Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:31]=[CH:30][C:5]2[N:6]=[C:7]3[CH2:12][C@H:11]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=4[F:21])[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9][N:8]3[C:4]=2[CH:3]=1.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH:32]1([C:2]2[N:31]=[CH:30][C:5]3[N:6]=[C:7]4[CH2:12][C@H:11]([C:13]5[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=5[F:21])[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])[CH2:9][N:8]4[C:4]=3[CH:3]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cnc(Cl)cc32)C[C@@H]1c1cc(F)c(F)cc1F
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cnc(C4CC4)cc32)C[C@@H]1c1cc(F)c(F)cc1F
Temperature: 25 °C

Procedure:
An oven dried flask charged with 52 mg (0.115 mmol) of tert-butyl [(7R,8R)-3-chloro-8-(2,4,5-trifluorophenyl)-6,7,8,9-tetrahydropyrido[3′,4′:4,5]imidazo[1,2-a]pyridine-7-yl]carbamate (Boc-protected intermediate of Example 5), 12 mg (0.14 mmol) of cyclopropylboronic acid, 64 mg (0.46 mmol) of potassium carbonate, 13 mg (0.0115 mmol) of tetrakis(triphenylphosphine)palladium(0) and 1.5 mL of dry dioxane was put under nitrogen and heated to reflux for 72 h. The reaction mixture was cooled to ambient temperature, filtered through a pad of Celite and the filter cake rinsed with 50 mL of ethyl acetate. The filtrate was evaporated in vacuo and the crude residue was purified directly by reverse phase HPLC(YMC Pro-C18 column, gradient elution, 5% to 90% acetonitrile/water with 0.1% TFA) to afford the title compound as a white foam. LC/MS 459.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:33]([CH2:36][CH3:37])=[CH:34][CH:35]=3)[N:11]=[C:12]([CH2:22][O:23][CH2:24][CH2:25][O:26]C3CCCCO3)[C:13]=2[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[N:6][CH:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:33]([CH2:36][CH3:37])=[CH:34][CH:35]=3)[N:11]=[C:12]([CH2:22][O:23][CH2:24][CH2:25][OH:26])[C:13]=2[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)CCCc1c(COCCOC2CCCCO2)nn2c(CC)ccc2c1-c1cncc(Br)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CCOC(=O)CCCc1c(COCCO)nn2c(CC)ccc2c1-c1cncc(Br)c1
Yield: 90.8 %

Procedure:
A mixture of ethyl 4-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)butanoate (89 mg) and pyridinium p-toluenesulfonate (0.8 mg) in MeOH (5 mL) was heated under reflux for 2 hours. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (10:1-1:1) to give ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate as yellow oil (69 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[C:4]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[N:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccnc1Oc1cccc(C=C2CCNCC2)c1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccnc1Oc1cccc(C=C2CCN(C(=O)Nc3cccnn3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
3-Methyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (500 mg, 1.42 mmol, from Example 42, Step 5), phenyl pyridazin-3-ylcarbamate (335 mg, 1.56 mmol) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4CH):CH2Cl2) to afford the title compound (380 mg) as a white foam. MS (APCI 10V) AP+ 402.0, 281.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.33 (s, 3H) 2.46 (td, J=5.86, 0.80 Hz, 2H) 2.59 (td, J=5.71, 0.82 Hz, 2H) 3.52-3.62 (m, 2H) 3.64-3.71 (m, 2H) 6.44 (s, 1H) 6.84-6.94 (m, 2H) 7.03 (d, J=7.24 Hz, 1H) 7.05 (d, J=7.33 Hz, 1H) 7.34 (dd, J=8.78, 7.66 Hz, 1H) 7.59 (dd, J=9.15, 4.67 Hz, 1H) 7.66-7.73 (m, 1H) 7.87-7.96 (m, J=4.96, 1.22, 0.55, 0.55 Hz, 1H) 8.12 (d, J=8.97 Hz, 1H) 8.78 (d, J=4.26 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][C:19]([O:21]CC)=[O:20])=[O:5])C.[OH-].[Na+].Cl>CCO>[C:19]([CH2:18][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[S:10][C:6]=1[C:4]([OH:5])=[O:3])([OH:21])=[O:20]
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-4-ethoxycarbonylmethyl-thiazole-5-carboxylic acid ethyl ester (99 g, 280 mmol) in EtOH (500 mL) and add 2 M NaOH (700 mL, 1400 mmol). Heat the mixture to 50° C. for 1.5 h, then cool the solution in an ice bath, and treat with 2.5 M HCl (1 L) and stir for 2 h. Collect the precipitate by filtration, washing with 50% EtOH/water (500 mL), and then washing with water (1 L). Dry in a vacuum oven overnight at 45° C. to give 80.2 g (95%) of the title compound. 1H NMR (DMSO-d6, 500 MHz): δ 13.66 (br s, 1H), 12.55 (br s, 1H), 8.01 (d, 2H, J=8.6), 7.60 (d, 2H, J=8.9), 4.11 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:26]4[CH:27]=[CH:28][O:24][CH:25]=4)=[CH:3][CH:4]=3)[C:9]([CH3:23])=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(Br)cc1
Reactant: OB(O)c1ccoc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(-c2ccoc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 35 using 1-(4-bromophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole instead of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole and 3-furanboronic acid instead of 2-furanboronic acid in step 4.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[NH:10][C@@H:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:48]([NH:55][NH2:56])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CCN(CC)CC>>[CH2:1]([NH:8][C:9]([NH:10][C@H:11]([C:12]([NH:56][NH:55][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:14])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@H](NC(=O)NCc1ccccc1)C(=O)O
Reactant: NNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H](NC(=O)NCc1ccccc1)C(=O)NNCc1ccccc1

