Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C@@H:9](OS(C)(=O)=O)[CH3:10])(=O)=O.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH2:16]([N:23]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH3:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](CCCOS(C)(=O)=O)OS(C)(=O)=O
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN1Cc1ccccc1
Yield: 100 %

Procedure:
First, 2.49 g (9.6 mmol) of (S)-1,4-bis(methanesulfonyloxy)pentane produced in Example 5 and 5.13 g (47.9 mmol) of benzylamine were stirred at 70° C. for three hours. Subsequently, 30 mL of ethyl acetate and 4.0 g of a 20 weight percent aqueous solution of sodium hydroxide were added to the mixture to perform an extraction. The organic layer was concentrated under a reduced pressure to obtain a yellow oily substance. This product was purified by silica gel column chromatography. Thus, (R)-1-benzyl-2-methylpyrrolidine was obtained as a light yellow oily substance (1.83 g, yield: 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[CH3:16])[CH3:9])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH:25]1[CH3:31])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([N:13]2[CH2:14][CH2:15][N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[CH3:9])[C@H:11]([CH3:16])[CH2:12]2)[CH2:26][CH:25]1[CH3:31])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: CC1CNCCN1C(C)c1ccc(Br)cc1
Product: CC1CC(N2CCN([C@@H](C)c3ccc(Br)cc3)[C@H](C)C2)CCN1C(=O)OC(C)(C)C

Procedure:
1-[1-(4-Bromo-phenyl)-ethyl]-2-methyl-piperazine (0.104 g) from preparation A step 4 was treated with 0.075 g 1-tert-butoxycarbonyl-2-methyl-4-oxo-piperidine from the previous step as described in preparation A step 5 to afford 1-tert-butoxycarbonyl-2-methyl-4-{4-[1 (S)-(4-Bromophenyl)-ethyl]-3(R)-methylpiperazin-1-yl}-piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[K].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:16]2[C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]3[C:12]2=[O:22])=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(CCl)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
A mixture of 20 g 4-methoxybenzyl chloride, 26 g phthalimide potassium, and 100 ml dimethylformamide was stirred at 50° C. for 5 hr. After cooling, the reaction solution was poured into ice water and the resulting precipitates were collected by filtration. These were washed with water and dried to give 31 g of N-(4-methoxybenzyl)phthalimide.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:8][C:9](=[O:22])[C:10](=[CH:18]OCC)[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[CH3:7].[C:23]([NH2:29])(=[O:28])[CH2:24][C:25]([CH3:27])=[O:26]>C(O)C>[C:25]([C:24]1[C:23](=[O:28])[NH:29][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([C:9]([O:8][CH2:6][CH3:7])=[O:22])[CH:18]=1)(=[O:26])[CH3:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Reactant: CC(=O)CC(N)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Reaction time: 0.5 h

Procedure:
Sodium acetate (30 g, 0.37 mol) is added to a stirred mixture of diethyl(ethoxymethylene)oxalacetate (87 g, 0.36 mol) and acetoacetamide (36 g, 0.36 mol) in absolute ethanol (300 mL). After stirring the reaction mixture for 30 minutes, the ethanol is distilled off under reduced pressure, the residue acidified to pH 2 with dilute aqueous hydrochloric acid and the resulting solid filtered off. Crystallization from an ethanol-water mixture affords diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate as crystals mp 200°-209° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][Br:12])([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(F)ccc1CBr

