Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[S:39]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1cnccc1Cl
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cnccc1Cl)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 20 mL resealable vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.26 g, 0.64 mmol, Example 91, Step 1), DCM (6 mL), triethylamine (0.44 mL, 3.2 mmol) and 4-chloro-3-pyridinesulfonyl chloride (0.16 g, 0.76 mmol). The mixture was stirred at room temperature for 15 min. To the reaction mixture was added saturated aqueous NaHCO3. The mixture was stirred for 5 min and then the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was concentrated and purified by silica gel chromatography (0 to 70% EtOAc/hexane) to afford 2-(4-(4-((4-chloro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](Cl)=[O:13].[CH3:15][C:16]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:17]=1[O:18][CH2:19][CH2:20][OH:21].CC(C)([O-])C.[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([O:21][CH2:20][CH2:19][O:18][C:17]1[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:16]=1[CH3:15])=[O:13]
Reactant: Cc1cccc(OCCO)c1C
Reactant: O=C(Cl)N1CCCc2c(Br)cccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cccc(OCCOC(=O)N2CCCc3c(Br)cccc32)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
A mixture of 5-bromo-3,4-dihydroquinoline-1(2H)-carbonyl chloride (0.05 g, 0.182 mmol), 2-(2,3-dimethylphenoxy)ethanol (0.038 g, 0.228 mmol) and TEA (0.076 mL, 0.546 mmol) in DCM (1.5 mL) was stirred at room temperature for 16 h. To the mixture was then added potassium tert-butoxide (1 M in THF, 0.364 mL, 0.364 mmol) and the resulting mixture was stirred at room temperature for 24 h before being quenched with water. The organic layer was separated and the aqueous phase was extracted with DCM. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate/hexanes) to afford the title compound (51 mg, 69.3% yield). LCMS, [M+Na]+=427.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:27][C:26]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:26]4[CH:27]=[CH:28][C:29]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:25]=4[F:24])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CS(C)(=O)=O)cc4F)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-4-(methanesulfonylmethyl)-phenylboronic acid acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.18 min; Mass spectrum (ESI+): m/z=491 [M+H]+.
Reaction SMILES: Cl.[CH2:2]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][NH:3]1.[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=O)[CH2:28][CH2:27]2.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH:29]([N:3]1[CH2:4][C:5]3([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]3)[CH2:2]1)[CH2:28][CH2:27]2
Reactant: O=C1CCc2cc(-c3ncccn3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C1CCc3cc(-c4ncccn4)ccc31)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.8 %

Procedure:
To a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (850 mg, 3.23 mmol) and 5-pyrimidin-2-ylindan-1-one (SM-1b, 680 mg, 3.23 mmol) in dichloromethane (10 mL) under nitrogen was added triethylamine (2.5 mL, 17.9 mmol) followed by titanium isopropoxide (2.9 mL, 9.70 mmol). The reaction was stirred at room temperature for 90 minutes and sodium triacetoxyborohydride (2.1 g, 9.9 mmol) was added. After stirring for 4 days, the reaction was quenched with saturated ammonium chloride. The mixture was diluted with 50 mL of dichloromethane and 50 mL of water and filtered through a Celite® pad. The aqueous layer was extracted with dichloromethane (2×30 mL). The combined organics layers were washed with brine and dried over MgSO4. The solvent was removed to give a dark green/brown paste which was chromatographed on a Combiflash ISCO purification system (Teledyne Corp., Lincoln Nebr.) using a dichloromethane/MeOH gradient to afford the title compound as light brown oil (785 mg, 57.7%). MS (ES+) 421.2 (M+H)+. 1H NMR (CDCl3) δ 1.39 (s, 9H), 1.59-1.69 (m, 4H), 1.75-1.94 (m, 1H), 2.12 (dq, 1H), 2.76-2.92 (m, 1H), 2.95-3.18 (m, 5H), 3.19-3.36 (m, 4H), 3.92 (dd, 1H), 7.09 (t, 1H), 7.33 (d, 1H), 8.18-8.26 (m, 2H), 8.71 (d, 2H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[C:54]([O-:57])([O-])=[O:55].[Na+].[Na+]>COCCOC.O>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:51])[CH3:52])[C:41]([F:53])=[C:40]([CH:26]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[C:4]2[N:5]([C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[C:2]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:54]([OH:57])=[O:55])[N:3]=2)[CH:45]=1)[CH3:48]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(=O)O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 170 °C

