Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[C:14]1(=O)[CH2:25]CCCCCCCC=C[CH2:15]1.C([Mg]Br)(C)=C>O1CCCC1>[C:14]([C:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)([CH3:25])=[CH2:15]
Reactant: O=C1CC=CCCCCCCCC1
Agent: C=C(C)C1(O)C/C=C/CCCCCCCC1
Agent: C=C(C)[Mg]Br
Agent: O=C1C/C=C/CCCCCCCC1
Solvent: C1CCOC1
Product: C=C(C)C1(O)CC=CCCCCCCCC1

Procedure:
A mixture of mainly E-cyclododec-3-en-1-one (74%) and Z-cyclododec-3-en-1-one (19%) is treated with isopropenylmagnesium bromide in tetrahydrofuran, to form mainly E-1-isopropenylcyclododec-3-en-1-ol. The purified E-1-isopropenylcyclododec-3-en-1-ol is treated with potassium hydride in N,N-dimethylacetamide in the presence of 18-crown-6, that forms a mixture of diastereomeric 2-methyl-4-vinylcyclododecanone and E-2-methylcyclotetradec-5-en-1-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:7]2=[O:19].P(Cl)(Cl)([Cl:22])=O.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:22])[N:8]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:7]2=[O:19]
Reactant: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CCOCC1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2cccc(Br)c2nc(Cl)n1C1CCOCC1
Temperature: 90 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
A mixture of 8-bromo-3-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione (515b, 1.67 g, 5.14 mmol), phosphoryl trichloride (4.70 mL, 51.4 mmol), and N-ethyl-N-isopropylpropan-2-amine (3.58 mL, 20.54 mmol) was stirred at 90° C. for 20 h. The reaction mixture was concentrated to give a brown oil. Ice was added until the mixture began to stir, and NaHCO3 was added to the mixture; a brown solid which formed was filtered and washed with water. The solid was dissolved in DCM, placed in a separatory funnel, separated, dried over Na2SO4, and concentrated to give 8-bromo-2-chloro-3-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (515c, 1.60 g, 4.66 mmol, 91% yield over two steps) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.70 (dd, J=12.23, 2.25 Hz, 2H) 3.00 (qd, J=12.36, 4.79 Hz, 2H) 3.51 (td, J=11.93, 1.76 Hz, 2H) 4.14 (dd, J=11.54, 4.69 Hz, 2H) 5.05-5.19 (m, 1H) 7.33 (t, J=7.92 Hz, 1H) 8.00 (dd, J=7.73, 1.27 Hz, 1H) 8.18 (dd, J=8.02, 1.37 Hz, 1H). MS (ESI, pos. ion) m/z: 343.0/344.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:45])[C:27]([CH3:44])([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[CH3:28]>>[CH3:24][O:25][C:26](=[O:45])[C:27]([CH3:28])([C:29]1[CH:30]=[CH:31][C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:33][CH:34]=1)[CH3:44]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Reactant: COC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester.
Reaction SMILES: C(O)(CC)(C)C.N.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O:17][C:18](=O)[CH2:19][C@@H:20]([OH:25])[CH2:21][C:22]([NH2:24])=[O:23].C(O)(=O)C(C(C(O)=O)O)O>C(OC(C)C)(=O)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].COC(C)(C)C>[CH2:8]([O:15][C:18](=[O:17])[CH2:19][C@@H:20]([OH:25])[CH2:21][C:22]([NH2:24])=[O:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)C[C@@H](O)CC(N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: N
Solvent: CC(=O)OC(C)C
Solvent: COC(C)(C)C
Solvent: CCC(C)(C)O
Product: NC(=O)C[C@H](O)CC(=O)OCc1ccccc1
Temperature: 22.5 °C