Procedure:
(L)-tert-Leucine (0.500 g, 3.81 mmol) was dissolved in dioxane (23 mL) and 2M NaOH (6.3 mL, 12.6 mmol) was added. After stirring for 10 min, phenylisocyanate (0.900 mL, 7.29 mmol) was added drop wise to yield a clear solution. The reaction mixture was stirred at room temperature for 18 h and then made acidic by addition of concentrated HCl and thereafter extracted with EtOAc. The organic phase was dried and evaporated to afford (2S)-2-(3-benzyl-ureido)-3,3-dimethyl-butyric acid (0.36 g, 36% yield), which was analysed by NMR and then used without further purification. The general procedure for the preparation of hydrazides described above was then followed using the crude (2S)-2-(3-benzyl-ureido)-3,3-dimethyl-butyric acid (0.646 g, 2.44 mmol), EDAC (0.515 g, 2.67 mmol), HOBT (0.363 g, 2.69 mmol), NMM (0.300 mL, 2.73 mmol), benzylhydrazine×2HCl (0.528 g, 2.71 mmol) and Et3N (0.753 mL, 5.38 mmol). The product was filtered through a short silica column (CHCl3/MeOH, 100:0-95:5) and then used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH3:9][N:10]([CH3:22])[CH2:11][C:12]#[C:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].[Cl-].[NH4+]>C(OCC)C>[CH3:22][N:10]([CH3:9])[CH2:11][CH:12]=[C:13]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15]
Reactant: CN(C)CC#CC(O)c1ccccc1
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)CC=C(c1ccccc1)C(O)c1ccccc1
Temperature: 0 °C
Yield: 27.6 %

Procedure:
A solution of bromobenzene (24.8 g) in ethyl ether (120 cc) is added dropwise over approximately 1 hour to a suspension of magnesium turnings (3.85 g) in ethyl ether (100 cc). 4-Dimethylamino-1-phenyl-2-butyn-1-ol (10 g) in ethyl ether (30 cc) is added over approximately 15 minutes to the black solution obtained. The reaction mixture is then refluxed for 3 hours and 30 minutes, and then poured into a mixture of ice (400 g) and a saturated aqueous solution (200 cc) of ammonium chloride. The organic phase is separated; the aqueous phase is extracted with methylene chloride (2×200 cc); the organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by "flash" chromatography [eluent: methanol/ethyl acetate (60/40 by volume)], fractions 18 to 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After the residue has been recrystallised from isopropyl ether, 4-dimethylamino-1,2-diphenyl-2-buten-1-ol (E) (3.9 g) is obtained in the form of white crystals melting at 113° C.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=3)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([CH3:38])=O)(O)=[O:28]>C(O)CO>[CH3:38][C:36]1[C:31]2[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27](=[O:28])[N:1]([C:3]2[CH:8]=[C:7]([C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=4)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=3)[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CCOc1cc2cc(CO)cc(-c3ccnc(NN)c3)c2cc1OCC
Reactant: CC(=O)c1ccccc1C(=O)O
Solvent: OCCO
Product: CCOc1cc2cc(CO)cc(-c3ccnc(-n4nc(C)c5ccccc5c4=O)c3)c2cc1OCC
Yield: 87.5 %