Procedure:
A suspension of 66.3 (100 mg, 0.13 mmol), 2-carboxyl phenylboronic acid (30 mg, 0.2 mmol), Na2CO3 (56 mg, 0.52 mmol) in 3:1 DME/H2O (3 mL) was degassed and then added in Pd(PPh3)4 (10 mg). The reaction mixture was heated to 170° C. for 15 mins in microwave. The reaction mixture was adjust to PH ˜4-5, then partitioned between EtOAc and sat. NaCl, the organic layer was collected and dried over (Na2SO4), filtered and concentrated to afford Intermediate 133.1. The crude material was used in the next step without further purification. LCMS (2 min grad.) RT=2.13 min, 814.3 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([CH2:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[C:17](OC)=[O:18])=O.O.[OH-].[Na+]>O1CCCC1>[OH:18][CH2:17][C:16]1[CH:15]=[CH:14][S:13][C:12]=1[CH2:11][CH2:9][OH:8]
Reactant: COC(=O)Cc1sccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1sccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
In a dried vessel, 600 mg of lithium aluminum hydride was charged under a nitrogen atmosphere, and then 26 mL of anhydrous tetrahydrofuran was added thereto. To the resulting suspension, a solution of 2.8 g of the compound obtained in Example 1 dissolved in 10 mL of tetrahydrofuran was added over about 5 minutes. The resulting mixture was stirred at room temperature for 1 hour, and then refluxed for 1 hour. The reaction solution was cooled to 0° C., and 0.5 mL of water, 0.5 mL of 15% sodium hydroxide aqueous solution, and 4 mL of water were added thereto slowly in succession. The resulting mixture was stirred for about 1 hour, and the insoluble materials was filtered and washed with 30 mL of tetrahydrofuran. Combined filtrate was concentrated by evaporation under reduced pressure to obtain 1.8 g (yield of 87%) of oily title compound.
Reaction SMILES: [F:1][C:2]([F:16])([C:5]([F:15])([F:14])[C:6]([F:13])([F:12])[C:7]([F:11])([F:10])[CH2:8][OH:9])[CH2:3][OH:4].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[OH:9][CH2:8][C:7]([F:10])([F:11])[C:6]([F:13])([F:12])[C:5]([F:14])([F:15])[C:2]([F:16])([F:1])[CH2:3][O:4][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=Cc1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)cc1
Temperature: 97.5 °C

Procedure:
A mixture of 2,2,3,3,4,4,5,5-octafluoro-1,6-hexanediol (7.86 g), 4-fluorobenzaldehyde (1.24 g), NMP (10 mL), and potassium carbonate (4.14 g) was heated to 95-100° C. for 48 hrs. The mixture was further processed as described in Example 1 to provide 4-(6-hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)benzaldehyde.
Reaction SMILES: C[O-].[Na+].C[O:5][C:6](=O)[CH:7]=[CH:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH2:25][CH2:26][CH2:27][OH:28])[C:14]([CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[N:15][C:11]=2[CH:10]=1.Cl.[NH2:33][OH:34]>CO>[OH:34][NH:33][C:6](=[O:5])[CH:7]=[CH:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH2:25][CH2:26][CH2:27][OH:28])[C:14]([CH2:16][CH:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])=[N:15][C:11]=2[CH:10]=1
Reactant: NO
Reactant: COC(=O)C=Cc1ccc2c(c1)nc(CC(C)c1ccccc1)n2CCCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(Cc1nc2cc(C=CC(=O)NO)ccc2n1CCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 6 %

Procedure:
Sodium methoxide (30% in methanol) (782 mg, 4.1 mmol) was added to a prestirred solution of 3-[1-(3-Hydroxy-propyl)-2-(2-phenyl-propyl)-1H-benzimidazol-5-yl]-acrylic acid methyl ester (130 mg, 0.34 mmol and hydroxylamine hydrochloride (242 mg, 3.4 mmol in MeOH (1.5 mL). The reaction mixture was continuously stirred for 40 minutes at room temperature and then poured into a solution of ice-water containing 1.0 mL concentrated hydrochloric acid. The mixture was extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and concentrated. The desired product was separated by reverse phase preparative HPLC. After lyopholyzation, 7.8 mg (6%) of N-Hydroxy-3-[1-(3-hydroxy-propyl)-2-(2-phenyl-propyl)-1H-benzimidazol-5-yl]-acrylamide was obtained as powder. HPLC: 96%; tR=(LC/PDA: Phenomenex Luna C18 2.0×150 mm 5μ column; 0.8 mL/min, gradient 5-65% B over 15.5 min, Solvent A: H2O with 0.1% trifluoroacetic acid; Solvent B: Acetonitrile with 0.1% trifluoroacetic acid; UV 254): 7.22 min; 92%. 