Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:36])[C:9](=O)[CH2:10][CH:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.CSC.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:36])[CH2:9][CH2:10][CH:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)CC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CN(CCC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Yield: 48.6 %

Procedure:
N-(4-Chlorophenyl)-beta-(3,4-Dichlorophenyl)-N-methyl-4-(phenylmethyl)-1-piperidinepentanamide (0.38 g) in THF (30 mL) was treated with BH3 :DMS (0.4 mL; 10M) and heated at reflux temperature for 18 hours. The cooled reaction mixture was then treated with MeOH (2.0 mL) and the solvent evaporated under reduced pressure. The residue was dissolved in EtOH (20 mL), treated with potassium carbonate and heated at reflux temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and partitioned between CH2Cl2 (20 mL) and saturated NaHCO3 solution (20 mL). The organic portion was separated and the aqueous rextracted with CH2Cl2 (2×20 mL). The combined organic was dried over MgSO4, filtered and evaporated to give an oil. Silica gel chromatography eluting with 5% MeOH:CH2Cl2 gave the title compound (0.18 g). Mass spectrum (CI): 529.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH:9]([CH3:11])[CH3:10])[C:6]=1[CH2:7]O.S(Cl)([Cl:14])=O>ClCCl>[ClH:14].[Cl:14][CH2:7][C:6]1[N:5]([CH:9]([CH3:11])[CH3:10])[CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: Cc1ncn(C(C)C)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ncn(C(C)C)c1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of [4-methyl-1-(propan-2-yl)-1H-imidazol-5-yl]methanol (703 mg, 4.6 mmol) in anhydrous dichloromethane (40 mL) was added thionyl chloride (1.7 mL). The mixture was stirred at room temperature overnight. Dichloromethane was evaporated, and then the mixture was co-evaporated with toluene (1×20 mL). The residue was dried in vacuo, affording 5-(chloromethyl)-4-methyl-1-(propan-2-yl)-1H-imidazole hydrochloride (824 mg, 86% yield). The product was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[N:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:19]1(=[O:33])[N:23]([CH2:24][C:25](Cl)=[O:26])[C:22](=[O:28])[C:21]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:20]12>C(Cl)Cl>[CH2:5]([N:4]1[C@H:3]([CH2:2][Cl:1])[C@H:24]([N:23]2[C:22](=[O:28])[C:21]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:20]3[C:19]2=[O:33])[C:25]1=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCC=NCc1ccccc1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)[C@@H](CCl)N1Cc1ccccc1
Reaction time: 0.33 h
Yield: 19.7 %

Procedure:
A solution of 3.34 g of the product of Step A in 20 ml of methylene chloride was cooled to -50° C. and 2.8 ml of triethylamine were added all at once. A solution of 4 g of phthalimidoacetic acid chloride in 20 ml of methylene chloride was added thereto over 20 minutes. The mixture was stirred for one hour at 0° to -5° C. and was then poured into a decanting flask. The decanted organic phase was washed with 50 ml of demineralized water and 5 ml of a molar aqueous solution of sodium bicarbonate, and then twice with 30 ml of demineralized water. The wash water was re-extracted with 20 ml of methylene chloride and the combined organic phases were dried, rinsed and evaporated to dryness under vacuum. The 6 g of residue were chromatographed over silica gel and eluted with methylene chloride containing 5% ether. The fraction with an Rf=0.45 was evaporated to dryness and the residue was triturated with 10 ml of ether. The separated product was rinsed three times with 2 ml of ether and dried under vacuum to obtain 1.25 g of cis N-benzyl-3-phthalimido-4-chloromethyl-2-azetidinone melting at 149° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:4].[CH2:15]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]=[N:36][N:35]=2)=[CH:24][CH:23]=1)[CH2:16][CH2:17][CH2:18][CH3:19].[I-].[K+].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:15]([N:20]([CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:4])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:37]=[N:36][N:35]=2)=[CH:26][CH:27]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Cc1cc(C)c(NC(=O)CCl)c(C)c1
Reactant: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCN(CC(=O)Nc1c(C)cc(C)cc1C)Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Yield: 38.7 %