Procedure:
Tert-pentanol (800 ml) was saturated with ammonia gas to about 1.0-1.5 mole. To this dimethyl-3-hydroxy glutarate (100 g) was added followed by the addition of 3 g immobilized CAL-B (CAL B-T1-AMD2). The flask was closed and stirred at 20-25° C. After completion of reaction enzyme was removed by filtration and washed the enzyme with tert-pentanol (100 ml). The filtrate was evaporated under reduced pressure at a temperature below 50° C. to yield a residue. To this residue mixture of Benzyl alcohol (131.0 g), (S)-methyl-3-hydroxyglutaramate (100 g) and Tetraisopropyl orthotitanate (17.5 g) are mixed in a flask. The mixture was stirred under vacuum at 50-60° C. for about 5 hrs. The reaction mixture was cooled and diluted with isopropyl acetate (500 ml). The reaction mixture was added to a stirred solution of Tartaric acid (37 g in 370 ml DM water) and 500 ml isopropyl acetate mixture. The reaction mixture was stirred and pH was adjusted to 7.0-8.0 by Aq ammonia solution. Layers were separated. The organic phase was removed and the aqueous phase was extracted with isopropyl acetate. Combined organic layer was washed with Aq ammonia and tartaric acid solution followed by brine wash. The organic phase was dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield oil. To this oil tert-butyl methyl ether (800 ml) was added, stirred, cooled, filtered and dried to give (S)-Benzyl-3-hydroxyglutaramate.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6]12([O:16][CH2:17][CH:18]3[O:20][CH2:19]3)CC3C[CH:12](CC(C3)C1)[CH2:13]2.C12([OH:31])CC3CC(CC(C3)C1)C2.C(C1OC1)Cl>>[CH2:6]([O:16][CH2:17][CH:18]1[O:20][CH2:19]1)[CH:13]1[O:31][CH2:12]1
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: C1C2CC3CC1CC(OCC1CO1)(C2)C3
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCC1CO1
Product: C(OCC1CO1)C1CO1
Yield: 61 %

Procedure:
The process gives a yield of 61% which is not bad. In this process, however, tin tetra-chloride (which is a Lewis acid) is used as the catalyst. For the safety reason of the catalyst, the solvent usable is limited to low-polarity solvents such as halides. Hence, in production of 1-adamantylglycidyl ether, when the starting raw material is changed from 1-adamantanol to an adamantanepolyol having two or more hydroxyl groups (which has very low solubility in low-polar solvents), the reactivity thereof is not certain. Further, there is a fear that epichlorohydrin itself polymerizes in the presence of an acid such as Lewis acid and the polymerizate remains as an impurity. As a process for obtaining a glycidyl ether from an alcohol, there is generally considered a process which comprises reacting an alcohol with an alkali metal or the like to synthesize an alcoholate and contacting the alcoholate with epichlorohydrin or epibromohydrin. However, there is no case in which this process has been applied to any polycyclic hydroxy compound having two or more hydroxyl groups.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:4][CH2:3]1.[N:23]#CBr.O>C1C=CC=CC=1>[C:1]([N:2]1[CH2:3][CH2:4][C:5](=[C:8]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:6][CH2:7]1)#[N:23]
Reactant: N#CBr
Reactant: CN1CCC(=C2c3ccccc3CCc3ccncc32)CC1
Solvent: c1ccccc1
Solvent: O
Product: N#CN1CCC(=C2c3ccccc3CCc3ccncc32)CC1
Yield: 36.9 %

