Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[BH4-].[Na+]>C(O)C>[OH:1][CH:2]1[CH2:6][S:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C(=O)O)c1ccc(CC2CSCC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(CC2CSCC2O)cc1
Yield: 19 %

Procedure:
2-[4-(4-Oxothiolan-3-ylmethyl)phenyl]propionic acid (24 mg) obtained in Example 8 was dissolved in ethanol (1.0 ml), sodium borohydride (9.4 mg) was added stirring on an ice bath, and stirred for 1 hour. The reaction mixture was quenched with 2.0 M aqueous hydrochloric acid, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the organic layers were combined, and washed with saturated brine. The organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/acetic acid=50/50/1) to give the compounds of Example 9-A (colorless crystals, 4.6 mg, 19%) and Example 9-B (colorless oil, 11.6 mg, 48%).
Reaction SMILES: [CH2:1]([N:8]([CH3:19])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]([CH3:19])[CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)c1ccc(F)cc1)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccccc1)CC(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Benzyl-methyl-amino)-1-(4-fluorophenyl)-ethanone (56.9 g) was dissolved in methanol (550 mL), and sodium borohydride was gradually added on an ice bath. After stirring at room temperature for 1 hour, the residue after evaporating methanol at reduced pressure was purified by NH silica gel column chromatography (hexane/ethyl acetate), and a yellow oily substance (54.6 g) was obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:9][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:13]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C[O:43][B:44](OC)OC>C1(C)C=CC=CC=1.CCCCCC>[C:31]1([CH2:30][N:8]([CH2:9][C@@H:10]2[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:13]=3[B:44]([OH:43])[O:11]2)[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COB(OC)OC
Reactant: O[C@H](CN(Cc1ccccc1)Cc1ccccc1)c1cccc(OCCCOCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OB1O[C@H](CN(Cc2ccccc2)Cc2ccccc2)c2cccc(OCCCOCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S)-2-[bis(phenylmethyl)amino]-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanol (240 mg, 0.50 mmol) in 5 mL of toluene at −20° C. was added 1.75 mmol of nBuLi in hexane (2.59 M, 0.67 mL) over about 5 minutes. The mixture was then stirred for 2 h and then quenched with freshly distilled trimethylborate (0.28 mL, 259 mg, 2.5 mmol). The cold bath was removed and the mixture warmed to room temperature. The reaction was then diluted with 10 mL of TBME, then 5 mL of saturated NaHCO3 solution was added. After vigorously stirring for about 30 min, the organic layer was washed with 5 mL of 0.1 M NaH2PO4, then 5 mL of saturated NaHCO3. The organic layer was then dried over Na2SO4 and concentrated.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[O:10][C:9]([CH2:13][OH:14])([CH2:11][OH:12])[C@@H:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:7]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:6]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1>CN(C)C=O>[CH2:1]([O:4][CH:5]1[O:10][C:9]([CH2:11][O:12][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)([CH2:13][O:14][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[CH:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC1OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1OC(COCc2ccc(OC)cc2)(COCc2ccc(OC)cc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Temperature: 0 °C
Yield: 51.7 %

