Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2I)=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2[C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Reactant: OB(O)c1ccncc1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 7, [4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-methanone (example 53) was reacted with pyridin-4-yl-boronic acid to give the title compound as colorless foam. MS: 530.1 (MH+).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([O:12][CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[C:9]([O:12][CH:13]([CH2:14][OH:15])[CH2:19][OH:20])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Oc1cc(-c2ccccc2)on1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(CO)Oc1cc(-c2ccccc2)on1

Procedure:
A solution of 9.118 g of diethyl 2-(5-phenyl-3-isoxazolyloxy)malonate (prepared as described in Preparation 22) in 50 ml of tetrahydrofuran wa added dropwise to a suspension of 4.33 g of lithium aluminum hydride in 50 ml of tetrahydrofuran, whilst ice-cooling. The reaction mixture was then heated under reflux for 5 hours, after which it was worked-up in a similar manner to that described in Preparation 20, to afford 4.394 g if the title compound as white crystals, melting at 117°-119° C. (from a mixture of methanol and methylene chloride).
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].[CH3:29][O:30][C:31](=[O:57])[NH:32][CH:33]([C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44]1[NH:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]#[CH:56])=[CH:51][CH:50]=2)=[CH:47][N:48]=1)=[O:38])[CH:34]([CH3:36])[CH3:35].C(N(CC)CC)C.N#N>CN(C=O)C.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.[Cu]I>[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:56]#[C:55][C:52]3[CH:53]=[CH:54][C:49]([C:46]4[NH:45][C:44]([CH:40]5[CH2:41][CH2:42][CH2:43][N:39]5[C:37](=[O:38])[CH:33]([NH:32][C:31]([O:30][CH3:29])=[O:57])[CH:34]([CH3:36])[CH3:35])=[N:48][CH:47]=4)=[CH:50][CH:51]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)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
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 47.4 %

Procedure:
A solution of (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (947 mg, 2.11 mmol), (1-{2-[5-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.00 g, 2.53 mmol), and triethylamine (882 μl, 6.33 mmol) in DMF (13 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (244 mg, 0.21 mmol) and CuI (40 mg, 0.21 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back-extracted two times then the organic phases were combined and dried over Na2SO4. After concentration, the crude material was purified by silica gel chromatography (0-20% MeOH-EtOAc gradient) then reverse phase preparative HPLC (10-85% MeCN—H2O; 0.1% formic acid modifier) to afford [1-(2-{5-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (600 mg, 1.00 mmol, 47% yield). 1H-NMR: 400 MHz, (DMSO-d6) δ: 11.84 (s, 2H), 7.75 (d, 4H), (7.56 (s, 2H), 7.47 (d, 4H), 7.28 (d, 2H), 5.06 (m, 2H), 4.06-4.04 (m, 2H), 3.80 (m, 4H), 3.54 (s, 6H), 2.14 (m, 4H) 2.00-1.90 (m, 6H), 0.89 (d, 6H), 0.84 (d, 6H). LCMS-ESI+: calc'd for C42H51N8O6: 763.4 (M+H+). Found: 763.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([Cl:13])[CH:3]=1.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:8](=[O:10])[CH2:7][O:6][C:5]2[CH:11]=[CH:12][C:2]([Br:1])=[CH:3][C:4]=2[Cl:13])[CH:18]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C(O)COc1ccc(Br)cc1Cl
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(NC(=O)COc2ccc(Br)cc2Cl)c1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To solution of (4-bromo-2-chloro-phenoxyacetic acid (100 mg, 0.378 mmol), 2-amino isonicotinic acid methyl ester (86.42 mg, 0.568 mmol) and DMAP (69.43 mg, 0.568 mmol) in DMF 2 mL was added PyBOP (295 mg, 0.568 mmol) at room temperature. Reaction mixture was stirred at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=1:9˜4:6) to give 2-[2-(4-bromo-2-chloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.084 g, 56% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([NH:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)(=[O:29])=[O:28]
Reactant: Nc1cccc(COCc2cccc(Cl)c2)n1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCc2cccc(Cl)c2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(3-chloro-benzyloxymethyl)-pyridin-2-ylamine (0.08 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.092g) as a light yellow gum (0.039 g). MS (ESI−): 469.0 ([M−H]−).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH2:18]([NH2:20])[CH3:19]>C(O)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:20][CH2:18][CH3:19])#[N:2]
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Reactant: CCN
Solvent: CCO
Product: CCNC(=NC#N)NC1CCCc2ccccc21
Reaction time: 20 h

