Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]2=[O:16])=[N:6][CH:7]=1.[CH:17]1([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25](B4OC(C)(C)C(C)(C)O4)[CH:26]=3)[C:21]2=[O:38])[CH2:19][CH2:18]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH:17]1([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:2]4[CH:3]=[CH:4][C:5]([CH2:8][N:9]5[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]5=[O:16])=[N:6][CH:7]=4)[CH:26]=3)[C:21]2=[O:38])[CH2:19][CH2:18]1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: CN1C(=O)CN(Cc2ccc(Br)cn2)C1=O
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)CN(Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)cn2)C1=O
Yield: 32 %

Procedure:
1-((5-Bromopyridin-2-yl)methyl)-3-methylimidazolidine-2,4-dione (9J5) (0.229 mmol, 65 mg), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (0.229 mmol, 68.0 mg), tris(dibenzylidineacetone)dipalladium (0.011 mmol, 10.5 mg), tricyclohexylphosphine (0.027 mMol, 7.7 mg) and potassium phosphate (0.389 mmol, 83.0 mg) were suspended in dioxane (1 ml) and water (0.5 ml) and heated to 130° C. in the microwave for 15 min. The reaction mixture was quenched with 2 ml of water and 3 ml of DCM and then passed through a hydrophobic fritted tube, washing with DCM. The organic layers were concentrated and the residue purified by basic prep HPLC to give 1-((5-(2-cyclopropyl-1-oxoisoindolin-5-yl)pyridin-2-yl)methyl)-3-methylimidazolidine-2,4-dione (Example 9a) 27.6 mg (32.1%); 1H NMR (400 MHz, CDCl3) 8.79 (dd, 1H) 7.91 (m, 2H) 7.64 (dd, 1H) 7.59 (s, 1H) 7.39 (d, 1H) 4.75 (s, 2H) 4.40 (s, 2H) 4.04 (s, 2H) 3.07 (s, 3H) 2.97 (m, 1H) 0.97-0.88 (m, 4H) LCMS m/z (M+H) 377.2.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH:9][NH2:10])=[CH:6][CH:5]=1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>C(O)C>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:9]([CH2:8][C:7]2[CH:11]=[CH:12][C:4]([F:3])=[CH:5][CH:6]=2)[N:10]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNCc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(Cc2ccc(F)cc2)n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 111.8 %

Procedure:
To a solution of (4-fluorobenzyl)hydrazine dihydrochloride (1.0 g, 4.7 mmol, Matrix) in ethyl alcohol (2 mL) was added 4,4-dimethyl-3-oxopentanenitrile (0.6 g, 4.7 mmol, Aldrich). After stirring at 85° C. for 2 h, the reaction mixture was cooled, concentrated, diluted with ethyl acetate (10 mL) and washed with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain 1.3 g (99%) of the title compound. MS (ESI m/z 248 (M+H)+.
Reaction SMILES: [OH:1][C:2]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12](C(OC(C)(C)C)=O)[CH3:13])[CH2:8][CH2:7]1)=[O:4].Cl>O1CCOCC1>[OH:1][C:2]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([NH:12][CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of trans-4-[(tert-butoxycarbonyl)(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 4; 8.1 g, 0.01 mol) in dioxane (13.5 mL) was added hydrogen chloride 4M in dioxane (27 mL). The mixture was stirred at room temperature for 24 hours. The precipitate obtained was filtrated and washed with ether. The crude was dissolved in water and potassium carbonate was added until pH=8-9. The product was extracted with ethyl acetate and the organic layer was washed with brine, dried and evaporated to dryness giving the title compound as a white solid (78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:24][C:23]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:16]=3[CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[ClH:32]>ClCCl.CO.C(OCC)C>[ClH:32].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:24][C:23]4[CH2:22][CH2:21][NH:20][CH2:19][C:18]=4[C:16]=3[CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc3oc4c(c3c2)CN(C(=O)OC(C)(C)C)CC4)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)c2ccc3oc4c(c3c2)CNCC4)cc1
Reaction time: 18 h
Yield: 30 %