Procedure:
To a solution of 400 mg (1.35 mmole) of 11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta [1,2-c]pyridine in 5.0 mL of benzene at room temperature and under an argon atmosphere was added dropwise a solution of 168 mg (1.59 mmole) of cyanogen bromide in 4 mL of benzene. After 30 min. the mixture was poured into water and extracted once with EtOAc. The organic layer was isolated, washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography [21/2% MeOH in CH2Cl2 ] to give 150 mg (37%) of the title compound as a solid: m.p. 212°-214° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:12][OH:13])=[N:9][C:10]=2I)[CH:7]=1.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:21]([Sn:25]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])Cl)[CH2:22][CH2:23][CH3:24]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:12][OH:13])=[N:9][C:10]=2[Sn:25]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: OCc1nc(I)c2ccc(F)cn12
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc(CO)n2cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a round-bottomed flask, (6-fluoro-1-iodo-imidazo[1,5-a]pyridin-3-yl)-methanol (156 mg, 0.53 mmol) was dissolved in THF (4 ml). Sodium hydride (60% dispersion in mineral oil, 26 mg, 0.65 mmol) was added and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.32 ml, 0.64 mmol) was added dropwise. The reaction was stirred at −16° C. for 25 min then tributylchlorostannane (0.17 ml, 0.63 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to afford (6-Fluoro-1-tributylstannanyl-imidazo[1,5-a]pyridin-3-yl)-methanol as a brown semisolid which was used without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(N(C)CCO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N(C)CCO)cc1
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution (30 ml) of ethyl 4-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)(methyl)amino]benzoate (2.33 g, 6.90 mmol) in tetrahydrofuran was added tetrabutyl ammoniumfluoride (1.0 M toluene solution, 10.4 ml, 10.4 mmol) at room temperature and the mixture was stirred overnight. After concentration of the reaction mixture under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (3:2-1:4, v/v) to give the title compound (1.11 g, 72%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Fc1cc(I)c(Cl)cn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(I)c(Cl)cn2)CC1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
To 5-chloro-2-fluoro-4-iodopyridine (600 mg, 2.331 mmol) was added DMSO (2.2 ml), trans-4-aminocyclohexanol (1074 mg, 9.32 mmol) and TEA (0.390 ml, 2.80 mmol). The resulting reaction mixture was stirred at 75° C. for 24 hr, followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (1×), water (1×), saturated salt solution (1×), dried over sodium sulfate, filtered and concentrated to yield a crude material. The crude material was purified by silica gel chromatography using a 40 g column eluting from 15%-75% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 750 mg of the title compound as free base, which was used in the next step without further purification. LCMS (m/z): 353.0 (MH+), retention time=0.56 min.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH3:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COCCOCCO
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: COCCOCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-(2-methoxyethoxy)-ethanol, there is obtained 2-(2-methoxyethoxy)-ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e:M+ 340 (20), 237 (80), 194 (100), 59 (45).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si](C=[N+]=[N-])(C)C.B(F)(F)F>CO.C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: FB(F)F
Solvent: CO
Solvent: c1ccccc1
Product: COc1cccnc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-amino-3-hydroxypyridine (Aldrich, 200 mg) in 20% methanol/benzene (4 mL) was treated with trimethylsilyldiazomethane (1.8 mL, 2.0 M), boron trifluoride diethyletherate (0.026 mL) and stirred at room temperature for 16 hr. The solvent was evaporated in vacuo and the crude oil was purified by medium pressure liquid chromatography on a 21×300 mm silica column eluted with 50% ethyl acetate/lmethylene chloride to give the title compound (50 mg).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O>>[C:1]([O:7][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: Oc1ccccc1Cl
Reactant: C#CCCC(=O)O
Product: C#CCCC(=O)Oc1ccccc1Cl
Yield: 87.1 %

Procedure:
According to the protocol described in Example 235(B), the reaction between pent-4-ynoic acid (590 mg, 6.0 mmol) and 2-chlorophenol (771 mg, 6.0 mmol) afforded 1.09 g of 2-chlorophenyl pent-4-ynoate (Yield: 87%) as colorless-oil.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[CH2:5][CH2:4]1>C(O)C>[CH3:1][N:2]([CH3:20])[CH:3]1[CH2:4][CH2:5][C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9]1
Reactant: CN(C)C1C=C(c2ccccc2)c2ccccc2CC1
Solvent: CCO
Product: CN(C)C1CCc2ccccc2C(c2ccccc2)C1
Temperature: 20 °C