Procedure:
A mixture of 2-nitro-4-fluorotoluene (1.65 g), N-bromo-succinimide (1.78 g), carbon tetrachloride 10.0 ml) and benzoyl peroxide (0.1 g) was heated at the reflux temperature until the solid residue was observed to be floating at the surface (ca. 3 hours). After removing the solid by filtration, the filtrate was diluted with diethyl ether, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvents under reduced pressure. The residue (estimated to contain ca. 35% w/w of the benzyl bromide in admixture with unchanged starting material) was subjected to column chromatography using a silica column and diethyl ether/petroleum ether (ratio 1:9 v/v) as eluent to yield pure 2-nitro-4-fluorobenzyl bromide.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.O[C:50]1[CH:57]=[CH:56][C:53]([CH:54]=[O:55])=[CH:52][CH:51]=1>ClCCl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:50]2[CH:57]=[CH:56][C:53]([CH:54]=[O:55])=[CH:52][CH:51]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CSc1ccc(CCO)cc1
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
1.7 g (10 mmole) 2-[4-(methylsulfanyl)phenyl]-1-ethanol, 5.24 g (20 mmole) triphenylphosphine and 5.05 g (20 mmole) 1,1-(azodicarbonyl)dipiperidine was added to a mixture of 2.47 g (20 mmole) 4-hydroxybenzaldehyde in 40 ml dichloromethane under argon atmosphere. Stirring at room temperature for 2 hours, (more dichloromethane was added after 20 minutes), gave a solid material that was removed by filtration. The filtrate was purified by chromatography on silica gel using dichloromethane as eluent to give 2.3 g (yield 84.4%) of 4-[2-(4-methylmercaptophenyl)ethoxy]benzaldehyde.
Reaction SMILES: CO[C:3]1[CH:19]=[C:18]2[C:10]([O:11][C:12](=[O:20])[C:13]3[CH:14]=[CH:15][O:16][C:17]=32)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[CH:21]1C2C(=CC=C3C=2OC(=O)C2C=COC3=2)C=CC=1.OC1C2C(=O)OC3C(=CC(OC)=C4C=3C=CC=C4)C=2OC1>>[CH3:21][C:14]1[C:13]2[C:12](=[O:20])[O:11][C:10]3[C:18](=[CH:19][CH:3]=[C:4]4[C:9]=3[CH:8]=[CH:7][CH:6]=[CH:5]4)[C:17]=2[O:16][CH:15]=1
Reactant: O=c1oc2c3ccccc3ccc2c2occc12
Reactant: COc1cc2c3occc3c(=O)oc2c2ccccc12
Agent: COc1cc2c3c(c(=O)oc2c2ccccc12)C(O)CO3
Product: Cc1coc2c1c(=O)oc1c3ccccc3ccc21