Procedure:
To the product of step A (221 mg, 0.50 mmol) in dichloromethane and methanol was added 2 M HCl in diethyl ether (5 mL). After stirring for 18 h, the product was filtered, washed with diethyl ether and lyophilized to give 8-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (50 mg, 30%) as a white solid: mp 270-272° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.64 (s, 2H), 8.35 (d, J=1.5 Hz, 1H), 7.92-7.78 (m, 4H), 7.14-7.09 (m, 2H), 4.38 (s, 2H), 3.82 (s, 3H), 3.52 (t, J=6.0 Hz, 2H), 3.13 (t, J=5.4 Hz, 2H); APCI MS m/z 344 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O=[C:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[C:20](OC)=[O:21]>>[CH3:3][C:1]([C:5]1[CH:10]=[CH:9][C:8]2[C:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[C:20](=[O:21])[O:11][C:7]=2[CH:6]=1)([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: COC(=O)C1CNCCC1=O
Agent: Cl
Product: CC(C)(C)c1ccc2c3c(c(=O)oc2c1)CNCC3
Yield: 57.1 %

Procedure:
Prepared by the method described for Example 1 from 3-t-butylphenol (15 g, 0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 0.1 moles). Recrystallization from ethyl acetate gave the product (14.7 g), mp 181°-186° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH:12]([C:13]([O:15][CH3:16])=[O:14])[O:11][C:10](=[O:17])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([C@H:8]1[C@H:12]([C:13]([O:15][CH3:16])=[O:14])[O:11][C:10](=[O:17])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1OC(=O)NC1Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1OC(=O)N[C@H]1Cc1ccccc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A solution of 70.0 g of a 92:8 mixture of the (4S,5S)- and (4S,5R)-isomers of methyl 4-benzyl-2-oxo-oxazolidine-5-carboxylate and 7.0 g of potassium tert.butylate in 700 ml of THF was stirred at 20° C. for four hours and at 45° C. for 2 hours, the solution was washed twice with semi-saturated sodium chloride solution, dried over MgSO4, filtered and the filtrate was evaporated to give 68 g (97%) of 95% methyl (4S,5R)-4-benzyl-2-oxo-oxazolidine-5-carboxylate (tlc (SiO2, ethyl acetate):Rf =0.5).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH3:13])[CH:6]=[C:7]([I:10])[C:8]=1[OH:9].Cl.[CH3:16][O:17][NH2:18].C>N1C=CC=CC=1.C(O)C>[CH3:16][O:17][N:18]=[C:11]([C:5]1[CH:6]=[C:7]([I:10])[C:8]([OH:9])=[C:3]([CH2:2][NH2:1])[CH:4]=1)[CH2:12][CH3:13]
Reactant: CON
Reactant: CCC(=O)c1cc(I)c(O)c(CN)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCC(=NOC)c1cc(I)c(O)c(CN)c1
Yield: 54.8 %

Procedure:
To a solution of 2.0 g of 3'-aminomethyl-4'-hydroxy5'-iodopropiophenone in 15 ml of pyridine and 7 ml of ethanol is added 1.4 g of O-methylhydroxylamine hydrochloride, and the mixture is refluxed with heating for 45 minutes. The reaction mixture is treated with activated charcoal and filtered. The filtrate is concentrated under reduced pressure and to the residue is added ice-cold water. To the mixture is added 1.4 g of sodium hydrogencarbonate and stirred. The precipitated crystals are collected by filtration, washed with water and then recrystallized from methanol to give 1.2 g of 3'-aminomethyl-4'-hydroxy-5'-iodopropiophenone O-methyloxime, melting at 156°-157° C. with decomposition.
Reaction SMILES: C([NH:4][C:5]12[CH2:18][C:9]3([NH:19]C(=O)C)[CH2:10][C:11]([NH:14]C(=O)C)([CH2:13][C:7]([NH:23]C(=O)C)([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.[ClH:27]>>[ClH:27].[ClH:27].[ClH:27].[ClH:27].[NH2:4][C:5]12[CH2:12][C:11]3([NH2:14])[CH2:13][C:7]([NH2:23])([CH2:8][C:9]([NH2:19])([CH2:10]3)[CH2:18]1)[CH2:6]2
Reactant: CC(=O)NC12CC3(NC(C)=O)CC(NC(C)=O)(C1)CC(NC(C)=O)(C2)C3
Agent: Cl
Product: NC12CC3(N)CC(N)(C1)CC(N)(C2)C3