Procedure:
The starting diol [((3S,4S,5R)-6-allyloxy-3,4,5-tris-benzyloxy-2-hydroxymethyl-tetrahydro-pyran-2-yl)-methanol (I-1b: 10 g, 19.208 mmol) was dissolved in N,N-dimethylformamide (70 mL) and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 1.69 g, 42.3 mmol) was added and the reaction was allowed to stir at 0° C. for 1 hour before the addition of 1-bromomethyl-4-methoxy-benzene (5.96 mL, 40.3 mmol). The reaction was then heated to 60° C. overnight. The mixture was cooled down to room temperature and the reaction was quenched with water and extracted with ethyl acetate (2 times). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The reaction was then chromatographed over silica gel (eluting with a gradient of 0 to 80% ethyl acetate in heptane) yielding 7.55 g (52% yield) of product (I-1c). MS 778.8 (M+NH4+; positive mode).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10](=[O:24])[C@H:11]([CH3:23])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]2[CH2:15][CH2:14]2)=CC=1)([O-])=O.[OH-].[Na+].O>CO>[C:16]([N:12]([CH:13]1[CH2:15][CH2:14]1)[C@H:11]([C:10]([OH:24])=[O:9])[CH3:23])([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: C[C@@H](C(=O)OCc1ccc([N+](=O)[O-])cc1)N(C(=O)OC(C)(C)C)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1CC1
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a solution of Boc-cyclopropylalanine p-nitrobenzyl Ester (4) (450 mg, 1.34 mmol) in MeOH (20 ml) was added 1N NaOH (2.6 ml, 2.6 mmol) at room temperature. After the mixture was stirred for 3 hr, water (10 ml) was added and the MeOH was removed in vacuo. The aqueous residue was washed with Et2O to remove p-nitrobenzyl alcohol and the aqueous layer was separated, cooled in an ice bath and 10% citric acid solution was added to pH 3. The mixture was saturated with NaCl and extracted with AcOEt and the extracts were washed with sat. NaCl solution, dried over Na2SO4 and evaporated in vacuo to give a white solid which was recrystallized from AcOEt-n-hexane to afford 260 mg of Boc-cyclopropyl Alanine (5) (96.3%) as colorless needles, mp 176°-177° C. (dec.); IR (KBr): 3230(NH), 1630-1680 (C=0). NMR (CDCl3 +DMSO)δ: 9.45 (br, s, IH, COOH), 5.88 (br, s, 1H, NH) 1.3-1.7 (m, 2H, CH2), 1.0-1.2 (m, 2H, CH2), 1.50 (s, 9H, Boc).
Reaction SMILES: O1CCCC1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:13]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[CH2:14][C:15]#[CH:16]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[C:7]1([C:16]#[C:15][CH2:14][CH2:13][N:17]2[C:21](=[O:22])[C:20]3[C:19](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]2=[O:27])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1ccccc1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Under a nitrogen atmosphere, 35 ml of tetrahydrofuran, 3.06 g of iodobenzene, and 9.0 ml of triethylamine were added to 535 mg of dichlorobis(triphenylphosphine)palladium, 145 mg of copper iodide, and 3.00 g of N-(3-butynyl)phthalimide. The obtained mixture was stirred under reflux for 4 hours. After completion of the stirring, the reaction solution was cooled to a room temperature, and a solid was then filtrated. The filtrate was concentrated, and the residue was then purified by column chromatography (Wako Gel C-200; toluene:ethyl acetate=4:1), so as to obtain 3.70 g of a phthalimide compound.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][C:42]1=[O:47]>CN(C=O)C>[O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([N:44]2[CH2:45][CH2:46][NH:41][C:42](=[O:47])[CH2:43]2)=[O:18])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1ccc(Oc2ccccc2)nc1
Reactant: O=C1CNCCN1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)C=Cc2ccc(Oc3ccccc3)nc2)CCN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.15 g (0.62 mmol) of 3-(6-phenoxy-pyridin-3-yl)-acrylic acid, 1.72 g (15 mmol) of NEM and 546 mg (1.6 mmol) of TOTU were dissolved in 5 ml of DMF and stirred at room temperature for 15 min. 163 mg (1.626 mmol) of piperazin-2-one were added and the reaction mixture was stirred at room temperature for 16 h. After evaporation, the product was purified by silica gel chromatography. Yield: 153 mg.
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:24])[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([C:14]([F:17])([F:16])[F:15])[C:11]([C:18]([O:20]CC)=[O:19])=[CH:10][C:9]=2[CH:23]=1>C1COCC1.CCO.O>[F:24][CH:4]([F:3])[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([C:14]([F:17])([F:15])[F:16])[C:11]([C:18]([OH:20])=[O:19])=[CH:10][C:9]=2[CH:23]=1
Reactant: CCOC(=O)C1=Cc2cc(C(F)F)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)C1=Cc2cc(C(F)F)ccc2OC1C(F)(F)F
Reaction time: 60 h
Yield: 60.1 %

