Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH2:6][CH:7]=[O:8])[CH:9]=[CH:10][CH:11]=1
Reactant: OCCc1cccc(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClC(Cl)Cl
Product: O=CCc1cccc(C(F)(F)F)c1
Yield: 60.1 %

Procedure:
To a solution of 3-(trifluoromethyl)phenethyl alcohol (2.00 g) in chloroform (50.0 mL), Dess-Martin periodinane (4.70 g) was added under cooling with ice. After being brought to room temperature, the reaction mixture was stirred for an hour. Subsequently, a saturated aqueous solution of sodium hydrogencarbonate (25.0 mL) and a saturated aqueous solution of sodium thiosulfate (25.0 mL) were added and the mixture was vigorously stirred for an hour. After phase separation, the organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-85:15) to give the titled compound as a pale yellow oil (1.19 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:17]([Cl:18])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:18][C:17]1[C:3]2[C:2]([N:19]3[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]3)=[N:7][C:6]([NH:8][C:9]3[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=3)=[N:5][C:4]=2[NH:15][CH:16]=1
Reactant: Cn1cc(Nc2nc(Cl)c3c(Cl)c[nH]c3n2)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2nc(N3CCCC(NC(=O)OC(C)(C)C)C3)c3c(Cl)c[nH]c3n2)cn1
Yield: 44 %

Procedure:
A solution of 4,5-dichloro-N-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (85 mg, 0.30 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (90 mg, 0.45 mmol) and DIEA (75 μL, 0.45 mmol) in DMSO (0.60 mL) was heated to 120° C. in a microwave for 10 min. The reaction solution was poured into water and filtered. The filtrate was extracted with EtOAc and the organic layer was dried over MgSO4, filtered and concentrated in vacuo. The solids were combined and purified via flash chromatography eluting with a gradient of 1%-5% of (10% NH4OH in MeOH) in DCM to give the title compound (59 mg, 44% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (br. s., 1H), 8.74 (s, 1H), 7.82 (s, 1H), 7.49 (s, 1H), 7.04 (d, J=2.69 Hz, 1H), 6.89 (d, J=7.83 Hz, 1H), 3.96-4.11 (m, 2H), 3.78 (s, 3H), 3.51 (br. s., 1H), 2.85 (t, J=11.25 Hz, 1H), 2.75 (t, J=11.13 Hz, 1H), 1.85-1.94 (m, 1H), 1.75-1.84 (m, 1H), 1.70 (t, J=12.10 Hz, 1H), 1.38 (s, 9H), 1.31 (br. s., 1H). m/z (APCI+) for C20H27ClN8O2 447.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16](S(C)(=O)=O)=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31].[CH3:32][O-:33].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16]([O:33][CH3:32])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2ccc(F)cc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2

Procedure:
The product of Example 3 (0.102 g, 0.22 mmol) was suspended in MeOH (2 mL) and stirred under argon. A 1 Molar solution of NaOMe in methanol (0.44 mL, 0.44 mmol) was added. After 10 min the solvent was removed in vacuo, and the residue partitioned between EtOAc and H2O. The organic phase was washed with H2O (2×), satd aq NaCl (1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product. Recrystallization from EtOAc/hexane gave the title compound as a white-crystalline solid. mp 210-211° C., LC MS m/z=401 (MH+) Rt=2.0 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([CH:13]3[CH2:15][CH2:14]3)[CH3:12])=[C:8]([C:16]([NH2:18])=[O:17])[CH:7]=[N:6][N:5]2[CH:19]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25]>>[CH:13]1([C@H:11]([NH:10][C:9]2[C:4]3[N:5]([CH:19]=[C:2]([N:20]4[CH2:24][CH2:23][CH2:22][C:21]4=[O:25])[CH:3]=3)[N:6]=[CH:7][C:8]=2[C:16]([NH2:18])=[O:17])[CH3:12])[CH2:15][CH2:14]1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Reactant: O=C1CCCN1
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(N3CCCC3=O)cc12)C1CC1