Procedure:
A process for preparing 1,3,5,7-tetraaminoadamantane which comprises reacting 1,3,5,7-tetraiodoadamantane with acetonitrile and water in the presence of actinic radiation to form 1,3,5,7-tetraacetamidoadamantane and hydrolyzing the 1,3,5,7-tetraacetamidoadamantane with hydrochloric acid to form 1,3,5,7-tetraaminoadamantane tetrahydrochloride.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=2)(=[O:10])=[O:9])[CH:2]=1.Br[CH2:22][C:23]([O:25]C(C)(C)C)=[O:24]>>[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([S:8]([N:7]([CH2:22][C:23]([OH:25])=[O:24])[C:3]2[CH:2]=[C:1]([CH3:20])[CH:6]=[CH:5][CH:4]=2)(=[O:10])=[O:9])=[N:12][CH:13]=1)([CH3:18])[CH3:19]
Reactant: Cc1cccc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Reactant: CC(C)(C)OC(=O)CBr
Product: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)c1

Procedure:
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid m-tolylamide with tert-butyl bromoacetate
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(Br)cc1
Yield: 87.4 %

Procedure:
4-bromophenol (10.46 g, 60.5 mmol), 1-bromooctane (15.43 g, 79.9 mmol) and potassiumcarbonate (90 g, 0.65 mol) in N,N-dimethylformamide and was heated to 90° C. for 4 h and then the potassiumcarbonate was filtered off. The reaction mixture was quenched with water and extracted three times with ether. The ether was then washed three times with 1M hydrochloric acid (HCl), one time with water, evaporated, and purified by distillation to obtain 1-bromo-4-(octyloxy)benzene (15.1 g, 52.9 mmol) as a colourless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[CH:14]([C:20]([OH:22])=[O:21])[C:15]([CH2:18][OH:19])=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.O.[C].[Pd]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[CH:14]([C:20]([OH:22])=[O:21])[CH:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(CO)=CS[C@H]12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(CO)CS[C@H]12
Reaction time: 5 h
Yield: 73.3 %

Procedure:
A suspension of palladium carbon (20 g.) in acetic acid (50 ml.) was added to a solution of 7-(2-phenylacetamido)-3-hydroxymethyl-2-cephem-4-carboxylic acid (19.0 g.) in acetic acid (150 ml.) and water (50 ml.). The solution was subjected to catalytic reduction in the presence of hydrogen gas of 20 kg./cm2 at 70° C. for 5 hours. After filtration, the filtrate was concentrated in vacuo. The residue was dissolved in aqueous solution of sodium bicarbonate, washed with ethyl acetate, adjusted to pH 3.0 and then extracted with ethyl acetate. The extract was washed with aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylic acid (14 g.).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH3:11])[C:3]([C:5]1[O:6][CH:7]=[CH:8][N:9]=1)=[O:4].Cl.[F:13][CH:14]([F:39])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][CH2:24][C@H:25]([C@H:29]([OH:38])[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31])[C:26](O)=[O:27]>>[O:6]1[CH:7]=[CH:8][N:9]=[C:5]1[C:3]([C@@H:2]([NH:1][C:26](=[O:27])[C@@H:25]([C@H:29]([OH:38])[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31])[CH2:24][CH2:23][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH:14]([F:13])[F:39])[CH2:10][CH3:11])=[O:4]
Reactant: O=C(O)[C@H](CCCc1ccccc1OC(F)F)[C@H](O)C(=O)N1CCOCC1
Reactant: CC[C@H](N)C(=O)c1ncco1
Agent: Cl
Product: CC[C@H](NC(=O)[C@H](CCCc1ccccc1OC(F)F)[C@H](O)C(=O)N1CCOCC1)C(=O)c1ncco1

Procedure:
It is similarly prepared according to the general procedure for Example 10 using (S)-2-Amino-1-oxazol-2-yl-butan-1-one; hydrochloride as the amino component and (R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid as the acidic component but without further oxidation step.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20]C(=O)O)[CH2:15]2)[N:7]([CH3:24])[C:6]1=[O:25].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([NH2:20])[CH2:15]2)[N:7]([CH3:24])[C:6]1=[O:25]
Reactant: Cn1c(=O)n(Cc2ccccc2Cl)c2c(N3CCC[C@@H](NC(=O)O)C3)ccnc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(Cc2ccccc2Cl)c2c(N3CCC[C@@H](N)C3)ccnc21
Yield: 60.2 %