Procedure:
N-(Chloroacetyl)-2,4,6-trimethylaniline (443.2 mg), N-pentyl-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (780.0 mg), potassium iodide (129.1 mg) and triethylamine (1.15 g) were suspended in dimethylformamide (6 mL). The resulting mixture was heated to about 80° C., and then stirred at that temperature. Three hours later, the reaction mixture was cooled, ethyl acetate (50 mL) was added, and the mixture was washed four times with brine (100 mL, each). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane/ethyl acetate) to afford N-pentyl-N-[[[(2,4,6-trimethylphenyl)amino]carbonyl]methyl]-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (395.4 mg). Yield: 39%.
Reaction SMILES: [NH2:1][CH:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C1(C)C(C)=CC=CC=1.C(N(CC)CC)C>O>[C:13]1(=[O:18])[N:1]([CH:2]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC(CCC(=O)O)c1cccs1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(O)CCC(c1cccs1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture containing one gram of 4-amino-4-(2-thienyl)butyric acid and 0.8 g. of phthalic anhydride in 25 ml. of xylene containing 0.55 g. of triethylamine is heated to reflux the water is removed by azeotroping. After 1.5 hours the mixture is cooled and stirred overnight at room temperature. It is then evaporated to dryness to afford the title compound as a glassy material.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH:8]=1)=O.[N+]([O-])(O)=O.[F:22][C:23]([F:38])([O:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]([NH2:37])=[NH:36])[CH:31]=[CH:32][CH:33]=1)[CH:24]([F:26])[F:25]>>[F:22][C:23]([F:38])([O:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[N:37]=[C:5]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=[N:9][CH:8]=3)[CH:4]=[CH:3][N:36]=2)[CH:31]=[CH:32][CH:33]=1)[CH:24]([F:25])[F:26]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: CN(C)C=CC(=O)c1cncc2ccccc12
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3cncc4ccccc34)n2)c1

Procedure:
In accordance with the general procedure described in Example 1, reaction of 226.2 mg (1.0 mmol) of 3-dimethylamino-(4-isoquinolyl)-2-propen-1-one and 185 g (0.60 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(4-isoquinolyl)-2-pyrimidine-amine; FAB-MS:415 (M+ +1), m.p. 158°-160° C.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)=[O:5].[CH3:16][Mg]Br.O>C1COCC1.CCOC(C)=O>[OH:11][CH:10]([C:9]1[CH:8]=[CH:7][C:6]([C:4](=[O:5])[CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])=[CH:13][CH:12]=1)[CH3:16]
Reactant: C[Mg]Br
Reactant: CC(C)(C)CC(=O)c1ccc(C=O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)c1ccc(C(=O)CC(C)(C)C)cc1
Temperature: -10 °C
Yield: 84.2 %

Procedure:
Dissolve 4-(3,3-dimethyl-butyryl)-benzaldehyde (1.67 g, 8.186 mmol) in anhydrous THF (20 mL) and cool the solution at −10° C. Add methyl magnesium bromide (2.7 mL, 8.186 mmol, 3M solution in diethyl ether) and stir the mixture for 30 min. Add water at 0° C., dilute with EtOAc and extract the aqueous layer three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter through a short pad of silica gel and concentrate in vacuo to give the desired intermediate as yellow oil (1.519 g, 84%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1>>[N:10]1([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[OH:9])[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: OCc1ccccc1O
Reactant: c1nc[nH]n1
Product: Oc1ccccc1Cn1cncn1
Temperature: 160 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
The mixture of 2-hydroxymethylphenol (25.3 g) and 1H-1,2,4-triazole (15.5 g) was agitated at about 160° C. for 1 hour. After left to stand for cooling, the mixture was solidified into crystal, which was then recrystallized from ethanol and collected to give the title compound (27 g; 76 %).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:9]=3[NH:10]2)=[CH:6][C:5]=1[F:24].[CH3:25]I>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][C:9]=3[N:10]2[CH3:25])=[CH:6][C:5]=1[F:24]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3cc(Br)c(F)cc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(F)c(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Sodium hydride (60% weight dispersion in mineral oil, 25 mg, 0.60 mmol) was added to a solution of tert-butyl 7-bromo-6-fluoro-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (150 mg, 0.40 mmol) in DMF (10 mL) at room temperature under N2 and stirred for 1 h at ambient temperature. Methyl iodide (230 mg, 0.16 mL, 0.60 mmol) was added, and the reaction mixture was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to approximately ⅓ of initial volume and treated with water (20 mL). The resulting precipitate was collected by filtration, washed with water and diethyl ether and dried under vacuum to afford the title compound (140 mg, 91%) as a yellow powder: ESI MS m/z 383 [M+H]+.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[C:8]([C:43]3[CH:48]=[C:47]([C:49](=[O:61])[NH:50][C@@H:51]4[C:60]5[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=5)[CH2:54][CH2:53][CH2:52]4)[CH:46]=[CH:45][N:44]=3)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:18]=[CH:19][CH:20]=3)=[O:14])=[C:8]([C:43]3[CH:48]=[C:47]([C:49](=[O:61])[NH:50][C@@H:51]4[C:60]5[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=5)[CH2:54][CH2:53][CH2:52]4)[CH:46]=[CH:45][N:44]=3)[CH:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reaction time: 0.08 h
Yield: 64 %