Procedure:
A solution of 6.13 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 10 ml of 70% aqueous ethylamine in 90 ml of ethanol was heated at reflux with stirring for 20 hours. The reaction mixture was cooled in a refrigerator to give 2.44 g of N"-cyano-N-ethyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 152°-153.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1.O>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:26][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](OCc2ccc3ccccc3c2)C1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A suspension of the title B compound, (3R*,4R*)-4-biphenyl-3-yl-3-hydroxy-piperidine-1-carboxylic acid t-butyl ester (318 mg, 0.9 mmol) and sodium hydride (60% dispersion in mineral oil, 72 mg, 1.8 mmol) in 8 mL of dry DMA is shaken for 10 min. at 50° C. After cooling to RT, 2-(bromomethyl)naphthalene (298 mg, 1.35 mmol) is added and the mixture shaken for 16 h at 50° C. After addition of H2O, the aqueous layer is extracted twice with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the residue (SiO2, hexane/ethyl acetate) affords (3R*,4R*)-4-biphenyl-3-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a yellowish viscous oil: MS (LC/MS) 494.2 [M+H]+; Rf 0.30 (hexane/ethyl acetate 8:2).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:23]=[C:22]([CH2:24][OH:25])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1)#[N:4].Cl[C:27]1[CH:28]=[C:29]2[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:34][N:30]2[C:31](=[O:33])[N:32]=1>>[C:3]([C:5]1[CH:23]=[C:22]([CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:18])([F:17])[F:19])[CH:9]=1)[CH2:24][O:25][C:27]1[CH:28]=[C:29]2[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:34][N:30]2[C:31](=[O:33])[N:32]=1)#[N:4]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C#N)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 4-(2-cyano-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:19][C:20]([O:22][CH:23]1[C:27]([CH3:29])([CH3:28])[CH2:26][N:25](C(OCC2C=CC=CC=2)=O)[C:24]1=[O:40])=[O:21])[CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6]>O1CCCC1.[Pd]>[OH:1][CH:2]([C@@H:14]([NH:19][C:20](=[O:21])[O:22][CH:23]1[C:27]([CH3:29])([CH3:28])[CH2:26][NH:25][C:24]1=[O:40])[CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6]
Reactant: CCCC[C@H](NC(=O)OC1C(=O)N(C(=O)OCc2ccccc2)CC1(C)C)C(O)C(=O)N[C@H](C)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC1C(=O)NCC1(C)C)C(O)C(=O)N[C@H](C)c1ccccc1
Yield: 65 %