1H NMR (400 MHz, DMSO-d6) δ 1.35 (3H, d, J=6.5 Hz), 1.83 (2H, m), 3.00-4.00 (6H, m), 4.33 (2H, t, J=7.1 Hz), 6.55 (1H, d, J=15.8 Hz), 7.19-7.33 (5H, m), 7.62 (1H, d, J=15.8 Hz), 7.70 (1H, d, J=8.60 Hz), 7.82 (1H, d, J=8.60 Hz), 7.92 (1H, s), 10.15 (1H, bs), 10.33 (1H, bs). MS (m/z): 380 [MH]+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>O1CCOCC1>[CH:21]1([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH:10]3[CH2:9][NH:8][CH2:11]3)=[CH:14][CH:15]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(OCC3CC3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1cc(OC2CNC2)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1.7 g (5.32 mmol) 3-(4-cyclopropylmethoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester in 15 mL 1,4-dioxane is added 12.8 mL (16.0 mmol) HCl in dioxane (1.25 mol/L) and the mixture is stirred for 2 h at rt. 1 N NaOH solution is added until the mixture is slightly basic followed by extraction with DCM (2×). The combined organic layers are washed and dried over MgSO4. The solvent is evaporated and the residue is purified by column chromatography (silica gel; DCM/MeOH; gradient 9:1→7:3) to yield the desired product.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][N:12]([CH2:20][C:21](O)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[N:30].CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([CH2:10][CH2:11][N:12]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:20][C:21]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29]#[N:30])=[O:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N(CCS(=O)(=O)c1ccccc1)CC(=O)O
Reactant: N#C[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCS(=O)(=O)c1ccccc1)CC(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
[(2-benzenesulfonyl-ethyl)-BOC-amino]-acetic acid (288 mg, 0.84 mmol) and (S)-pyrrolidine-2-carbonitrile (111 mg, 0.84 mmol) were combined in CH2Cl2 (10 mL) at 0° C. EDCI (192 mg, 1.0 mmol) and triethylamine (280 μL, 2.0 mmol) were added, and the reaction stirred for 3 h while warming to r.t. The solution was washed with 0.1 N HCl and brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (75% EtOAc/hexanes) gave 188 mg (53%) of (S)-1-[2-(2-benzenesulfonyl-ethyl-BOC-amino)-acetyl]-pyrrolidine-2-carbonitrile as a white foam. 1H NMR (300 MHz, CDCl3): δ 7.91 (t, 2H, J=4.8 Hz), 7.54-7.69 (m, 3H), 4.69-4.79 (m, 1H), 4.17 (t, 1H, J=12.0 Hz), 3.87 (t, 1H, J=12.0 Hz), 3.40-3.77 (m, 6H), 2.12-2.32 (m, 4H), 1.39 (d, 9H, J=5.1 Hz). MS (ES) [m+H]/z calculated for C20H27N3O5S+H 422.17, found 422.10.
Reaction SMILES: N1C=CC=CC=1.[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([OH:20])[CH:18]=[CH2:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:24][C:25]1([CH3:35])[CH:27]([CH:28]=[C:29]([Cl:31])[Cl:30])[CH:26]1[C:32](Cl)=[O:33]>C1C=CC=CC=1>[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([O:20][C:32]([CH:26]1[CH:27]([CH:28]=[C:29]([Cl:30])[Cl:31])[C:25]1([CH3:35])[CH3:24])=[O:33])[CH:18]=[CH2:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C=CC(OC(=O)C1C(C=C(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 g of pyridine in 10 ml of benzene is added dropwise at 5° C. to a solution of 8 g of 3-phenoxy-α-vinyl-benzyl alcohol in 30 ml of benzene, and at 10° C. is subsequently added 8 g of 2,2-dimethyl-3-(dichlorovinyl)-cyclopropanecarboxylic acid chloride. The reaction mixture is stirred for two hours at room temperature and is then allowed to stand for 12 hours. In further processing, the reaction mixture is diluted with ice water, the organic phase is extracted 3 times with 100 ml of 3% HCl solution each time and 3 times with 100 ml of 3% sodium bicarbonate solution each time; it is dried over sodium sulfate, and the benzene is distilled off. There is obtained the compound of the formula ##STR7## as colourless oil have a refractive index of nD40 =1.5710. (isomeric mixture 40% cis and 60% trans compound)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.[OH-].[Na+].