Procedure:
1-(2-Hydrazino-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (177 mg), 1-carboxy-2-methylcarbonylbenzene (86 mg) and ethylene glycol (1 ml) are treated in the same manner as in Example 104-(3) to give 1-{2-(4-methyl-1(2H)-phthalazinon-2-yl)-4-pyridyl}-3-hydroxymethyl-6,7-diethoxynaphthalene (211 mg), which is listed in Table 14.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[F:30])=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[C:24]([F:30])=[CH:25][CH:26]=[CH:27][C:28]=1[F:29]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3c(F)cccc3F)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1c(F)cccc1F

Procedure:
The 2-trifluoroacetamido-3-(2,6-difluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (6.01 g, 13.5 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 3.42 9. (72.6%). EA, MS(FD).
Reaction SMILES: C([O:4][C:5]1[C:6]([O:19][CH3:20])=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[O:9])(=O)C.[OH-].[Na+].Cl>>[OH:4][C:5]1[C:6]([O:19][CH3:20])=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9]
Reactant: COC(=O)CCC(=O)c1cccc(OC(C)=O)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1c(O)cccc1C(=O)CCC(=O)O

Procedure:
Methyl 3-(3-acetoxy-2-methoxybenzoyl)propionate was warmed on a steam bath with dilute sodium hydroxide solution, and the resultant solution was acidified with hydrochloric acid to give 3-(3-hydroxy-2-methoxybenzoyl)propionic acid.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([CH2:5][CH2:6][CH2:7]2)[C:3](=O)[CH2:2]1.[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[AlH](Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C1COCC1.C1CCCCC1.CCOCC.CCOCC.CC(O)C.O>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[C:10]1([CH:3]2[N:4]3[CH:8]([CH2:7][CH2:6][CH2:5]3)[CH2:1][CH2:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [Li]c1ccccc1
Reactant: O=C1CCC2CCCN12
Agent: Cl[AlH]Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: [Al+3]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(C2CCC3CCCN32)cc1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 9 %

Procedure:
Into a round bottom flask was placed 5 g (0.04 moles) hexahydro-3H-pyrrolizin-3-one, described in CA, 86 89512 (1977) in 100 mL of dry THF. This was cooled to -40° C. and 20 mL of 2.0M phenyllithium in cyclohexane/ether was added over 40 min keeping the temperature below -20° C. The reaction mixture was stirred at -20° C. for 40 min and added to a suspension of AlCl2H made by adding 5.34 g (0.04 moles) aluminum chloride in 25 mL of dry ether to a suspension of 1.52 g (0.04 moles) LAH in ether. The reaction mixture was stirred overnight under nitrogen. To the reaction mixture was added 120 mL of water and it was stirred for one hr. The solid was filtered off and washed well with ether. The filtrate was made basic with 3N sodium hydroxide and extracted several times with ether. The ether layers were combined, washed with brine and dried (K2CO3). The solvent was removed in vacuo. The residue was taken up in ether, washed with water and extracted with 3N hydrogen chloride. The acidic layer was made basic by sodium hydroxide addition and extracted with ether. The ether layer was washed with brine, dried (K2CO3) and the solvent evaporated in vacuo. The resulting oil was flashed chromatographed on silica gel using 1:7 acetone:hexane as the eluant. The resulting oil was treated with one equivalent of fumaric acid in 2-propanol to give the salt which was recrystallized from 2-propanol to give 680 mg of hexahydro-3-phenyl-1H-pyrrolizine (E)-2-butenedioate (9%), mp 143°-145.5° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[C:36]([OH:38])[CH:35]=[C:34]([OH:39])[CH:33]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C=O)C>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[C:34]([OH:39])[CH:35]=[C:36]([O:38][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:37]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCc4cc(O)cc(O)c4)C[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCc4cc(O)cc(OCc5ccccc5)c4)C[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
17β-(tert-Butyldimethylsilyloxy)-7α-(3-(3,5-dihydroxyphenyl)propyl)-5α-androstan-3-one (75 mg), benzyl bromide (16.9 μl) and potassium carbonate (56 mg) were suspended in DMF (1 ml) and stirred overnight at 25° C. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then filtered. After evaporation under reduced pressure to remove the solvent, the resulting residue was subjected to silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4) to give 17β-(tert-butyldimethylsilyloxy)-7α-(3-(3-benzyloxy-5-hydroxyphenyl)propyl)-5α-androstan-3-one (21.0 mg, yield 24%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)nc2)CC1
Yield: 25 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (525 mg) described in Preparation Example 106 and oxazolidin-2-one (183 mg), the title compound (133 mg) was obtained.
Reaction SMILES: C[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+]>CS(C)=O>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[CH:2]1
Reactant: Cc1nc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: c1ccc2ocnc2c1
Yield: 196.7 %