Procedure:
A solution of 120 mg (0.22 mmol) of benzyl 3-[({[(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentyl]amino}carbonyl)oxy]-4,4-dimethyl-2-oxo-1-pyrrolidinecarboxylate in 5 mL of tetrahydrofuran was stirred in the presence of 15 mg of 10% Pd/C under a hydrogen atmosphere (50 psi) for 18 h. The catalyst was filtered off over celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 3:2 acetone:dichloromethane to afford 60 mg (66%) of 4,4-dimethyl-2-oxo-3-pyrrolidinyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate. ES-LCMS m/z 420 (M+H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].O1CCCC1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:12]([N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1NCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1NCCN1C(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
8.6 parts by weight of imidazolid-2-one in 100 parts by volume of dry tetrahydrofurane were treated with 15.5 parts by weight of benzoyl chloride in 30 parts by volume of tetrahydrofurane over the course of 15 minutes, at 5°-10°C, and the mixture was subsequently stirred for 3 hours at 10°C. The solvent was stripped off, the residue was shaken with a mixture of chloroform and aqueous NaHCO3 solution for 15 minutes, the chloroform was separated off, the water was again extracted with chloroform and the combined organic phases were washed with water, dried over MgSO4 and evaporated. The residue was recrystallized from ethyl acetate/ether.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[ClH:15].[CH2:16]([NH:23][CH2:24][CH2:25][Cl:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[ClH:26].[ClH:15].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:25][CH2:24][NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: ClCCNCc1ccccc1
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CNCCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of 39.5 g (0.82 mol) sodium hydride in 500 mL DMF add 37.3 g (0.233 mol) 4-(1H-imidazol-yl)phenol portionwise. Chill the reaction mixture on an ice/MeOH bath during the addition. After addition, stir the reaction mixture at room temperature until gas evolution ceases. After this time, return the reaction mixture to the ice bath and add 50.2 g (0.29 g) N-benzyl-2-chloroethylamine hydrochloride portionwise. After addition is complete, heat the stirring suspension to 65° C. Followthe progress of the reaction by thin-layer chromatography on silica gel (methylene chloride:methanol, 9:1). At the completion of the reaction, cool to room temperature and slowly add 20 mL H2O. Remove the solidsby suction filtration and evaporate the solvents. Chromatograph the resulting oil on silica gel using (CH2Cl2 :MeOH, 98:2), to isolate the title compound as the free base. Dissolve the free base in excess 3 M methanolic HCl and evaporate the solvents to give the title compound.
Reaction SMILES: C1COCC1.[Br-].[O:7]1[CH2:12][CH2:11][CH2:10][O:9][CH:8]1[CH2:13][CH2:14]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O=[C:41]1[CH2:46][CH2:45][CH:44]([CH:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=3)[CH2:49][CH2:48]2)[CH2:43][CH2:42]1>O>[O:9]1[CH2:10][CH2:11][CH2:12][O:7][CH:8]1[CH2:13][CH2:14][CH:41]1[CH2:42][CH2:43][CH:44]([CH:47]2[CH2:48][CH2:49][CH:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:62])([F:63])[F:64])=[CH:57][CH:56]=3)[CH2:51][CH2:52]2)[CH2:45][CH2:46]1
Reactant: c1ccc([PH](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(C2CCC(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc(CCC2CCC(C3CCC(CCC4OCCCO4)CC3)CC2)cc1
Reaction time: 3 h
Yield: 41.9 %

Procedure:
THF (70 ml) was added to 1,3-dioxan-2-ylethyltriphenylphosphinebromide (6.80 g, 14.9 mmol), followed by adding to the mixture, potassium-t-butoxide (1.68 g, 14.9 mmol) at 0° C., stirring the mixture at the same temperature for 3 hours, dropwise adding to the reaction solution, a 10 ml THF solution of the above 4-(4-oxocyclohexyl)-1-(2-(4-trifluoromethylphenyl)ethyl)cyclohexane (2.7 g, 7.7 mmol), stirring the mixture at the same temperature for one hour, further stirring at room temperature for 3 hours, adding water (50 ml) to the reaction solution, extracting the resulting product with ethyl acetate, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, purifying the resulting residue according to column chromatography treatment using heptane/ethyl acetate (3/1) as a developing solvent, on silica gel, distilling off the solvent, hydrogenating the residue (3.2 g) in the presence of a catalyst of 5% Pd/C (0.15 g), in ethanol solvent, filtering off the catalyst distilling off the solvent under reduced pressure, and recrystallizing the residue from heptane/ethanol (5/1), to obtain 4-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)-1-(2-(4-trifluoromethylphenyl)ethyl)cyclohexane (1.46 g, 3.23 mmol). The yield of this product from 4-(4-oxocyclohexyl)-1-(2-(4-trifluoromethylphenyl)ethyl)cyclohexane was 42%.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[CH:2]1.CC1(C)C(C)(C)OB(C2C=C3[O:27][CH:26]=[CH:25][C:22]3=[N:23]C=2)O1>>[O:27]1[CH2:26][CH2:25][C:22]([O:10][C:7]2[CH:8]=[C:9]3[O:1][CH:2]=[CH:3][C:4]3=[N:5][CH:6]=2)=[N:23]1
Reactant: CC1(C)OB(c2cnc3ccoc3c2)OC1(C)C
Reactant: Oc1cnc2ccoc2c1
Product: c1cc2ncc(OC3=NOCC3)cc2o1