Procedure:
Aqueous NaOH (1.31 mL, 3.277 mmol, 2.5 M solution) was added in one portion to the ester (Step 1) (0.880 g, 2.731 mmol) in THF:EtOH:H2O (7:2:1, 10 mL). The resulting solution was stirred for 60 hours. The reaction mixture was partially concentrated in vacuo to remove the organic solvents and was diluted with H2O. The resulting aqueous solution was washed with diethyl ether, sparged with nitrogen to remove trace ether, and acidified with concentrated HCl. The resulting oily suspension was extracted with diethyl ether. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo yielding the title compound (0.483 g, 60%) as an oil which solidified as a white crystalline mass: mp 134.7-136.2° C. 1H NMR (acetone-d6/300 MHz) 7.97 (s, 1H), 7.73 (s, 1H), 7.67 (dd, 1H, J=8.5, 1.0 Hz), 7.17 (d, 1H, J=8.5 Hz), 6.89(t, 1H, J=56.2 Hz), 5.90 (q, 1H, J=7.1 Hz). FAB-ESLRMS m/z 293 (M−H). EIHRMS m/z 293.0235 (M−H, Calc'd 293.0237). Anal. Calc'd for C12H7F5O3: C, 49.00; H, 2.40. Found: C, 48.78; H,2.21.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:4]3[NH:14][CH:7]([CH2:8][C:9]=2[CH:10]=[CH:11][C:12]=1[NH2:13])[CH2:6][CH2:5]3.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1>>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][CH:7]4[NH:14][CH:4]([CH2:5][CH2:6]4)[C:3]=3[C:2]=2[Cl:1])=[N:17][CH:18]=1
Reactant: Nc1ccc2c(c1Cl)C1CCC(C2)N1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2Cl)C2CCC(C3)N2)ncc1Cl
Yield: 48 %

Procedure:
Following a procedure analogous to 61e, 3-Chloro-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (140 mg, 0.67 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (200 mg, 0.67 mmol) were converted to the title compound as a yellow solid (151 mg, 49%). 1HNMR (400 MHz, CDCl3) δ 11.1 (s, 1H), 8.6 (d, 1H, J=8.6 Hz), 8.1 (s, 1H), 8.2 (d, 1H, J=8.3 Hz), 7.5-7.4 (m, 2H), 7.3 (s, 1H), 7.1 (t, 1H, J=7.6 Hz), 6.9 (d, 1H, J=8.3 Hz), 6.2 (bs, 1H), 4.7 (d, 1H, J=5.0 Hz), 3.9 (m, 1H), 3.1 (dd, 1H, J=16.5, 5.0 Hz), 3.0 (d, 3H, J=4.8 Hz), 2.5 (d, 1H, J=16.5 Hz), 2.2-2.1 (m, 2H), 1.9 (m, 1H), 1.7 (bs, 1H), 1.6 (m, 1H); MS (m/e) 438 (M−NCH3); mp 132-136° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[N:3]=1.[CH:34]1[C:39]([OH:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].[Al+3].[Cl-].[Cl-].[Cl-].N1C=CC=NN=1>ClC1C=CC=CC=1>[OH:40][C:39]1[CH:34]=[C:35]([CH3:41])[CH:36]=[CH:37][C:38]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[N:3]=1
Reactant: Clc1nc(-c2ccc(Oc3ccccc3)cc2)nc(-c2ccc(Oc3ccccc3)cc2)n1
Reactant: Cc1cccc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: c1cnnnc1
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)nc(-c3ccc(Oc4ccccc4)cc3)n2)c(O)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 0.9 gm of 2-chloro-4,6-bis(4-phenoxyphenyl)-1,3,5-triazine, 0.24 gm of m-cresol and 0.4 gm AlCl3 in 5 ml chlorobenzene was heated to 70° C. under nitrogen and efficient stirring. After about 4 hr at 70° C., the reaction mixture was analyzed by HPLC, which showed the formation of a new product, and almost disappearance of the starting triazine. The reaction mixture was cooled to room temperature and quenched with water. It was then extracted with methylene chloride, and the organic layer separated, washed with water, dried, and concentrated to give a crude product. The crude product was crystallized from acetone to give almost pure 2-(2-hydroxy-4-methylphenyl)-4,6-bis(4-phenoxyphenyl)-1,3,5-triazine identified by HPLC, NMR and mass spectroscopy.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:3][CH:2]=1>CO.C(Cl)Cl>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8](=[O:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2nnc(CC(=O)Cc3ccc(-c4ccccc4)cc3)o2)n1
Solvent: ClCCl
Solvent: CO
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Cc1nnc(-c2cccc(C(=O)O)n2)o1
Yield: 85.1 %