Procedure:
To a solution of this product (8.0 g, 35 mmol) and 2-methylbenzoxazole (4.5 ml, 35 mmol) in DMSO (35 ml) was added a 50% aqueous sodium hydroxide solution (15 ml) and worked up as in Example 8 to give (E)-2-[2-(3,5-dimethyl)-4-chloropropoxyphenyl)ethenyl]benzoxazole as a solid (8.2 g, 70% yield). 1H NMR (CDCl3): δ 7.81-6.88 (m, 8H), 4.01 (t, 2H), 3.66 (t, 2H), 2.31 (s, 6H), 2.00 (m, 2H).
Reaction SMILES: [OH-].[Li+].[C:3]1([S:9]([CH2:12][C:13]2[C:18]([C:19]([O:21]CC)=[O:20])=[C:17]([O:24][CH3:25])[C:16]([CH2:26][CH2:27][CH3:28])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)=O>O1CCOCC1>[C:3]1([S:9]([CH2:12][C:13]2[C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:24][CH3:25])[C:16]([CH2:26][CH2:27][CH3:28])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OCC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=CO
Product: CCCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)O)c1OC
Temperature: 160 °C
Yield: 76.3 %

Procedure:
Lithium hydroxide (1M aqueous solution, 0.45 ml) was added to a solution of ethyl 6-(benzenesulphonylmethyl)-2-methoxy-3-propylbenzoate (Intermediate 24, 0.034 g) in dioxane and the solution was stirred and heated in the microwave at 160° C. for 15 minutes. The cooled solution was acidified by addition of formic acid and then purified by preparative HPLC (C18) eluting with a mixture of methanol and water containing 0.1% formic acid to give 6-(benzenesulphonylmethyl)-2-methoxy-3-propylbenzoic acid (0.024 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)([CH2:13]O)[CH2:11]O)=[CH:6][CH:5]=1)[CH3:2].C1(C)C=CC([S:37](Cl)(=O)=O)=CC=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:19]=3)[CH2:13][S:37][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(CO)(CO)CCCc2cccc(Oc3ccccc3)c2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOc1ccc(C2(CCCc3cccc(Oc4ccccc4)c3)CSC2)cc1
Reaction time: 2 h
Yield: 161.2 %

Procedure:
2-(4-Ethoxyphenyl)-2-[3-(3-phenoxyphenyl)propyl]propane-1,3-diol (25 g) was dissolved in pyridine (150 ml) and 4-dimethylaminopyridine added (20 mg). p-Toluenesulphonyl chloride (23.4 g), dissolved in pyridine (20 ml), was added dropwise at -5° C. The mixture was allowed to rise to room temperature over 2 hours and stirred overnight. It was then added to a hydrochloric acid-ice mixture, extracted with ether and the extract dried and evaporated to give 40.1 g of crude product which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][C:18](=[CH:21][O:22]C)[CH2:17][CH2:16]3)[C:12]2=[O:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:16][CH2:17][CH:18]([CH:21]=[O:22])[CH2:19][CH2:20]3)[C:12]2=[O:24])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC=C1CCC2(CC1)CCN(c1ccc(C(C)(C)C)cc1)C2=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(N2CCC3(CCC(C=O)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of 2-(4-tert-butylphenyl)-8-(methoxymethylene)-2-aza-spiro[4.5]decan-1-one (793 mg, 2.42 mmol,) in THF (10 mL) was added 2N HCl (12.1 mL, 24.2 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with sat NaHCO3 (aq), and extracted with EtOAc. The organic layers were combined washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the desired product as a white solid (750 mg, 98%) which did not require any further purification. MS (m/e): 314.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:29]([Si:31]([CH3:34])([CH3:33])[CH3:32])#[CH:30].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:30]#[C:29][Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1)C(C)C
Temperature: 70 °C
Yield: 85.7 %

Procedure:
A mixture of (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (364 mg, 0.81 mmol), Ethynyl-trimethyl-silane (0.68 mL, 4.9 mmol), Copper(I) iodide (154 mg, 0.81 mmol), tetrakis(triphenylphosphine)palladium (94 mg, 0.08 mmol) and triethylamine (0.67 mL, 4.9 mmol) in 5 ml DMF was heated to 70° C. overnight. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) and followed by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA) to give (2-Methyl-1-{2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (324 mg).