Procedure:
6-(4,5-dihydroisoxazol-3-yloxy)furo[3,2-b]pyridine I-69a and I-69b were prepared in 2 steps from racemic compound I-10 and furo[3,2-b]pyridin-6-ol using Method 5 after furo[3,2-b]pyridin-6-ol is prepared from 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine using Method 11. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=374.2 m/z. Activity: A
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C:10]1([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([CH:49]2OCC[O:50]2)[CH:42]=1)[OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([C:10]2([OH:40])[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:11]2)=[CH:42][C:43]=1[CH:49]=[O:50]
Reactant: COc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C1OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Reaction time: 16 h
Yield: 71 %

Procedure:
To a stirred solution of compound prepared in step II (4.80 g, 6.68 mmol) in THF (20 mL) was added 6N HCl (10 mL) and stirred for 16 h. This reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (100 mL) washed with sat. NH4Cl (20 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 2-Methoxy-5-((3R,4S,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-2-hydroxy-tetrahydro-pyran-2-yl)-benzaldehyde (3.2 g).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15]>O1CCCC1>[CH2:12]([NH:16][C:17](=[O:18])[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccccc1N
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Product: CCCCNC(=O)Nc1ccccc1C(=O)OC
Reaction time: 48 h

Procedure:
To a solution of 13.55 gm of methyl anthranilate in 12 ml dry tetrahydrofuran, was added 8.9 ml of n-butyl isocyanate dropwise. The solution was stirred for 51/2 days and filtered. The filtrate was reduced to half of its original volume and further precipitated with hexane and filtered. The two residues were combined to yield the title compound as a white solid, m.p. 84°-85° C.; NMR(delta CDCl3): 0.79, 1.02 (m, 3H, CH3), 1.16-1.76 (m, 4H, CH2CH2), 3.27 (t, 2H, NCH2), 3.87 (s, 3H, OCH3), 4.82 (br, 1H, NH), 6.81-8.59 (m, 4H, ArH), 11.09 (s, 1H, NH). IR: 3305, 3260, 1708, 1642, 1560 cm-1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[S:19][CH:20]=[C:21]([CH3:22])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>CO>[ClH:23].[CH3:22][C:21]1[C:17]2[O:16][N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:18]=2[S:19][CH:20]=1
Reactant: Cc1csc2c(C3CCN(C(=O)OC(C)(C)C)CC3)noc12
Agent: Cl
Solvent: CO
Product: Cc1csc2c(C3CCNCC3)noc12

Procedure:
Stir a solution of 4-(6-methyl-thieno[2,3-d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (8.84 mmol, 2.85 g, 1.00 equivalents) in hydrochloric acid (48.75 mL, 1 M solution in diethyl ether) and methanol (2.00 mL) at room temperature for 3.5 hours. Filter the suspension, collect the white solid and dry to yield the desired product (659 mg). Allow the mother liquor to age overnight, filter, collect the white solid and dry to yield additional desired product (1.252 g). LC/MS (ESI), m/e 223 (MH+), retention time 1.14 minutes. Condition II.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:24][C:22](=[O:23])[CH:21]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)[CH3:27])[CH3:26]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C

Procedure:
To a mixture of NaH (60%, 4.92 g, 0.205 mol) in DMF (60 mL) is added 5-benzoxyindole at 0˜5° C., then stirred 30 min. ethyl 2-bromopropionate is added dropwise, the mixture is allowed to warm to room temperature and heated at 70° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate. Concentration and column chromatography on silica gel eluted with hexanes and ethyl acetate yields the title compound (29 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[S:8][CH2:7]1)[CH3:2].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:20][C:19]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=3[Cl:17])=[CH:14][C:9]=2[S:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CSc2cc(O)ccc21
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CSc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 20 °C
Reaction time: 72 h
Yield: 68.3 %

Procedure:
To a solution of ethyl(6-hydroxy-2,3-dihydro-1-benzothiophen-3-yl)acetate (17.2 g) in DMF (300 mL) were added 2,4-dichlorobenzyl chloride (17.0 g) and K2CO3 (15.0 g) and the resulting solution was stirred at 20° C. for 72 h. The mixture was diluted with EtOAc, washed successively with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc) to give the title compound (19.6 g).