Procedure:
The specific operation referred to the step (6) described in Example 1 for details. 161 mg (R)-1-[1-(2-chlorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]piperidin-3-yl carbamic acid ter.-butyl ester (0.342 mmol) and 2.4 mL trifluoroacetic acid were charged to afford 100 mg titled product with a yield of 60.2%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])=[O:23].[OH:25]O.O>CO.C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])(=[O:25])=[O:23]
Reactant: OO
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 20 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
A mixture of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-mehtylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.38 g), 30% hydrogen peroxide (1.38 ml) sodium tungstate dihydrate (0.17 g) in methanol/acetic acid was stirred at 20° C. overnight, then at 50° C. for 4 hours, and again at 20° C. overnight. Water was added and the solid filtered, water-washed and dried to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfonyl-1H-pyrazole-3-carboxaldehyde oxime (0.93 g) m.p.209.5-211° C. (decomposition). Compound 16.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH2:32][CH3:33])[C:3](=[O:31])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11](=[O:30])[CH2:12][CH2:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[CH:18][CH:17]=1)=[O:5]>C(OCC)(=O)C.[Pd]>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][C:11]([CH:7]2[CH2:8][CH2:9][CH2:10][N:6]2[C:4](=[O:5])[C:3](=[O:31])[C:2]([CH3:1])([CH3:34])[CH2:32][CH3:33])=[O:30])=[CH:21][CH:20]=1
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)CCC=Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)CCCCc1ccc(O)cc1
Yield: 60.7 %

Procedure:
A mixture of 1.63 g (3.53 mmol) of 3,3-dimethyl-1-(2-{5-[4-(phenylmethoxy) phenyl]pent-4-enoyl}pyrrolidinyl)pentane-1,2-dione and 400 mg of 10% Pd/C in 100 ml of ethyl acetate was hydrogenated at 50 psi overnight. The mixture was filtered through Celite, concentrated, and chromatographed (25% ethyl acetate/hexane) to obtain 800 mg (61%) of 1-{2-[5-(4-hydroxyphenyl)pentanoyl]pyrrolidinyl}-3,3-dimethylpentane-1,2-dione (68). 1H NMR (CDCl3, 400 MHz): δ 0.87 (t, 3H, J=7.50); 1.21 (s, 6H); 1.63 (m, 4H); 1.67 (m, 2H); 1.93 (m, 3H); 2.04 (m, 1H); 2.52 (m, 4H); 3.47 (m, 2H); 4.57 (m, 1H); 6.72 (d, 2H, J=8.40); 7.03 (d, 2H, J=8.40). Anal. Calcd. for C22H31NO4: C, 70.75; H, 8.37; N, 3.75. Found: C, 70.64; H, 8.44; N, 3.65. TLC: Rf=0.45 (25% ethyl acetate/hexane).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][NH:11][C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCCCC1
Reactant: NCC(O)c1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: Oc1cccc(C2CNC3(CCCCC3)O2)c1

Procedure:
A suspension of 20 g. of 1-(3'-hydroxyphenyl)-2-amino-ethanol hydrochloride in 100 ml. of cyclohexanone is heated, while stirring vigorously, in a three-necked flask equipped with a dropping funnel, water separator, and thermometer. Above a temperature of 80°C., up to 100 ml. of benzene are added dropwise in such a manner so that the water of reaction formed together with the benzene is distilled of azeotropically. The temperature of the flask contents is, at the finish, about 130°C. After cooling, the crystalline reaction product is separated off, digested with benzene, and collected on a frit. There is obtained 20.3 g. (71.5% of theory) of 2-(3'-hydroxyphenyl)-1-oxa-4-azospiro[4,5]decane hydrochloride. After recrystallization from isopropanol/ethyl acetate, the product is obtained in the form of colorless crystals with a melting point of 138°-139°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:26]=[C:27]([C:33]5[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][C:34]=5[CH3:46])[CH:28]=[N:29][C:30]=4[O:31][CH3:32])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[C@H:13]2[CH3:51])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[F:53][C:54]1([F:58])[CH2:57][NH:56][CH2:55]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[F:53][C:54]1([F:58])[CH2:57][N:56]([C:21]2[N:20]=[C:19]([CH2:18][N:14]3[C@@H:13]([CH3:51])[C@@H:12]([C:4]4[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([F:1])[CH:3]=4)[O:16][C:15]3=[O:17])[C:24]([C:25]3[CH:26]=[C:27]([C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:35][C:34]=4[CH3:46])[CH:28]=[N:29][C:30]=3[O:31][CH3:32])=[CH:23][N:22]=2)[CH2:55]1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-{5-[4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (INTERMEDIATE 48, 96 mg, 0.131 mmol) in THF (1.5 mL) was added 3,3-difluoroazetidine hydrochloride (51.1 mg, 0.394 mmol) and triethylamine (0.082 mL, 0.591 mmol). The resulting mixture was subjected to microwave irradiation at 135° C. for 40 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (sodium sulfate), filtered and concentrated to give crude tert-butyl 4-{5-[2-(3,3-difluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (98 mg, 0.131 mmol). LCMS (M+H)+: 744.2.
Reaction SMILES: C(OC(N1CCC(C2C=CC(OCCCOCC3C=CC=CC=3OC)=CC=2)C(O)C1)=O)(C)(C)C.ClCC1C=CC2C(=CC(OCOCC[Si](C)(C)C)=CC=2)C=1.[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([C:69]2[CH:74]=[CH:73][C:72]([O:75][CH2:76][CH2:77][CH2:78][O:79][CH2:80][C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=3[O:87][CH3:88])=[CH:71][CH:70]=2)[CH:65]([O:89][CH2:90][C:91]2[CH:100]=[CH:99][C:98]3[C:93](=[CH:94][C:95]([O:101]COCC[Si](C)(C)C)=[CH:96][CH:97]=3)[CH:92]=2)[CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>>[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([C:69]2[CH:74]=[CH:73][C:72]([O:75][CH2:76][CH2:77][CH2:78][O:79][CH2:80][C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=3[O:87][CH3:88])=[CH:71][CH:70]=2)[CH:65]([O:89][CH2:90][C:91]2[CH:100]=[CH:99][C:98]3[C:93](=[CH:94][C:95]([OH:101])=[CH:96][CH:97]=3)[CH:92]=2)[CH2:64]1)=[O:62])([CH3:59])([CH3:57])[CH3:58]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccc(OCOCC[Si](C)(C)C)cc3c2)cc1
Agent: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: C[Si](C)(C)CCOCOc1ccc2ccc(CCl)cc2c1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccc(O)cc3c2)cc1