Procedure:
Example 185 was prepared from 6-bromo-4-(((1R)-1-cyclopropylethyl)amino)-pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 4) and 2-pyrrolidinone according to the procedure described for Example 37. HPLC (condition G): retention time=7.10 min. LCMS (ES+) m/z: 328.1.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O>>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=3)[N:13]=2)[CH2:2][CH2:3]1
Reactant: COc1ccccc1C=O
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: COc1ccccc1CN1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methoxybenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-methoxyphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:41])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:24]2)[C:19]1=[O:40])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-:43].[K+].[K+].OO.C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:41])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:24][CH2:25][CH:26]([O:29][Si:30]([CH:34]([CH3:35])[CH3:36])([CH:37]([CH3:39])[CH3:38])[CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:28]2)[C:19]1=[O:40])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([NH2:11])=[O:43])=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(Oc4ccc(C#N)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(Oc4ccc(C(N)=O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
Cool a solution of (R)-4-{3,5-dichloro-4-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenoxy}-benzonitrile (0.295 g, 0.48 mmol) in DMSO (5 mL) on an ice bath. Add to the solution potassium carbonate (0.331 g, 2.4 mmol) and hydrogen peroxide (30% in water, 1 mL) and stir the reaction at 0° C. for 1.5 hours and then at room temperature for 12 hours. Dilute the reaction with ethyl acetate, and wash three times with water and then one time with brine. Dry the organic phase over sodium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography by eluting with 40% ethyl acetate in hexanes to 100% ethyl acetate gradient to afford 0.210 g (69%) of the title compound. MS (m/z): 633 (M+).
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3][N:2]1[C:12]([CH2:14][N:15]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])=[N:18][CH:17]([NH:33]C(OC(C)(C)C)=O)[C:16]1=[O:41])=[O:13])[CH2:9]2.Cl>[N+](C)([O-])=O>[NH2:33][CH:17]1[N:18]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:15]([CH2:14][C:12]([N:2]2[CH2:3][CH:4]3[CH2:10][CH:8]4[CH2:7][CH:6]([CH2:11][CH:1]2[CH2:9]4)[CH2:5]3)=[O:13])[C:16]1=[O:41]
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CC4CC(C3)CC2C4)C1=O
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CC4CC(C3)CC2C4)C1=O
Yield: 72.5 %

Procedure:
To a solution of (3RS)-1-[(2-azatricyclo[4.3.1.14,8 ]-undec-2-yl) carbonylmethyl]-3-tert-butoxycarbonylamino-2,3-di-hydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (0.445 g) in nitromethane was treated with hydrogen chloride under stirring at cooling in an ice-bath. The mixture was concentrated in vacuo. The residue was dissolved with ethyl acetate and extracted with 1N hydrochloric acid aqueous solution three times. The combined aqueous layers were alkalined with sodium bicarbonate, extracted with ethyl acetate twice. The extracts were dried over sodium sulfate. Removal of the solvent gave (3RS)-3-amino-1-[(2-azatricyclo[4.3.1.14,8 ]undec-2-yl)carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (0.265 g), which was used in a following reaction step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][CH:51]1[CH2:56][NH:55][CH2:54][CH:53]([CH3:57])[NH:52]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][C@H:53]([CH3:57])[NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC1CNCC(C)N1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-4-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.15 mmol) in DCM (2 mL) was added 2,6-dimethylpiperazine (predominantly cis) (26 mg, 0.23 mmol), AcOH (0.01 mL, 0.18 mmol) followed by NaBH(OAc)3 (64.3 mg, 0.30 mmol). The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was purified using a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 90% CH3CN in water at a flowrate of 20 mL/min. Fractions containing product were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}-4-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide as a white solid (23 mg, 20%). LC-MS m/z 757 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH:7]=[CH:8][CH2:9]Cl)([O-:3])=[O:2].[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:23]=2[N:24]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][N:20]([CH2:9][CH:8]=[CH:7][C:6]3[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:21][CH2:22][C:23]=2[N:24]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: O=[N+]([O-])c1cccc(C=CCCl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc([N+](=O)[O-])c1)CC2
Yield: 56 %