Procedure:
6-Methoxy-11,15-dioxa-cyclopenta[a]phenanthren-12-one (4e) The procedure was identical to that used for the preparation of 4a: 85% yield (starting with 12 mg 3e); mp 194-195° C.; LC/MSD-Trap-positive (m/z, %): 267 (M++1, 100), 289 (M++Na, 30); 1H NMR δ 4.11 (1H, s, OCH3-6), 7.07 (1H, d, J=2.1 Hz, H-17), 7.13 (1H, s, H-7), 7.68 (3H, m, H-2, 3, 16), 8.31 (1H, dd, J=1.8 Hz, 6.9 Hz, H-4), 8.57 (1H, dd, J=1.8 Hz, 7.8 Hz, H-1).
Reaction SMILES: [H-].[Na+].[C:3]([SH:7])([CH3:6])([CH3:5])[CH3:4].[F:8][CH:9]([F:31])[C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12](Br)[C:11]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)C>C1COCC1>[C:3]([S:7][C:12]1[C:11]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:10]([CH:9]([F:31])[F:8])[N:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[C:13]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)S
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1SC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A mixture of 0.44 g (0.011 mol) of 60of NaH in mineal oil dispersion was washed twice with 10 ml portions of dry THF. To the resulting oil free NaH was added 30 ml of dry THF followed by 1.08 g (1.4 ml, 0.012 mol) of t-butylmercaptan. The resulting mixture was heated up to 50° C. for 20 minutes and a white precipitate was formed. This suspension was added dropwise at room temperture to a solution of 4.20 g (0.01 mol) of product of Example 106 in 40 ml of dry THF. The reaction temperature rose to 35° C. After stirring at room temperature for 3 hours, the reaction mixture was poured into 3.7HCl. The aqueous layer was extractad twice with diethyl ether, dried (MgSO4) and concentrated to give 4.23 g of a light yellow oil. The crude product was purified by HPLC using 2EtOAC/cyclohexane as eluting solvent followed by kugelrohr distillation at 100°-110 ° C./100 Pa to give 2.86 g (67) of product as a colorless oil, nD25 1.4678.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Cl:25][C:26]1[CH:37]=[CH:36][C:29]([C:30](N(OC)C)=[O:31])=[CH:28][C:27]=1[S:38](=[O:41])(=[O:40])[NH2:39]>O1CCCC1>[Cl:25][C:26]1[CH:37]=[CH:36][C:29]([C:30](=[O:31])[C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[CH:28][C:27]=1[S:38]([NH2:39])(=[O:41])=[O:40]
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: Brc1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(N3CCC(c4ccccc4)CC3)cc2)ccc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.227 g of 1-(4-bromo-phenyl)-4-phenyl-piperidine in tetrahydrofuran (5 mL) is cooled to −78° C. and treated with 2 portions of 0.29 mL each of tert-butyllithium (1.5 M in pentane). After 20 min at −78° C. the reaction mixture is treated with 0.1 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (5 mL) and stirred for another 1.5 h. The temperature is then increased slowly to 0° C. and after completion the reaction is quenched by addition of 2 mL of saturated aqueous ammonium chloride and extracted with diethyl ether. The organics are washed with water, dried over magnesium sulfate, concentrated to 0.27 g of crude product which is purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 2-chloro-5-[4-(4-phenyl-piperidin-1-yl)-benzoyl]-benzenesulfonamide as a powder. MS (m/z): (M−1) 453; Rf 0.65 (1:1 hexanes/ethyl acetate)
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[C:22]([NH:26][NH2:27])[N:23]=[N:24][CH:25]=2)=[CH:16][CH:15]=1>C1COCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[N:24][N:23]3[C:1](=[O:2])[NH:27][N:26]=[C:22]3[C:21]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:18][CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNc1nncc(-c2ccc(F)cc2)c1-c1ccncc1
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(F)cc3)cnn12
Temperature: 66 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (1.27 g, 7.86 mmol) in THF (20 mL) was added a suspension of 1-(5-(4-fluorophenyl)4-(pyridin-4-yl)pyridazin-3-yl)hydrazine (442 mg, 1.57 mmol) in THF (5 mL). After addition, the reaction mixture was heated to 66° C. After 20 min., the reaction mixture was cooled to RT and the reaction mixture was then concentrated under reduced pressure. The residue was diluted with water. The resultant mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with EtOAc-hexane to give the title compound, 7-(4-fluorophenyl)-8-(pyridine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (440 mg, 91%) as a yellow solid. LC/MS (method A): RT=1.27 min, (M+H)+=308.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]3[C:17]([CH2:18][NH:19][CH2:20][C:11]=2[CH:10]=1)=[N:16][N:15]=[C:14]3[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]3[C:17]([CH2:18][N:19]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:20][C:11]=2[CH:10]=1)=[N:16][N:15]=[C:14]3[CH:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:25][CH2:26]1
Reactant: O=C1CCOCC1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc2c(c1)CN(C1CCOCC1)Cc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Temperature: 40 °C
Reaction time: 18 h
Yield: 50.6 %

