Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:4](=[O:31])[C:3]=1[CH3:32].[H-].[Na+].[C:35](Cl)(=[O:37])[CH3:36]>C1COCC1.CCOC(C)=O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[N:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:5]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:4](=[O:31])[C:3]([CH3:32])=[C:2]3[NH:1][C:35](=[O:37])[CH3:36])=[CH:17][CH:16]=1
Reactant: CC(=O)Cl
Reactant: Cc1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(CC(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C)c(=O)n(CC(C)C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
To the product of EXAMPLE 42 (28 mg) in THF (0.5 mL) at 0° C. was added NaH (5 mg, 60% dispersion in mineral oil). The reaction stirred 10 minutes before acetyl chloride (7 μL) was added. Two hours later an additional 20 μL portion of acetyl chloride was added and again after an additional 90 minutes. After an additional hour of reaction time the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and dried (Na2SO4). The concentrated residue was purified by preparative TLC on silica gel eluted with 70% EtOAc in hexane affording the title compound. HPLC/MS: 528.0 (M+1), 530.0 (M+3); Rt=4.27 min.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:40][S:41]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)(=[O:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:47]2[CH:48]=[CH:49][C:44]([S:41]([CH3:40])(=[O:43])=[O:42])=[CH:45][CH:46]=2)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCOCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cnc2c(c1)cc(C(=CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 50.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (1.1 g, 1.94 mmol), 4-(methanesulfonyl)phenylboronic acid (775 mg, 3.88 mmol), dichlorobis(triphenylphosphine)palladium (II) (136 mg, 0.194 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 2.5 mL, 5 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The resulting mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (540 mg, 54%) as a light yellow solid: LC/MS m/e calcd for C28H28N2O6S2 [M+H]+ 553.67, observed 553.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[C:19]([Cl:35])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.O>CN(C)C=O>[Cl:35][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:7]([O:36][CH3:37])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34])=[O:25]
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea, 59 mg), potassium carbonate (857 mg), and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 53 mg (yield 89%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH3:19])[CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH:17]=[O:18])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(#N)C.O.I([O-])(=O)(=O)=[O:26].[Na+]>C(Cl)(Cl)(Cl)Cl.[Ru](Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:19])[CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]([OH:26])=[O:18])[CH2:12][CH2:11]1)=[O:20])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(CC[C@H]1CC[C@H](CC=O)CC1)C(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CN(CC[C@H]1CC[C@H](CC(=O)O)CC1)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
0.66 g (2.3 mmol) of trans-methyl-{2-[4-(2-oxo-ethyl)-cyclohexyl]-ethyl}-carbamic acid tert-butyl ester were dissolved in 2 mL of CCl4, 2 mL of acetonitrile and 3 mL of water. To this mixture were added 2.4 mg (0.012 mmol, 0.01 eq) of anhydrous ruthenium (III) chloride, followed by 2.04 g (9.5 mmol, 4.1 eq) of sodium metaperiodate in small portions. Stirring was continued at RT for 2 h, the mixture was filtered and partitioned between CH2Cl2 and water. The organic phase was washed with water and dried over magnesium sulfate. Column chromatography of the crude product with a gradient of n-heptane: EtOAc 1:4 to 1:1 gave 430 mg (62%) of trans-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-acetic acid as colorless oil, MS: 317 (M+NH4+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[OH-].[K+].O.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[Cl:23]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: OCc1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 60 °C
Yield: 62.7 %