Procedure:
Prepared from 3-nitro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform. Yield: 56% of theory, Melting point: 165°-168° C. (ether).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O.[H][H].O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2CCOCC2=O)cc1
Temperature: 40 °C

Procedure:
60 g (0.27 mol) of 4-(4-nitrophenyl)-3-morpholinone (VII) are suspended in 480 g of ethanol, admixed with 3 g of palladium on activated carbon (5%) and contacted with 5 bar of hydrogen at 80° C. for one hour. After hydrogenation has ended, the suspension is admixed with 80 g of ethanol and 270 g of water and heated to 40° C., and the catalyst is filtered off. The solution is concentrated under reduced pressure and the remaining solid is dried to constant weight at 50° C. under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][C:41]([NH2:43])=[O:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][C:41]([NH2:43])=[O:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@@H]3C(CC(N)=O)CO[C@@H]32)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1

Procedure:
2-[(3aR,6R,6aS)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetamide was dissolved in TFA (0.5 mL) and DCM (0.5 mL) and stirred at room temperature for 2 hours. The reaction mixture was evaporated to give an oil. The oil was dissolved in methanol (0.5 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient. The desired fractions were lyophilized to give the title compound as a solid. Major isomer LC-MS: calculated for C26H23ClN4O4 490.14 observed m/e: 491.23 (M+H)+ (Rt 0.53/2 min); 1H NMR δ (ppm) (CD3OD): 7.94 (s, 1H), 7.76 (ABq, 4H), 7.71 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 5.58 (qt, 1H), 5.00 (t, 1H), 4.56 (t, 1H), 4.12 (dd, 1H), 4.02 (m, 2H), 3.54 (dd, 1H), 2.64 (dd, 1H), 2.58 (m, 1H) and 2.38 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[CH3:30].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:26]4[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=4)[CH2:32][CH2:33]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(-c4ccccc4)n3)CC2)cc1C

Procedure:
60 mg (71%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (50 mg, 0.170 mmol), 1-(3,4-dimethylphenyl)piperazine (32 mg, 0.170 mmol), DIPEA (0.030 mL, 0.170 mmol) and NaBH(OAc)3 (108 mg, 0.510 mmol).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.I[CH2:21][CH3:22].[BH4-].[Na+]>C(O)C>[CH2:21]([N:17]1[CH2:16][CH:15]=[C:14]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]3([CH3:13])[O:9][CH2:10][CH2:11][O:12]3)[C:2]=2[F:1])[CH2:19][CH2:18]1)[CH3:22]
Reactant: CCI
Reactant: CC1(c2cccc(-c3ccncc3)c2F)OCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CC=C(c2cccc(C3(C)OCCO3)c2F)CC1

Procedure:
Preparation according to preparation 6: 4-[2-fluoro-3-(2-methyl-1,3-dioxolan-2-yl)phenyl]pyridine (0.95 g, 3.66 mmol), 1-iodoethane (4 ml), ethanol (40 ml), sodium borohydride (1.0 g, 29.3 mmol). Yield: 0.88 g. MS m/z (rel. intensity, 70 eV) 291 (M+, bp), 276 (94), 219 (29), 110 (46), 87 (29).
Reaction SMILES: [CH2:1]([CH2:8][CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[K+]>O>[CH2:1]([CH2:8][CH:9]([C:15]([OH:17])=[O:16])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CCc1ccccc1)C(=O)O
Yield: 83.3 %

Procedure:
The diethyl benzylmethylmalonate (75 g) was combined with 300 ml of ethanol and a solution of 100 g of potassium hydroxide in 300 ml of water and heated at gentle reflux for 5 hours. After cooling, the mixture was extracted with diethyl ether (2×300 ml). The aqueous layer was then acidified with 120 ml of concentrated hydrochloric acid and extracted with diethyl ether (3×300 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to yield 49.2 g of benzylmethylmalonic acid as a yellow solid (83% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:13][CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(C(C)C)cccc1C(C)C
Yield: 72.7 %