Procedure:
The title compound was prepared from 35 (4.5 mg, 0.010 mmol) following general procedure A. Flash chromatography (SiO2, 10% MeOH—CH2Cl2) afforded the title compound (3.4 mg, 85%) as a yellow solid: 1H NMR (DMSO-d6+0.1% TFA, 600 MHz) δ 8.29 (d, 1H, J=7.8 Hz), 8.17 (d, 1H, J=7.8 Hz), 8.08 (t, 1H, J=7.8 Hz), 7.57-7.55 (m, 4H), 7.36 (t, 2H, J=7.8 Hz), 7.29-7.25 (m, 2H), 4.02 (s, 4H); 13C NMR (DMSO-d6+0.1% TFA, 150 MHz) δ 202.1, 166.2, 164.7, 163.3, 150.0, 143.1, 142.2, 141.0, 139.9, 133.9, 131.1, 128.9, 128.0, 127.7, 127.5, 127.3, 126.7, 48.0, 39.8; HRMS-ESI-TOF m/z 400.1299 ([M+H]+, C23H17N3O4 requires 400.1292).
Reaction SMILES: [OH-].[Na+].[CH2:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:21]([OH:29])([CH3:28])[CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:15]=1>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[C:16]([C:21]([OH:29])([CH3:28])[CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:15]=1
Reactant: CC(O)(Cn1ccnc1)c1cc(Cl)ccc1O
Reactant: CCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1ccc(Cl)cc1C(C)(O)Cn1ccnc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.9 %

Procedure:
Sodium hydroxide powder (20 mg, 0.5 mmol) and n-nonyl bromide (122 mg, 0.59 mmol) were added to a solution of 4-chloro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol [compound (2-1)] (100 mg, 0.40 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred for 17 hours at room temperature. Ice-water was added to the resultant mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography and dried under reduced pressure, to thereby yield 2-(5-chloro-2-(n-nonyloxy)phenyl)-1-(1H-1-imidazolyl)-2-propanol as a colorless oily product (81.7 mg, yield: 54.5%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[N:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][CH:3]=1>[Ni]>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:10]([CH2:11][NH2:12])=[CH:13][CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ncccc2C#N)cn1
Agent: [Ni]
Product: Cc1ccc(Oc2ncccc2CN)cn1

Procedure:
The product of Example 62A and Raney/nickel were processed according to the method of Example 131C to provide the product. MS (ESI+) m/z 216 (M+H)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25][C@H:26]2[O:83][C@H:82]([CH2:84][O:85]C(=O)C)[C@@H:37]([O:38][C@H:39]3[O:56][C@H:55]([CH2:57][O:58][C@H:59]4[O:76][C@H:75]([CH2:77][O:78]C(=O)C)[C@@H:70]([O:71]C(=O)C)[C@H:65]([O:66]C(=O)C)[C@H:60]4[O:61]C(=O)C)[C@@H:50]([O:51]C(=O)C)[C@H:45]([O:46]C(=O)C)[C@H:40]3[O:41]C(=O)C)[C@H:32]([O:33]C(=O)C)[C@H:27]2[O:28]C(=O)C)[C@@H:18]([CH2:89][O:90]C(=O)C)[O:17][C@H:6]1[O:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=O)C.[Na].C(Cl)(Cl)Cl.CO.O>CO>[C@H:59]1([O:58][CH2:57][C@H:55]2[O:56][C@H:39]([O:38][C@@H:37]3[C@@H:82]([CH2:84][OH:85])[O:83][C@H:26]([O:25][C@@H:19]4[C@@H:18]([CH2:89][OH:90])[O:17][C@@H:6]([O:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C@H:5]([OH:4])[C@H:20]4[OH:21])[C@H:27]([OH:28])[C@H:32]3[OH:33])[C@H:40]([OH:41])[C@@H:45]([OH:46])[C@@H:50]2[OH:51])[O:76][C@H:75]([CH2:77][OH:78])[C@@H:70]([OH:71])[C@H:65]([OH:66])[C@H:60]1[OH:61]
Reactant: COC(=O)CCSCCO[C@@H]1O[C@H](COC(C)=O)[C@@H](O[C@H]2O[C@H](COC(C)=O)[C@@H](O[C@H]3O[C@H](CO[C@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COC(=O)CCSCCO[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO[C@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reaction time: 9 h
Yield: 83.9 %