Procedure:
To (S)-tert-butyl 16-(3-((4-cyclobutoxy-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)phenyl)-4,7,10,13-tetraoxahexadecan-1-oate Example 284 was added trifluoracetic acid (1 mL). The mixture was stirred for 5 minutes, concentrated and purified by prep. TLC to give a yellow syrup (7.2 mg, 64%). MS (ES, m/z): 780.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[N:6]2[C:7](=[O:10])[CH2:8][CH2:9][C@@H:5]2[CH2:4][O:3]1.[CH:12]([N-]C(C)C)([CH3:14])[CH3:13].[Li+].[CH2:20](Br)[CH:21]=[CH2:22]>C1COCC1>[CH2:14]([C:8]1([CH2:22][CH:21]=[CH2:20])[C:7](=[O:10])[N:6]2[C:2]([CH3:11])([CH3:1])[O:3][CH2:4][C@H:5]2[CH2:9]1)[CH:12]=[CH2:13]
Reactant: C=CCBr
Reactant: CC1(C)OC[C@H]2CCC(=O)N21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1(CC=C)C[C@@H]2COC(C)(C)N2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (2.55 g, 16.43 mmol) in THF (54.8 ml) cooled to −78° C., was added lithium diisopropylamide (14.79 ml, 29.6 mmol) solution. The solution was stirred at this temperature for 1 h before adding allyl bromide (2.133 ml, 24.65 mmol). The reaction mixture was warmed to rt (1 h) then cooled to −78° C. prior addition of lithium diisopropylamide (14.79 ml, 29.6 mmol). The mixture was stirred at −78° C. for 1 h before adding allyl bromide (2.133 ml, 24.65 mmol). The mixture was slowly warm to rt and stirred overnight. The reaction was quenched with sat. NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 25% EtOAc in hexane, to provide (R)-6,6-diallyl-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (3.31 g, 14.07 mmol, 86% yield) as light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.66-5.90 (m, 2H), 5.06-5.19 (m, 4H), 4.01-4.11 (m, 2H), 3.29-3.38 (m, 1H), 2.32-2.48 (m, 2H), 2.20-2.29 (m, 1H), 2.12 (dd, J=8.97, 13.79 Hz, 1H), 1.86-1.98 (m, 1H), 1.73-1.84 (m, 1H), 1.65 (s, 3H), 1.46 (s, 3H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]2)(=O)=O)=CC=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)C.O>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([CH2:11][C@H:12]2[CH2:16][O:15][C:14]([CH3:17])([CH3:18])[O:13]2)[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@H](CN2CCN(C(=O)OCc3ccccc3)CC2)O1
Temperature: 127 °C

Procedure:
(S)-(+)-2,2-Dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (286 mg, 1.0 mmol, Aldrich) and piperazine-1-carboxylic acid benzyl ester (235 mg, 1.1 mmol, Aldrich) were combined with potassium carbonate (148 g, 1.1 mmol) in dry toluene (6 mL) in a 10 mL pressure vessel. This was well stirred and heated to 127° C. for 20 h. The reaction was cooled, diluted with ethyl ether (20 mL) and 20 mL of water. The organics were washed with water, brine, dried (MgSO4) and evaporated to give 4-(S)-(−)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-piperazine-1-carboxylic acid benzyl ester as a heavy oil which was purified by flash column chromatography (silica gel, eluting with 3% triethylamine and 1:1 ethyl acetate:hexane to ethyl acetate). LR-MS: 334 [(M+H)+].4-(S)-(−)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-piperazine-1-carboxylic acid benzyl ester (220 mg, 0.65 mmol) was dissolved in 20 mL of ethanol and 10% palladium on carbon (50 mg, Aldrich). The mixture was hydrogenated in a Parr reactor at 40 psi for 18 h. The reaction mixture was filtered through Celite and evaporated to give an oil. The oil was mostly dissolved in hexane, treated with Norite, filtered and crystallized from cold hexane to give 1-(S)-(−)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-piperazine. LR-MS: 200 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)CCC>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:23]=3)[CH2:18][CH2:17]2)[N:3]=1
Reactant: COc1cc2nc(N3CCN(c4ccnc(Cl)n4)CC3)nc(N)c2cc1OC
Reactant: C1COCCN1
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4ccnc(N5CCOCC5)n4)CC3)nc(N)c2cc1OC
Yield: 35.4 %