Procedure:
To a mixture of 3-fluorobenzyl alcohol (7.88 g, 62.5 mmol), Aliquot 336 (8.08 g, 20.0 mmol), potassium hydroxide (3.51 g, 62.5 mmol) and water (40 mL) were added toluene (80 mL) and 1,2-dichloro-4-nitrobenzene (10.0 g, 52.1 mmol). The mixture was heated to 60° C. overnight with vigorous stirring. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with hot petroleum ether and tert-butyl methyl ether to yield 9.20 g (63%) of the title compound.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[O:6]1[C:10]2(CCC(=O)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1.CC(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:10]([O-:9])(=[O:6])[CH3:11].[CH2:4]=[C:3]1[CH2:12][CH2:11][C:10]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:1][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C=C1CCC2(CC1)OCCO2
Product: CC(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of 1.6 M n-butyllithium in hexanes (46 mL, 73.6 mmol) was slowly added to a heterogeneous mixture of methyltriphenylphosphonium bromide (28.07 g, 78.6 mmol) in tetrahydrofuran (150 mL) at −10° C. After stirring for 1 h, 1,4-dioxa-spiro[4.5]decan-8-one (8.01 g, 51.3 mmol) was added. After stirring for 3 h, during which time the solution warmed to ambient temperature, acetone was added and the heterogeneous mixture was concentrated. The residue was diluted with 1:1 methylene chloride:ethyl ether, filtered and concentrated. The residue was flash chromatographed with 49:1, 24:1, and 23:2 hexanes:etheyl acetate as the eluant to yield 6.22 g (79% yield) of 8-methylene-1,4-dioxa-spiro[4.5]decane as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C:10]1[CH:15]=[C:14]([NH:16][C:17](=[O:33])[CH2:18][C:19](=[O:32])[CH2:20][O:21][C:22]23[CH2:31][CH:26]4[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]4)[CH2:23]2)[CH2:29]3)[CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[N:36]([O-])=[O:37].[Na+]>C(O)(=O)C.C1COCC1>[CH2:1]([O:8][C:9](=[O:34])[C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([NH:16][C:17](=[O:33])[C:18](=[N:36][OH:37])[C:19](=[O:32])[CH2:20][O:21][C:22]23[CH2:29][CH:28]4[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]4)[CH2:23]2)[CH2:31]3)[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: O=C(COC12CC3CC(CC(C3)C1)C2)CC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(COC12CC3CC(CC(C3)C1)C2)C(=NO)C(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a solution of the product of step b (2.10 g, 4.55 mmol) in acetic acid (20 ml) and THF (20 ml) was added water (2 ml). The mixture was cooled to 5° C. and an aqueous solution (3 ml) of sodium nitrite (0.41 g, 5.92 mmol) was added dropwise while maintaining the temperature below 10° C. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The THF and acetic acid were removed in vacuo and the solution was partitioned between water (100 ml) and ethyl acetate (100 ml). 1M NaOH was added until pH 8 was reached, the layers were separated, and the aqueous layer was washed with ethyl acetate (20 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and the solvent was evaporated to yield a yellow oil (2.13 g, 96%). The crude product was purified by flash column chromatography (silica, DCM/ethyl acetate 95:5) to afford a yellow foam (1.29 g, 58%). 1H NMR (300 MHz, CDCl3) 11.04 (1H, br s), 8.23 (1H, s), 7.94 (1H, d), 7.86 (1H, d), 7.50-7.36 (6H, m), 5.39 (2H, s), 4.82 (2H, s), 2.20 (3H, br s), 1.81 (6H, s), 1.65 (6H, m).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])N[N:3]=1.O[CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[NH2:11][C:9]1[C:10]2[C:2]([I:1])=[N:3][CH:24]([CH:13]3[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(C2N=C(I)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.52 g, 2.0 mmol), ethyl 4-hydroxycyclohexanecarboxylate (0.806 mL, 5.0 mmol, triphenylphosphine (1.05 g, 4.0 mmol), diethyl azodicarboxylate (0.628 mL, 4.0 mmol) were suspended in tetrahydrofuran (15 mL), and the mixture was stirred at ambient temperature under a gentle flow of nitrogen for 48 h. The mixture was diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was partially purified by flash column chromatography (100% ethyl acetate) to afford ethyl 4-(4-amino-5-iodo-7H-pyrrolo[3,4-d]pyrimidin-7-yl)-1-cyclohexanecarboxylate as a mixture of cis- and trans-diastereomers, along with triphenylphosphine oxide. Repurification of the mixture by flash column chromatography on silica gel deactivated with triethylamine (0.5% methanol/dichloromethane as eluant) afforded the desired cis-ethyl 4-(4-amino-5-iodo-7H-pyrrolo[3,4-d]pyrimidin-7-yl)-1-cyclohexanecarboxylate as a yellow solid (0.260 g, 0.625 mmol): RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 9.55 min; MS (MH)+ 416.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].Br[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH2:16][C:17](Cl)=[O:18].[C:20]([OH:28])(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:20]([S:27][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH2:16][C:17]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:18])(=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Br
Reactant: NCC(=O)O
Reactant: OC(=S)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)Cc1ccc(Cl)cc1SC(=O)c1ccccc1
Yield: 76.9 %

