Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1.C[Al](C)C.N#N.FC1C=C(C=CC=1)O[CH2:33][C:34]([NH:36]/[C:37](/[CH3:43])=[CH:38]\[C:39](OC)=[O:40])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:39](=[O:40])[CH:38]=[C:37]([CH3:43])[N:36]=[C:34]2[CH3:33])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1
Reactant: CC(C)(Cc1ccc(Cl)c(F)c1)Nc1ccc(N)cc1Cl
Reactant: COC(=O)/C=C(/C)NC(=O)COc1cccc(F)c1
Agent: C[Al](C)C
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1cc(=O)n(-c2ccc(NC(C)(C)Cc3ccc(Cl)c(F)c3)c(Cl)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a solution of 2-chloro-N1-(1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl)benzene-1,4-diamine (408 mg, 1.25 mmol) in toluene (15 mL) was added trimethylaluminium (2.5 mL, 5.00 mmol, 2.0 M in toluene) dropwise under N2 and the mixture was stirred at rt for 30 min after addition was completed. A solution of (Z)-methyl 3-(2-(3-fluorophenoxy)acetamido)but-2-enoate (295 mg, 1.88 mmol) in toluene (5 mL) was added slowly and the resulting mixture was stirred at rt for 22 h. Trimethylaluminium (2.0 mL, 4.00 mmol, 2 M in toluene) was then added dropwise and the mixture was stirred at rt for 30 min. A solution of (Z)-methyl 3-(2-(3-fluorophenoxy)acetamido)but-2-enoate (295 mg, 1.88 mmol) in toluene (3 mL) was added and the mixture was stirred further for 18 h. The mixture was quenched with saturated NH4Cl aqueous solution (50 mL) and filtered and the organic phase was separated from the filtrate. The aqueous phase was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4 (15 g) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:3) to give the title compound as a yellow solid (183 mg, 33.7%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@H:9]1[CH2:10][CH2:11][C@@H:12]2[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1COCC1>[CH2:21]([O:20][C:18]([NH:17][C@H:12]1[CH2:11][CH2:10][C@@H:9]2[CH2:16][C@H:13]1[CH:14]([OH:15])[N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
To a cooled (0° C.) solution of (1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (4.6 g, 12.3 mmol) in CH2Cl2 (100 mL) was added DIBAL-H (37 mL of a 1.0 M solution in THF). The mixture was stirred for 105 min at 0° C. The reaction was quenched with 1N HCl and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried,(Na2SO4), filtered, and concentrated in vacuo to afford tert-butyl (1R,2S,5R,7R/S)-2-(benzyloxycarbonylamino)-7-hydroxy-6-aza-bicyclo[3.2.1]octane-6-carboxylate as a mixture of diastereomers. MS found: (M−H2O+H)+=359.2. This material was dissolved in THF (20 mL) and added by cannula (6 mL THF rinse) to a pre-mixed (15 min), pre-cooled (0° C.) solution of ethyltriphenylphosphonium iodide (6.4 g, 14.8 mmol) and KHMDS (31 mL of a 0.5 M solution in toluene). The reaction was stirred for 25 min at 0° C. before being quenched with the addition of sat. NH4Cl. The biphasic mixture was extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue via flash chromatography afforded the desired [(1R,3R,4S)-(4-benzyloxycarbonyl-amino-3-propenyl-cyclohexyl)-carbamic acid tert-butyl ester as a colorless oil (3.44 g, 72% yield). MS found: (M+H)+=389.3.
Reaction SMILES: C([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:13]([OH:15])=[O:14])=O)C1C=CC=CC=1.S(Cl)(Cl)=O>C(Cl)Cl>[CH2:21]([O:20][C:18]([NH:17][CH2:16][C@H:12]1[C:13](=[O:15])[O:14][C:9](=[O:8])[NH:11]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(NC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(NC[C@@H]1NC(=O)OC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Suspend the product of Step A (2 g) in CH2Cl2 (25 mL) and treat with thionyl chloride (1.6 mL). Stir the resulting mixture at room temperature for 1 hr and then heat under reflux for 1.5 hr. Concentrate the mixture in vacuo and triturate with hexane (3 times). Dissolve the residue in CH2Cl2 (10 mL), treat with hexane (30 mL), and stir overnight. Filter to give 4(S)-benzyloxycarbonylaminomethyl-2,5-oxazolidinedione.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([OH:14])[C:3]=1[C:15]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][O:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:30]([O:33][CH2:34][CH2:35]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:30]([O:33][CH2:34][CH2:35][O:14][C:4]1[C:3]([C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[C:2]([NH2:1])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OCCBr
Reactant: Nc1c(-c2ccc3c(c2)OCO3)c(O)nn1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(Cc2ccccc2)c(N)c1-c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a stirred mixture of 5-amino-4-(1,3-benzodioxol-5-yl)-1-benzyl-1H-pyrazol-3-ol (30 g) (Preparation 59) and cesium carbonate (94.8 g) in anhydrous dimethylformamide (340 ml), under an atmosphere of nitrogen, 2-bromoethyl acetate (16.2 g) was added drop-wise over 10 minutes and the reaction was stirred overnight. The reaction was quenched by the addition of an aqueous solution of HCl (2N, 260 ml) then ethyl acetate (600 ml) and water (100 ml) were added. The aqueous phase was extracted with ethyl acetate (3×500 ml) and the combined organic fractions were washed with brine (500 ml) and dried over Na2SO4. The dark oil was purified by flash chromatography (heptane/EtOAc; 1/1) (silica, 1000 g) yielding of the title compound as a dark oil (22.5 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]2[O:8][C@@H:4]([CH2:5][CH2:6]2)[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10].CCN(CC)CC.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C(#N)C>[C:24]([O:23][C:21]([NH:1][C@@H:2]1[C@@H:7]2[O:8][C@@H:4]([CH2:5][CH2:6]2)[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H]1[C@H](N)[C@H]2CC[C@@H]1O2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H]1[C@H](NC(=O)OC(C)(C)C)[C@H]2CC[C@@H]1O2
Temperature: 80 °C
Yield: 92.1 %