Procedure:
4-Amino-6,7-dimethoxy-2-[4-(2-chloropyrimidin-4-yl)-piperazino] quinazoline (2.0 g, 5.0 mmole) and morpholine (1.1 g, 12.6 mmole) in n-butanol (150 ml) were heated in a bomb at 160° C. for 19 hours. The solvent was evaporated in vacuo and the residue partitioned between 5% methanol in chloroform and 5N sodium hydroxide solution. The organic layer was separated, washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel (20 g, "Kieselgel" (Trade Mark) 60H) eluting with chloroform. Appropriate fractions were combined and evaporated in vacuo. Crystallization from ethyl acetate gave 0.8 g of the desired product, m.p. 232°-233° C.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][N:7]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:8]1([C:16](=[O:19])[NH:17][OH:18])[CH2:14][CH:13]2[O:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C.C1(C)C=CC=CC=1.O.[OH-].[Na+]>ClCCl>[F:36][C:33]1[CH:32]=[CH:31][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([S:20]([N:7]([C:8]3([C:16](=[O:19])[NH:17][OH:18])[CH2:9][CH:10]4[O:15][CH:13]([CH2:12][CH2:11]4)[CH2:14]3)[CH2:6][CH2:5][C:4]([OH:37])=[O:3])(=[O:21])=[O:22])=[CH:24][CH:25]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)CCN(C1(C(=O)NO)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCN(C1(C(=O)NO)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 15.1 mmoles of the product from Step G in dichloromethane is concentrated by rotary evaporation with the addition of 75 mL of toluene. This solution is treated with 75 mL of water, cooled to 0° C., and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide pellets over 10 minutes with vigorous stirring. This mixture is stirred for 15 minutes at 0° C. and warmed to ambient temperature over one hour. The aqueous phase is separated, diluted with 7.5 mL of tetrahydrofuran, cooled to 0° C., and treated with 33 mL of 6N aqueous hydrochloric acid over 20 minutes. This mixture is stirred with 75 mL of ethyl acetate at 0° C. to ambient temperature, and the ethyl acetate phase is separated and washed with water. The ethyl acetate solution was concentrated to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H]>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Product: Fc1ccc(C2CCC3(CC2)OCCO3)cc1

Procedure:
8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene is hydrogenated using Pd/C with hydrogen. After filtering-off of the catalyst over celite and evaporating-off of the solvent, 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decane is obtained in a quantitative yield: tR 3.65 min (LC-1); ESI-MS(+): m/z 237.26 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C@@H:7]([C@H:9]1[C:15](=[O:16])[N:14]2[C@@H:10]1[C@@H:11]([CH3:26])[C:12]([S:23]([CH3:25])=O)=[C:13]2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:32][C:33]([N:35]1[CH2:39][C@@H](S)[CH2:37][C@H:36]1[CH2:41][O:42][CH2:43][CH2:44][F:45])=[O:34])[CH:30]=[CH2:31].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)C>[CH2:29]([O:32][C:33]([N:35]1[CH2:39][C@@H:25]([S:23][C:12]2[C@H:11]([CH3:26])[C@H:10]3[N:14]([C:15](=[O:16])[C@@H:9]3[C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:28])[CH3:27])[CH3:8])[C:13]=2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:37][C@H:36]1[CH2:41][O:42][CH2:43][CH2:44][F:45])=[O:34])[CH:30]=[CH2:31]
Reactant: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1COCCF
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a mixture of allyl (4R,5S,6S)-6-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (33 mg) and (2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-mercaptopyrrolidine (21 mg) in N,N-dimethylformamide (1.0 ml) was added diisopropylethylamine (10 mg). After stirring for 2 hours at ambient temperature, the solution was diluted with diethyl ether (10 ml) and washed with water, 1N hydrochloric acid, aqueous sodium bicarbonate solution and brine, dried, and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography [ethyl acetate-n-hexane (1:1.5, V/V)] to give allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)pyrrolidin-4-ylthio]-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (21 mg).