Procedure:
4.9g (0.065 mol) of glycine was dissolved in 250 ml of 0.5 N--NaOH and then to the solution was added dropwise 14.6g (0.054 mol) of 2-bromo-p-chlorophenylacetyl chloride over 1 hour while stirring and cooling with a freezing mixture. After completion of the addition, the reaction mixture was stirred at room temperature for an additional 2 hours. During stirring, the pH of the mixture was adjusted to 8. The filtrate which had been prepared by dissolving 11.6g (0.08 mol) of thiobenzoic acid in 40 ml of 2N--KOH and filtering the solution to remove undissolved substances was added to the reaction mixture followed by stirring at room temperature overnight. The next morning, the mixture was acidified with hydrochloric acid while ice-cooling to precipitate crystals. These crystals were recovered by filtration, washing with water and washing with benzene to give 15.1g of crude N-(2-benzoylmercapto-p-chlorophenylacetyl)glycine. The product had a melting point of 158° - 159°C after recrystallization from ethyl acetate-benzene. 11.0g (0.03 mol) of N-(2-benzoylmercapto-p-chlorophenylacetyl)glycine was dissolved in 75 ml of concentrated aqueous ammonia followed by stirring at room temperature for 1 hour. After removal of benzamide by extraction with ethyl acetate, the resulting aqueous layer was treated in a similar manner in accordance with Example I to give 6.0g of N-(2-mercapto-p-chlorophenylacetyl)glycine, ClC6H4CH(SH)--CONHCH2COOH. (m.p. 148° - 149°C, Purity; 100 % (iodometry))
Reaction SMILES: C(#N)C.[NH:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]#[N:14])=[N:5]1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])[CH2:24][CH2:25]I>CCOC(C)=O>[F:27][C:23]([F:28])([C:22]([F:30])([F:29])[F:21])[CH2:24][CH2:25][N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]#[N:14])=[N:5]1
Reactant: FC(F)(F)C(F)(F)CCI
Reactant: N#Cc1n[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Temperature: 75 °C

Procedure:
An acetonitrile solution (150 mL) containing the intermediate from Step C above (10.5 g, 43.7 mmol), potassium carbonate (30.2 g, 219 mmol) and 1,1,1,2,2-pentafluoro-4-iodobutane (23.95 g, 87 mmol) was heated at 75° C. for 48 hours. The reaction solution was cooled to room temperature and diluted with EtOAc. The solution was washed with water, brine and concentrated in vacuo. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the title compound. 1H NMR (400 MHz, CH3CN-d3): δ 8.71 (dd, J=4.47, 1.51 Hz, 1H); 8.31 (dd, J=8.22, 1.52 Hz, 1H); 7.44 (dd, J=8.24, 4.48 Hz, 1H); 4.92 (t, J=6.98 Hz, 3H); 3.00-2.82 (m, 2H). m/z=291.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:28]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][C:27]#[N:28])=[CH:31][CH:32]=2)=[CH:20][CH:19]=1)[CH3:9]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Product: Cc1noc(-c2ccc(-c3ccc(CC#N)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1F

Procedure:
Prepared as described in Example 36, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester and 4-cyanomethylphenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[CH:4][N:3]=1.Br[CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][N:3]=1
Reactant: CCC(CC)CBr
Reactant: Nc1ncc(O)c(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)COc1cnc(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 0.50 gram (0.003 mole) of 2,4-diamino-5-hydroxypyrimidine hydrosulfate salt, 0.47 gram (0.007 mole) of 1-bromo-2-ethylbutane and 0.95 gram (0.007 mole) of anhydrous potassium carbonate in 5 mL of N,N-dimethylformamide was heated at 84°-86° C. for about two hours. After this time the reaction mixture was allowed to cool to ambient temperature as it stirred during about a 16 hour period. The reaction mixture was then stirred with 50 mL of water and 50 mL of methylene chloride. The methylene chloride layer was separated and washed with 50 mL of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The residue was recrystallized from 2:1 water and methanol, yielding, when dried, 0.20 gram of 2,4-diamino-5-(2- ethylbutoxy)pyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [K].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[CH:6]=1)([O-:4])=[O:3].Cl[CH2:17][CH:18]([OH:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[OH:20][CH:18]([CH3:19])[CH2:17][O:11][C:8]1[CH:9]=[CH:10][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][C:7]=1[NH:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCC(C)O