Procedure:
Tetrahydro-pyran-4-one (68 mg, 0.68 mmol) was added to a solution of the amine of example 4 (130 mg, 0.34 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (217 mg, 1.0 mmol) was added, and the reaction mixture was stirred for a further 18 hours. Further tetrahydro-pyran-4-one (68 mg, 0.68 mmol) and sodium triacetoxyborohydride (217 mg, 1.0 mmol) were added and the reaction mixture was heated to 40° C. for 24 hours. The reaction mixture was partitioned between 2N aqueous sodium carbonate solution (10 ml) and ethyl acetate (50 ml). The organic layer was washed three times with 2N aqueous sodium carbonate solution (10 ml), once with saturated aqueous brine, and then dried over magnesium sulphate before filtering and evaporating the filtrate under reduced pressure. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate in pentane (0% to 30%) as eluant, followed by chromatography on silica gel using a gradient of methanol in dichloromethane (0% to 5%) as eluant, to afford the title compound as a brown foam (80 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[C:20]1([O:10][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a solution of the 4-methanesulfonyl-benzoic acid (20 g, 99.9 mmol) in CH2Cl2 (150 mL), was oxalyl chloride (13.1 mL, 149.9 mmol) added. The reaction mixture was cooled to 0° C. and treated with DMF (2 mL). The reaction was warmed to room temperature and maintained for 10 h. The reaction was concentrated under vacuum and dissolved with CH2Cl2 (200 mL). The reaction was treated with phenol (10.5 mL, 120 mmol) followed by Et3N (16.7 mL, 120 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 7 hr. The reaction was extracted with CH2Cl2 (500 mL), dried and concentrated under vacuum. The desired compound, 4-methanesulfonyl-benzoic acid phenyl ester, was obtained by recrystallization from methanol (200 mL) as a white crystal in 78% yield (21.5 g). 1H NMR (400 Mz, DMSO-d6) δ 8.41 (d, J=7.1, 2H), 8.39 (d, J=7.1, 2H), 7.55˜7.51 (m, 2H), 7.37˜7.35 (m, 3H), 3.35 (s, 3H). LCMS 277.0 [M+H].
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH:9]C([C@@H](O)[C@H](N)CC1C=CC=CC=1)=O)[C:6]([OH:8])=[O:7])[CH3:3]>Cl>[NH2:9][C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][CH:2]([CH3:3])[CH3:1]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](O)[C@H](N)Cc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
The hydrolysis of bestatin in 6N HCl at 100° C. for 18 hours yields L-leucine and an unusual amino acid. The ratio of these amino acids is 1:1. Bestatin gives positive Rydon-Smith and ninhydrin reactions. The amino acid sequence of bestatin shown in the structure was elucidated by fragmentation pattern in mass spectrum of bestatin methyl ester hydrochloride. Thus, the structure of bestatin is (2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl-L-leucine.
Reaction SMILES: C(N=CC)(C)(C)C.C([N-]C(C)C)(C)C.[Li+].P(Cl)(OCC)([O:18][CH2:19][CH3:20])=O.O=[C:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]1>>[O:18]=[CH:19][CH:20]=[C:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]1
Reactant: CCOP(=O)(Cl)OCC
Reactant: COC(=O)C1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: CC=NC(C)(C)C
Agent: [Li+]
Product: COC(=O)C1CCC(=CC=O)CC1

Procedure:
The epoxides used as the starting materials in the general process described above can be obtained from available starting materials using an appropriate series of reactions. Thus, methyl 4-hydroxybenzoate is hydrogenated using 5% rhodium on alumina as catalyst to give methyl 4-hydroxycyclohexanecarboxylate. This is then oxidized with pyridinium chlorochromate resulting in methyl 4-oxocyclohexanecarboxylate. The 2-carbon homologation of methyl 4-oxocyclohexanecarboxylate to give methyl 4-(oxoethylidene)cyclohexanecarboxylate is carried out using the method developed by A. I. Meyers. Acetaldehyde t-butylimine is metalated with lithium diisopropylamide and then treated with diethyl chlorophosphate to provide the lithioeneaminephosphonate. Addition of methyl 4-oxocyclohexanecarboxylate and subsequent acid hydrolysis gives methyl 4-(oxoethylidene)cyclohexanecarboxylate. The reduction of this oxoethylidene compound with sodium borohydride gives methyl 4-(2-hydroxyethylidene)cyclohexanecarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[Si:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)CCc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared as described in General Method 5 using 10 g (60.9 mmol) of 4-(4-hydroxyphenyl)-2-butanone, 10.1 g (67 mmol) of tert-butyldimethyl silyl chloride, 4.56 g (67 mmol) of imidazole and 150 mL of DMF. The crude product was carried on "as is" to the next step (see Example KK).
Reaction SMILES: Cl[C:2]([CH3:20])([CH3:19])[C:3]([C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]([CH3:20])([CH3:19])[C:3]([C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: C[O-]
Reactant: CC(C)(Cl)C(=O)c1ccc(C(=O)c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Product: COC(C)(C)C(=O)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
28.7 g of 4-(2-chloro-2-methyl-propanoyl)-benzophenone and 5.4 g of sodium methoxide are boiled in 120 ml of methanol for 4 hours. After cooling, the mixture is filtered, the filtrate is evaporated and water is added to the residue. The mixture is extracted with ether and, after drying and evaporating the combined extracts, 4-(2-methoxy-2-methyl-propanoyl)-benzophenone is obtained as a viscous oil.
Reaction SMILES: [NH2:1][C:2]([CH3:28])([CH3:27])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)[N:11]=2)=[CH:7][CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]([CH3:28])([CH3:27])/[CH:3]=[CH:4]/[C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)[N:11]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(N)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(N)/C=C/c1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
A solution of {4-[5-(3-Amino-3-methyl-but-1-ynyl)-thiophen-2-yl]-pyrimidin-2-yl}-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (Example 5, 100 mg, 0.252 mmol) in 10 ml of THF and LAH (1M in THF, 0.25 ml, 0.25 mmol) was refluxed for 3 hours, poured on water and extracted 3 times with TBME. The combined organic phases were dried over sodium sulfate, filtered and purified via chromatography on silicagel (DCM/MeOH/ammonia:90/10/1 to 85/15/2) to give the title compound as yellow solid. Yield: 20 mg (20%).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:16])=[C:9]([C:14]#[N:15])[CH:10]=[N:11]2)=[CH:6][CH:5]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21]>>[CH3:17][O:18][CH2:19][CH2:20][O:21][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:16])[C:9]([C:14]#[N:15])=[CH:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: N#Cc1cnc2cc(F)ccc2c1O
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Product: COCCOc1ccc2c(=O)c(C#N)c[nH]c2c1
Temperature: 25 °C