Procedure:
Compound 94 (3.0 g, 2.2 mmol) was dissolved in methanol (25 ml) and added to a solution of sodium (1 mg) in methanol (75 ml). The reaction mixture was monitored by TLC (chloroform:methanol:water 65:35:10, lower phase). After 9 h at room temperature and 30 min at 40°, the solvent was removed and the residue was chromatographed (SiO2, chloroform:methanol:water, 65:35:10, lower phase) to give 98 (1.50 g, 84%). [α]D25 +113° (c 0.7, water). 1H-NMR (D2O, TSP) δ 5.41 (d, 2H, J=3.5 Hz, H1' and H1"), 4.98 (d, 1H, J=3.6 Hz, H1"'), 4.53 (d, 1H, J=7.9 Hz, H1), 3.75 (s, 3H, MeO). 13C-NMR (D2O, TSP) δ 177.4 (CO), 104.3 (Cl), 102.0, 101.6, 100.2 (Cl', Cl", Cl"'), 79.3, 79.1, 78.3, 76.7, 75.4, 75.2, 75.1, 73.9, 73.8, 73.6, 73.5, 73.3,,71.6, 71.5, 71.1, 68.0, 62.8, 62.7, 62.6, 62.6, 54.5, 36.3, 32.9, 28.6.
Reaction SMILES: [CH2:1]([CH:5]1[N:10]([C:11](=[O:26])[CH2:12][CH2:13][C:14]2[NH:18][C:17](C(OC(C)(C)C)=O)=[N:16][CH:15]=2)[CH2:9][CH2:8][N:7]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[N:29]=[C:6]12)[CH2:2][CH2:3][CH3:4].Cl>CO>[CH2:1]([CH:5]1[N:10]([C:11](=[O:26])[CH2:12][CH2:13][C:14]2[NH:18][CH:17]=[N:16][CH:15]=2)[CH2:9][CH2:8][N:7]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[N:29]=[C:6]12)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1c2nc(-c3ccccc3OC)cn2CCN1C(=O)CCc1cnc(C(=O)OC(C)(C)C)[nH]1
Agent: Cl
Solvent: CO
Product: CCCCC1c2nc(-c3ccccc3OC)cn2CCN1C(=O)CCc1cnc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
The product from Step 1.g. (450 mg, 0.89 mmol) was dissolved in MeOH (5 ml) and 4N HCl was added and the reaction was stirred at room temperature for about ½ hour. Solvents were removed under reduced pressure to yield 420 mg of crude product. Part of the crude (100 mg) was purified by preparative HPLC on a RAININ™ C18 column (Varian Analytical, Walnut Creek, Calif.) using a gradient of 10–30% CH3CN/aq. HCl (pH=2.0) over 45 minutes with UV detection at 254 nm. Product fractions were concentrated to about ½ volume and lyophilized to yield pure product (47 mg, 47%) as the di-hydrochloride. Mass spec. 508.2 MH+.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][S:28]([CH2:31][C:32](O)=[O:33])(=[O:30])=[O:29]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (101 mg, 90%), MS (ISP) m/z=449.3 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-methanesulfonyl-acetic acid.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:10]([N:17]1[CH2:22][C@@H:21]2[CH2:23][C@H:18]1[CH2:19][NH:20]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH3:9][O:8][C:7]1[C:2]([N:20]2[CH2:19][C@@H:18]3[CH2:23][C@H:21]2[CH2:22][N:17]3[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Reactant: COc1cccnc1Br
Solvent: ClCCl
Product: COc1cccnc1N1C[C@@H]2C[C@H]1CN2Cc1ccccc1
Temperature: 100 °C
Yield: 51 %

Procedure:
A mixture of 2-bromo-3-methoxy pyridine (9.9 g) and (1S,4S)-N-benzyl-2,5-diazabicyclo[2.2.1]heptane (10.9 g) was heated at 100° C. in a Parr bomb for 67 h. The reaction mixture was cooled to 23° C., dissolved in CH2Cl2, extracted with 5% NaHCO3, and finally wit:h H2O. The organic layer was dried over K2CO3, filtered, and concentrated under reduced pressure. The crude oil was purified by silica gel chromatography (CH2Cl2 :MeOH; 96:4) to give the desired product (7.93 g, 51%).