Procedure:
A mixture of 2,6-diisopropyl phenol (20 g, 0.11 mol), potassium carbonate (62 g, 0.45 mol), acetone (160 ml) and methyl iodide (28 ml, 0.45 mole) is refluxed for three days. The reaction mixture is filtered through celite, evaporated, dissolved in ether, washed twice with 1M sodium hydroxide, dried over magnesium sulphate and concentrated to afford 15.1 g (0.08 mol, 70%) of 2,6-diisopropyl anisole as a slightly yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.CCCCCCC.[NH4+].[Cl-]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A sol. of 3-(4-bromo-phenyl)-propan-1-ol (49.4 g, 230 mmol) in DMF (500 mL) is cooled to 0° C., and imidazole (23.77 g, 349 mmol) and TBDMS-Cl (52.6 g, 349 mmol) are added. The mixture is stirred overnight, while warming up to rt. The mixture is diluted with heptane (1.0 L) and aq. sat. NH4Cl (800 mL), and the mixture is shaken. The layers are separated. The aq. layer is extracted with heptane, and the combined org. extracts are washed with brine. The org. extracts are dried over MgSO4, filtered, and the solvents are removed under reduced pressure. Purification by FC (Et2O/heptane 1:99→1:19) yields the title compound (68.1 g, 90%). LC-MS: tR=1.24 min.
Reaction SMILES: C([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([Cl:16])[CH:6]=1)(=O)C.C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>ClCCl>[Cl:16][C:7]1[C:8]([C:9]([NH:33][CH:30]2[CH2:32][CH2:31]2)=[O:11])=[CH:12][C:13]([O:14][CH3:15])=[C:5]([OH:4])[CH:6]=1
Reactant: COc1cc(C(=O)O)c(Cl)cc1OC(C)=O
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CC2)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-acetoxy-2-chloro-5-methoxybenzoic acid (8.6 g, 35.2 mmol) and triethylamine (8.9 g, 88 mmol) in dry dichloromethane (100 ml) was cooled to 0° C. and ethylchloroformate (7.6 g, 70 mmol) was added at such a rate that the temperature stayed below 5° C. After 1 h cyclopropylamine (6.0 g, 105 mmol) was added. After stirring overnight at room temperature the organic phase was washed with water (2×200 ml). Drying over magnesium sulfate was followed by reduction of the solvent volume to half. Petrol ether was added and the product was filtered off. Yield 570 mg, 6.7%, mp 214-216° C.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C@@:6]12[O:13][C@@H:10]([CH2:11][CH2:12]1)[C:9](=[O:14])[CH2:8][C:7]2=[O:15].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH3:42])=[C:37]([Pb+3])[CH:36]=2)=[CH:31][CH:30]=1.Cl>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH3:42])=[C:37]([CH:8]3[C:9](=[O:14])[C@H:10]4[O:13][C@:6]([CH3:5])([CH2:12][CH2:11]4)[C:7]3=[O:15])[CH:36]=2)=[CH:33][CH:34]=1
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 67.8 %

Procedure:
To a mixture of chloroform (2.0 ml) and toluene (0.5 ml) is added (1R*,5S*)-1-methyl-8-oxa-bicyclo[3.2.1]octane-2,4-dione (0.10 g, 0.6 mmol) and N,N-dimethylamino-pyridine (0.395 g, 3.2 mmol) under a nitrogen atmosphere with stirring. To this reaction mixture is added 4′-chloro-4-ethylbiphenyl-3-yllead triacetate (0.42 g, 0.70 mmol) in one portion, then the mixture is heated at 80° C. for 1-2 hours. The reaction mixture is cooled to room temperature, acidified with dilute aqueous hydrochloric acid then filtered through diatomaceous earth to remove inorganic residues (subsequent washing with dichloromethane). The aqueous fractions are extracted with dichloromethane (2×5 ml), all organic fractions are combined, dried over sodium sulfate then concentrated under vacuum to give the crude product which is purified by flash chromatography (hexane/ethyl acetate) to give (1R*,5S*)-3-(4′-chloro-4-ethylbiphenyl-3-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.150 g) as a white solid.