Procedure:
A mixture of sodium hydride (500 mg, 12.5 mmol) and 7-fluoro-4-hydroxyquinoline-3-carbonitrile (1.30 g, 6.9 mmol) in 2-methoxyethanol (30 mL) is heated at reflux overnight. Additional sodium hydride (250 mg, 6.25 mmol) is added and the reaction mixture is heated at reflux overnight. Additional sodium hydride (250 mg, 6.25 mmol) is added and the reaction mixture is heated at reflux for 8 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The basic layer is acidified with aqueous HCl and the resultant solid is collected by filtration to provide 1.05 g of 7-(2-methoxyethoxy)-4-oxo-1,4-dihydroquinoline-3-carbonitrile as a white solid, mp>250° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][C@H:33]1[CH:34]=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].CO>C(Cl)Cl.CCOC(C)=O.CCCCCC.[Zn]>[Br:21][C:20]([Br:24])=[CH:34][C@@H:33]1[CH2:36][CH2:37][CH2:38][N:32]1[C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(Br)Br
Reaction time: 0.08 h
Yield: 91 %

Procedure:
At room temperature and under nitrogen, triphenylphosphine (13.0 g, 49.5 mmol), zinc dust (2.16 g, 33.0 mmol) and carbon tetrabromide (11.0 g, 33.0 mmol) were added to CH2Cl2 (80 mL). After stirring for 5 minutes, a solution of N-t-butyloxycarbonyl-(S)-prolinal (3.29 g, 16.5 mmol) in CH2Cl2 (25 mL) was added. The reaction was slightly exothermic. After stirring for 1 hour, the reaction mixture was diluted with EtOAc/hexane (1:1) and filtered through basic alumina. The filter cake was then washed with a mixture of CH2Cl2 /EtOAc/hexane (1:1:1). The filtrate was concentrated in vacua, and the residue was taken up in EtOAc/hexane (1:1). The resulting precipitate was filtered, and the filtrate was taken up in EtOAc/hexane (1:1). The resulting precipitate was filtered, and the filtrate was (1:6.5 to 1:5) as the eluant. The resultant pure solid product was isolated in 91% yield (5.31 g): mp 65-66° C.; [α]D≤ +20.1 (c 1.10, MeOH); 1H NMR (DMSO-d6, 70° C., 300 MHz) δ 6.57 (d, J=8.1 Hz, 1H), 4.26 (ddd, J=7.9, 7.9, 4.9 Hz, 1H), 3.30 (m, 2H), 2.11 (m, 1H), 1.72-1.92 (m, 2H), 1.65 (m, 1H), 1.40 (s, 9H); MS m/e 354 (M+H)+ ; Anal. Calcd for C11H17Br2NO2 : C, 37.21; H, 4.83; N, 3.95. Found: C, 37.45; H, 4.85; N, 3.97.