyl)phenyl]-3—(4-methylphenyl)cinnamamide (200 mg), and to the solution were added 3—(hydroxymethyl)piperidine (191 mg). The mixture was starred at room temperature for 72 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[3—(hydroxy-methyl)piperidinomethyl]phenyl]-3—(4-methylphenyl)cinnamamide (Compound 66) (160 mg) as colorless crystals.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:24])[CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:3][CH:2]=1.[N+:25]([C:28]1[O:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([O-:27])=[O:26].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(O)(=O)C.ClCCl>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:24])[CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:32][C:31]3[O:34][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)=[CH:3][CH:2]=1
Reactant: OC(COc1cccc2[nH]c3ccccc3c12)CN1CCNCC1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCN(CC(O)COc3cccc4[nH]c5ccccc5c34)CC2)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 28.8 %

Procedure:
To a mixture of 1-(9H-carbazol-4-yloxy)-3-piperazin-1-yl propan-2-ol (0.5 g 1.54 mmol) in THF (10 mL), was added 2-3 drops of glacial acetic acid, followed by 5-nitrofurfural (0.325 g, 2.3 mmol). To the above solution Na(OAc)3BH (0.98 g, 4.6 mmol) was added carefully at room temperature and the reaction mixture was stirred at room temperature for 6 hours. Subsequently the reaction mixture was diluted with dichloromethane (50 mL), washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography using dichloromethane/MeOH (9:1) to afford the title compound as a yellow colored solid (0.2 g, 29% yield) with m.p.: 54-59° C. 1H NMR (400 MHz, CDCl3): δ 2.40-2.65 (m, 6H), 2.70-2.80 (m, 4H), 3.67 (s, 2H), 4.20-4.25 (m, 1H), 4.27-4.34 (m, 2H) 6.49 (d, 1H, J=3.6 Hz), 6.67 (d, 1H, J=8.0 Hz), 7.06 (d, 1H, J=8.0 Hz), 7.20-7.50 (m, 5H), 8.27 (s, 1H), and 8.30 (d, 1H, J=8 Hz). MS m/z: 451 (M+1).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[C:11]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]#[N:34]>ClCCl>[C:19]([C:11]1[CH:10]=[C:9]([Cl:8])[CH:14]=[CH:13][C:12]=1[S:15]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:28]#[N:27])(=[O:17])=[O:16])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1S(=O)(=O)Cl
Reactant: N#CCCCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
15 ml of redistilled triethylamine are added to 15.7 g of 4-chloro-2-benzoylbenzenesulphonyl chloride in 100 ml of anhydrous dichloromethane, and 5.6 g of 6-aminocapronitrile in 20 ml of dichloromethane are then added dropwise at 0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[F:22])[C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]=3[N:9]=2)=[C:4]([OH:27])[CH:3]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[F:22])[C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]=3[N:9]=2)=[C:4]([O:27][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:3]=1
Reactant: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3O)nc3ccccc32)c(F)c1
Reactant: ICC1CCCC1
Product: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3ccccc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 4-[2-(4-chloro-2-hydroxy-phenyl)-benzoimidazol-1-ylmethyl]-3-fluoro-benzonitrile and iodomethyl-cyclopentane (CAS Reg. No. 27935-87-1). Light yellow sticky solid (35%). MS (Turbo Spray): m/z=460.2 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][N:4]([CH2:14][CH:15]([OH:24])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[K+]>C(O)CC>[CH2:33]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][N:4]([CH2:14][CH:15]([OH:24])[CH2:16][O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:3][CH:2]([OH:1])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:12][CH:11]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Oc1ccc(CCN(CC(O)COc2ccccc2)CC(O)COc2ccccc2)cc1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: OC(COc1ccccc1)CN(CCc1ccc(OCc2ccccc2)cc1)CC(O)COc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 1.0 g of p-[2-[bis[(RS)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenol, 0.27 ml of benzyl bromide and 257 mg of potassium hydroxide in 30 ml of n-propanol was heated to 120° for 18 hours. The reaction mixture was poured on to ice-water and extracted with ethyl acetate. The crude product obtained after evaporation of the solvent was chromatographed on silica gel. The fractions which were uniform according to thin-layer chromatography were recrystallized from acetone-hexane and yielded pure 1,1'-[[p-(benzyloxy)phenethyl]imino]bis-[(RS)-3-phenoxy-2-propanol], m.p. 106°-110°, ε219 =30020.