[NH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=2)=[O:11])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofuran (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridine-acrylic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.46 g, 82%). HRMS calcd for C16H14N2O3: 282.2988. Found: 282.2990. MA calcd for: C16H14N2O3: C, 68.07%; H, 5.00%; N, 9.92%. Found: C, 68.21%; H, 5.03%; N, 9.90%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:25](OCC)(=O)C>CN(C)C=O.O>[CH3:25][N:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)=[O:14])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)N1CCOCC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(CCCCC(=O)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[5-(N-t-butoxycarbonylamino)valeryl]morpholine (1.656 g) in dry N,N-dimethylformamide (20 ml) were added sodium hydride (60% dispersion in mineral oil: 347 mg) and methyl iodide (2.462 g) at 0°-5° C. under nitrogen atmosphere. After being stirred for 6 hours at room temperature, the reaction mixture was added to ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with 0.5N hydrochloric acid (200 ml), water (200 ml), aqueous sodium bicarbonate (200 ml), water (200 ml) and brine (200 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave 4-[5-(N-methyl-N-t-butoxycarbonylamino)valeryl]morpholine (1.093 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[N:41]([CH:43]=[CH:44][N:45]=2)[N:42]=1>O>[N:45]1[CH:44]=[CH:43][N:41]2[C:40]=1[CH:39]=[CH:38][C:37]([CH2:36][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]3[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:6][CH:7]=1)=[N:42]2
Reactant: ClCc1ccc2nccn2n1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5nccn5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (1.2 g, 3.8 mmol) was added to a mixture of cesium carbonate (3.7 g, 11.6 mmol) and DMF (25 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 6-(chloromethyl) imidazo[1,2-b]pyridazine (0.96 g, 5 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 30% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.8 g, 47%) as Off-white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.35 (s, 1H), 8.2 (d, 1H), 7.8 (s, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.3 (s, 2H), 3.9 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=442.1. HPLC: (95.8%, Condition-A).
Reaction SMILES: C(OCC)(=O)CCCCCCCCCCCCCCCCCCCCC.C([O:50][CH:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH3:52])(=O)CCCCCCCCCCCCCCCCCCCCC>O>[C:53]1([C@@H:51]([OH:50])[CH3:52])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)OC(C)c1ccccc1
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC
Solvent: O
Product: C[C@H](O)c1ccccc1
Yield: 97 %

Procedure:
Interesterification was carried out by using 1 g of Lipase QL, 40 g of (R,S)-1-phenylethanol, and 60 g of ethyl behenate under the same conditions as in Example 6 at 95° C. for a period of 20 hours. The water content of the reaction system was 0.03% by weight, and 95% of the lipase particles had a particle size of 20 to 40 μm. Gas chromatography of the reaction mixture revealed that 47 mol % of (R,S)-1-phenylethanol had been converted to 1-phenylethyl behenate. The reaction mixture was treated in the same manner as in Example 6 and subjected to simple distillation at 85° C. and 5 mmHg to give (S)-(-)-1-phenylethanol (yield: 97%; chemical purity: 99.9%; optical purity: 88.9% ee). On the other hand, the residue, i.e., a mixture of (R)-(+)-1-phenylethyl behenate and unreacted ethyl behenate was alkali-hydrolyzed in the same manner as in Example 1, and 1000 ml of acetone was added to the reaction mixture, followed by cooling to 5° C. The precipitated behenic acid was removed by filtration to obtain (R)-(+)-1-phenylethanol (yield: 88%; chemical purity: 99.9%; optical purity: 98.5% ee).
Reaction SMILES: [C:1]([C:3]1[CH:41]=[CH:40][C:6]([CH2:7][NH:8][C:9]([C:11]2[N:12](COCC[Si](C)(C)C)[C:13]([CH3:31])=[C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([C:25]3[O:29][N:28]=[C:27]([CH3:30])[N:26]=3)=[CH:19]4)[N:15]=2)=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]([C:11]2[NH:12][C:13]([CH3:31])=[C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([C:25]3[O:29][N:28]=[C:27]([CH3:30])[N:26]=3)=[CH:19]4)[N:15]=2)=[O:10])=[CH:40][CH:41]=1)#[N:2]
Reactant: Cc1noc(-c2cc3cc(-c4nc(C(=O)NCc5ccc(C#N)cc5)n(COCC[Si](C)(C)C)c4C)ccc3[nH]2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc(-c2cc3cc(-c4nc(C(=O)NCc5ccc(C#N)cc5)[nH]c4C)ccc3[nH]2)n1
Temperature: 100 °C
Yield: 21.1 %

Procedure:
To 5-Methyl-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-indol-5-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid 4-cyano-benzylamide (75 mg, 0.13 mmol) in of dioxane (2.5 ml) is added aqueous HCl (3M, 2.5 ml) and is the mixture is heated at 100° C. for 4 hours. The solvent is evaporated and the residue is purified on silica with ethyl acetate/hexane as the eluent to give product 12 mg, 21%, LC/MS ESI m/z (M+H)+=438.4.