Procedure:
5 g of palladized carbon [10% Pd(OH)2 ] were added to a solution of 5 g of 7-dimethylamino-9-phenyl-6,7-dihydro [5H] benzocycloheptene in 250 ml of ethanol and the mixture was stirred under a hydrogen atmosphere at 20° C until absorption ceased. The mixture was filtered and the filtrate was evaporated to dryness. The residue was chromatographed over silica gel and elution with a 9-1-1 cyclohexane-ethyl acetate-triethylamine mixture yielded 0.52 g of isomer A (equatorial 5-H) and 2.9 g of isomer B (axial 5-H) of 7-dimethylamino-5-phenyl-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[C:7]2[C:14]([C:15](=[O:19])[C:16]([NH2:18])=[O:17])=[C:13]([CH2:20][CH3:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[OH-].[Na+].Cl>CO>[NH2:18][C:16](=[O:17])[C:15]([C:14]1[C:7]2[C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[N:11][CH:10]=[N:9][C:8]=2[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:13]=1[CH2:20][CH3:21])=[O:19]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)ncnc2n1Cc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)ncnc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 37.3 %

Procedure:
A mixture of 28 mg (0.067 mmol) of [[5-(aminooxoacetyl)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and 5 mL of methanol were treated with 0.05 mL of 2 M sodium hydroxide and stirred at ambient temperature for 22 hours. The reaction was adjusted to pH 3 by the addition of 1 M HCl and concentrated to provide 10 mg (40%) of [[5-(aminooxoacetyl)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a white solid. nmr (300 MHz, dmso-d6) δ1.02 (t, 3H), 2.94 (q, 2H), 4.91 (s, 2H), 5.59 (s, 2H), 6.90 (d, 1H), 7.04 (d, 1H), 7.10 (dt, 1H), 7.36 (dt, 1H), 7.60 (br s, 1H), 8.02 (br s, 1H), 8.45 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]2[CH:41]=[CH:40][C:15]([CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:19][CH2:18]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1.N1CCCCC1.[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([CH2:16][N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:40][CH:41]=2)=[N:6][CH:7]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCN(Cc2ccc(/C=C/COc3ccc(Br)cn3)cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Brc1ccc(OC/C=C/c2ccc(CN3CCNCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of 9H-fluoren-9-ylmethyl 4-(4-{(E)-3-[(5-bromopyridin-2-yl)oxy]-prop-1-en-1-yl}benzyl)piperazine-1-carboxylate (0.604 g) in CH2Cl2 (10 mL) was added piperidine (0.196 mL). After stirring at room temperature for 1 hour, to the reaction mixture was added piperidine (0.784 mL) and stirred at room temperature for 4 hours. Then to the reaction mixture was added saturated aqueous NH4Cl and CH2Cl2. The organic layer was washed with saturated aqueous NH4Cl and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was washed with Et2O to afford 1-(4-{(E)-3-[(5-bromopyridin-2-yl)oxy]prop-1-en-1-yl}benzyl)piperazine as a white powder (0.282 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][CH:14]3[NH:16][CH:10]([CH:11](C(OC)=O)[C:12](=[O:21])[CH:13]3C(OC)=O)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Na+].[Cl-]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][CH:14]3[NH:16][CH:10]([CH2:11][C:12](=[O:21])[CH2:13]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1C(=O)C(C(=O)OC)C2CC(c3cccc(Br)c3)CC1N2
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CC2CC(c3cccc(Br)c3)CC(C1)N2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Dimethyl 7-(3-bromophenyl)-3-oxo-9-azabicyclo[3.3.1]nonane-2,4-dicarboxylate (89) and NaCl (61.22 g, 1.05 mol) in DMSO (200 ml) and water (10 ml) was placed into a preheated oil bath at 160° C. After stirring for 14 h, the solution was cooled to ambient temperature and exhaustively extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated to afford compound 90.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][NH2:8])[CH:3]=1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])[CH:13]=[N:8][CH2:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(CN)no1
Product: Cc1cc(CN=CN(C)C)no1
Temperature: 25 °C