Procedure:
0.5 mol (117 g) of the potassium salt of 4-nitro-2-acetylaminophenol is introduced into 300 ml of dimethylformamide in a boiling water-bath, with stirring. The mixture is treated with 0.5 mol (47.25 g) of 1-chloropropan-2-ol. With the heating maintained, 0.5 mol (47.25 g) of 1-chloropropan-2-ol and 0.25 mol (34.5 g) of potassium carbonate are added four times at 2-hour intervals. After heating for 10 hours, the reaction mixture is poured into 1,500 ml of iced water. The expected product, which has precipitated, is filtered off. It is washed with a 0.5N solution of sodium hydroxide and then with water. After drying in vacuo at 60° C., it melts at 123° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21]>>[ClH:1].[C:12]1([C:4]2[CH:3]=[C:2]([NH:18][CH2:19][CH:20]([OH:22])[CH3:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Reactant: CC(O)CN
Product: CC(O)CNc1cc(-c2ccccc2)nc2ccccc12
Product: Cl

Procedure:
The title compound, m.p. 251-253° C., and MS: m/e=279.2 (M+H+), was prepared from 4-chloro-2-phenyl-quinolin and (RS)-1-amino-2-propanol.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:14]C(=O)OCC1C=CC=CC=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1>CO.[Pd]>[NH2:14][C@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)[CH2:2][OH:1]
Reactant: O=C(N[C@@H](CO)c1cccc(C(F)(F)F)c1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H](CO)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
To a solution of (R)-Benzyl 2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethylcarbamate (4.54 g, 13.4 mmol) in MeOH (100 mL) is slowly added 10 wt % Pd/C (454 mg). The reaction mixture is stirred at room temperature under hydrogen (balloon) for 1.5 h, filtered through celite, and evaporated in vacuo to provide crude (R)-2-amino-2-(3-(trifluoromethyl)phenyl)ethanol (2.70 g, 98% yield) as a white solid product; 1H NMR (CDCl3, 400 MHz) δ 7.62 (s, 1H), 7.55 (m, 2H), 7.47 (t, 1H), 4.15 (dd, 1H), 3.77 (dd, 1H), 3.57 (dd, 1H); HPLC-MS calculated for C9H10F3NO (M+H+) 206.1, found 206.1.
Reaction SMILES: [C:1]([O:4][CH:5]1[NH:8][C:7](=[O:9])[CH:6]1[CH2:10][CH2:11][CH3:12])(=[O:3])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([N:8]1[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]([CH2:10][CH2:11][CH3:12])[C:7]1=[O:9])(=[O:15])[CH3:14]
Reactant: CCCC1C(=O)NC1OC(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCC1C(=O)N(C(C)=O)C1OC(C)=O
Reaction time: 24 h
Yield: 23 %

Procedure:
A mixture of 56 mg (0.33 mM) 4-acetoxy-3-propylazetidin-2-one, 1 ml acetic anhydride and 1 ml pyridine was stirred at 100° in a sealed tube for 24 hours. After concentrating in vacuo the residue was chromatographed on silica gel in hexane/ethyl acetate, to yield 16 mg (23%) 1-acetyl-4-acetoxy-3-n-propyl-azetidine-2-one.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8](N(CC)CC)C.[CH3:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C)C(=O)C>[CH2:16]([C:17]1[CH2:18][CH:19]2[CH:6]([CH:8]=1)[C:5](=[O:7])[CH2:20]2)[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC
Reactant: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC1=CC2C(=O)CC2C1
Temperature: 116 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
(2E)-4-Ethylhepta-2,6-dienoic acid (100.57 g) obtained by the method described above was dissolved in N,N-dimethylacetamide (255 mL) under a nitrogen atmosphere. To the solution, acetic anhydride (108 mL, 1.14 mol) and triethylamine (79 mL, 0.57 mol) were added. The reaction mixture was warmed and stirred at 115 to 117° C. for 5 hours. The reaction mixture was cooled to room temperature, and n-hexane (510 mL) and water (714 mL) were added thereto to separate an organic layer. The aqueous layer was subjected to two extractions with hexane (each with 255 mL), and all the organic layers were combined and then washed with a 5% aqueous sodium bicarbonate solution (102 mL) and water (102 mL) in this order. The obtained organic layer was concentrated under reduced pressure, and the residue was distilled (90-100° C., approximately 25 mmHg) to obtain the title compound (50.92 g, colorless oil substance) (overall yield from 1,1-bis(allyloxy)butane: 62%).