Procedure:
in an analogeous manner as described in Example 95 (a) there was obtained from (3RS,4RS)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-1-carboxylic acid tert-butylester [Example 120 (g) (a)] and 2-chloromethyl-7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene [Example 6 (u)] (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidin-1-carboxylic acid tert-butylester as a pale yellow oil; MS: 758 (M+H)+. Then, (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidin-1-carboxylic acid tert-butylester was reacted in analogy to Example 95 (b) by cleaving of the SEM protecting group to afford (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(7-hydroxy-naphthalen-2-ylmethoxy)-piperidin-1-carboxylic acid tert-butylester [yellow oil; MS: 628 (M+H)+] which, on alkylation with 1-(2-chloro-ethyl)-4-methyl-piperazine hydrochloride (1:2) [Chim. Ther. 4, 283 (1969)] in analogy to Example 90 (n) gave (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-naphthalen-2-ylmethoxy]-piperidin-1-carboxylic acid tert-butylester as a light brown oil; MS: 754 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([NH2:12])[CH3:11]>O>[CH2:10]([NH:12][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:11]
Reactant: N#Cc1cccnc1Cl
Reactant: CCN
Solvent: O
Product: CCNc1ncccc1C#N

Procedure:
A stirred mixture of 4 g. of 2-chloronicotinonitrile in 200 ml. of a saturated ethanolic ethylamine solution was heated under reflux for 5 hours. The solution was cooled and was diluted with 400 ml. of water. The precipitate of 2-ethylaminonicotinonitrile which formed was collected, air dried and was used directly in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[O:7][C:8]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:9]=3[C:10]=2[C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:12])[N:3]=[CH:2]1.[H-].[Na+].[CH3:33]I>C1COCC1>[CH3:33][N:1]1[CH:5]=[C:4]([C:6]2[O:7][C:8]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:9]=3[C:10]=2[C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:12])[N:3]=[CH:2]1
Reactant: CI
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3c[nH]cn3)oc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cn(C)cn3)oc2c1
Yield: 58 %

Procedure:
This material was prepared by N-methylation of [2-(1H-Imidazol-4-yl)-6-methoxy-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone (entry 45, Table 1) was made from I1-0085 by N-methylation. 20 mg of starting material (0.049 mmol) was dissolved in 1 ml dry THF then treated with 9 mg of 60% NaH (0.225 mmol) then after 10 minutes with MeI (15 uL, 0.24 mmol) and left over night then quenched with 10% NH4Cl extracted with EtOAc and chromatographed with straight EtOAc to give 12 mg product (58% yield). Proton data is 7.86 (s, 1H), 7.62 (s, 1H), 7.13-7.09 (m, 2H), 7.12 (s, 2H), 6.79 (dd, J=8.7, 2.1 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.76 (s, 6H), 3.72 (s, 3H).