Procedure:
A solution of the C-(5-methyl-isoxazol-3-yl)-methylamine (150 mg, 1.3 mmol) in N,N-dimethylformamide dimethylacetal (2 mL, 14.4 mmol) was heated under reflux for 3 h. After cooling to room temperature, the solvent was evaporated to leave the title compound as a yellow oil (220 mg, 98%. m/z 168.2 (MH)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([C:13]2[C:21]3[CH:20]=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[O:12])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH3:10].[CH3:25][C:26]1[N:30]([CH2:31][C:32](O)=[O:33])[N:29]=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1>>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:32](=[O:33])[CH2:31][N:30]2[C:26]([CH3:25])=[CH:27][C:28]([C:35]([F:38])([F:37])[F:36])=[N:29]2)=[CH:3][C:4]([C:11]([C:13]2[C:21]3[CH:20]=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH:22]([CH3:23])[CH3:24])[CH:14]=2)=[O:12])=[CH:5][N:6]=1)[CH3:10]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CCOc1ncc(C(=O)c2cn(C(C)C)c3ncncc23)cc1N
Product: CCOc1ncc(C(=O)c2cn(C(C)C)c3ncncc23)cc1NC(=O)Cn1nc(C(F)(F)F)cc1C

Procedure:
The title compound was prepared according to the method described for Example 1 using (5-Amino-6-ethoxy-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 242) and (5-Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid to afford the title compound as off white solid in 50% yield, 40 mg.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:6]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7](Br)=[C:8]([Br:10])[N:9]=1)[CH2:2][CH3:3].CC[Mg+].[Br-].[CH3:24][S:25]SC.[NH4+].[Cl-]>C1COCC1.CCOCC.CCOC(C)=O>[CH2:1]([S:4][C:5]1[N:6]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]([S:25][CH3:24])=[C:8]([Br:10])[N:9]=1)[CH2:2][CH3:3]
Reactant: CCCSc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Reactant: CSSC
Agent: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCSc1nc(Br)c(SC)n1COCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
2.4 g of the expected product from Stage B is dissolved in 25 cm3 of anhydrous THF. 3 ml of a 3M solution of EtMgBr in ether is added. After 1 hour at ambient temperature, 1.08 cm3 of dimethyl disulphide is added and the reaction medium is left for 1 hour at ambient temperature followed by hydrolysis with saturated NH4Cl, extraction with AcOEt, drying and evaporating to dryness.
Reaction SMILES: C([N:4](C(=O)C)[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=3[O:25][CH3:26])[CH:13]=2)[N:8]=[CH:7][N:6]=1)(=O)C.[OH-].[Na+]>O1CCOCC1>[NH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=3[O:25][CH3:26])[CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: COc1ccc(OC)c(CCc2ccc3ncnc(N(C(C)=O)C(C)=O)c3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(OC)c(CCc2ccc3ncnc(N)c3c2)c1
Reaction time: 0.5 h

Procedure:
A solution of 50 mg of 4-diacetylamino-6-[2-(2,5-dimethoxyphenyl)ethyl]-quinazoline and 10 ml of 1 N aqueous sodium hydroxide solution in dioxane is stirred for 3 hours at room temperature. The mixture is poured onto water and extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. The residue is taken up in methanol, stirred for 30 minutes, filtered and concentrated again. Chromatographic purification (silica gel, ethyl acetate) gives the title compound as colourless crystals. mp.: 160-165°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1>C(Cl)Cl>[Br:1][C:18]1[C:11]2[C:10]([Cl:9])=[N:15][CH:14]=[N:13][C:12]=2[N:16]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2c1ccn2C1CCCC1
Solvent: ClCCl
Product: Clc1ncnc2c1c(Br)cn2C1CCCC1
Yield: 61.3 %

Procedure:
N-Bromosuccinimide (15.4 g, 86.8 mmol) was added to a solution of 4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine (15.4 g, 69.5 mmol) in CH2Cl2 (100 mL). After 12 h the reaction was quenched with saturated aqueous NaHCO3 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated. Purification by flash column chromatography (hexanes/ethyl acetate 9:1) afforded the title compound as a white solid (12.8 g, 61%). MS: 300.1/302.0/304.1 (MH+); HPLC Rf: 6.68 min. (HPLC method 4).