Procedure:
A solution of (1S,2R,3S,4R)-methyl 3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxylate (11) (500 mg, 2.4 mmol), Et3N (0.85 ml, 6 mmol) and BOC2O (0.66 ml, 2.88 mmol) in acetonitrile was stirred at rt for 2 h and then heated at 80° C. for 30 min when TLC confirmed completion of reaction. Acetonitrile was removed and the crude product was purified by column chromatography using silica gel (100-200 mesh) to afford the desired compound (600 mg, 92%) as a colourless oil.
Reaction SMILES: [CH:1]([C@@H:4]1[C@H:9]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C@@H:6]([OH:31])[CH2:5]1)[C@:18]1([CH3:19])[C@H:13]([CH2:14][C@H:15]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:16][C@@H:17]1[CH3:23])[CH2:12][CH2:11]3)=[CH:2][CH3:3].[N+](C1C=CC(C(OO)=O)=CC=1)([O-])=[O:33]>C(Cl)CCl>[OH:31][C@H:6]1[CH2:5][C@H:4]([CH:1]2[O:33][CH:2]2[CH3:3])[C@H:9]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:7]12[CH3:8])[C@:18]1([CH3:19])[C@H:13]([CH2:14][C@H:15]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:16][C@@H:17]1[CH3:23])[CH2:12][CH2:11]3
Reactant: O=C(OO)c1ccc([N+](=O)[O-])cc1
Reactant: CC=C[C@H]1C[C@H](O)[C@@]2(C)CC[C@H]3[C@@H](CC[C@H]4C[C@H](OC5CCCCO5)C[C@H](C)[C@@]43C)[C@H]12
Solvent: ClCCCl
Product: CC1OC1[C@H]1C[C@H](O)[C@@]2(C)CC[C@H]3[C@@H](CC[C@H]4C[C@H](OC5CCCCO5)C[C@H](C)[C@@]43C)[C@H]12
Reaction time: 1 h
Yield: 74.2 %

Procedure:
36.0 g of 15α-propenyl-17β-hydroxy-1α-methyl-3α-tetrahydropyranyloxy-5α-androstane (German Laid-Open Application 35 39 244, Example 15a) is dissolved in 900 ml of ethylene chloride, combined with 63.0 g of p-nitroperbenzoic acid, and stirred for one hour at 0°-5° C. After dilution with methylene chloride, the mixture is washed with 1-molar sodium hydroxide solution and with water, and evaporated under vacuum. By chromatography on silica gel and crystallization from ether-pentane, 27.7 g of 17β-hydroxy-15α-(1,2-epoxypropyl)-1α-methyl-3α-tetrahydropyranyloxy-5α-androstane is produced, mp 172°-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=2[CH3:26])=[C:4]([O:27][CH3:28])[CH:3]=1.[OH-].[Na+].OO.CC[O:35]C(C)=O>CS(C)=O.CO>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[O:27][CH3:28])[CH:12]=[CH:11][C:10]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:19]([CH3:26])[CH:20]=1)(=[O:35])[NH2:25]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1ccn(-c2ccc(Cl)cc2OC)c1-c1ccc(C#N)cc1C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)c1ccn(-c2ccc(Cl)cc2OC)c1-c1ccc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.1 %

Procedure:
To a solution of ethyl 1-(4-chloro-2-methoxyphenyl)-2-(4-cyano-2-methylphenyl)-1H-pyrrole-3-carboxylate (5.0 g, 12.7 mmol) in DMSO (10 mL) was added aqueous NaOH solution (2 mol/L, 1.0 mL) and 30% aqueous solution of H2O2 (1.0 mL), the reaction mixture was stirred at room temperature for four hours. TLC (EtOAc: MeOH=10:1) indicated that the starting material was consumed. Saturated aqueous Na2SO3 solution was added to quench the reaction, and the aqueous layer was extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatograph to afford the titled compound as a yellow oil (1.2 g, yield: 23.1%). MS (ESI): m/z 413.1 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([N:48]3[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]3)[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([C@H:42]3[CH2:47][CH2:46][C@H:45]([N:48]4[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]4)[CH2:44][CH2:43]3)=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CN1CCN([C@H]2CC[C@H](c3ccc(N)c4c3CN(C)C4=O)CC2)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-2-methyl-4-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-2,3-dihydro-1H-isoindol-1-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([CH2:24][CH:25]=[CH2:26])([OH:23])[CH2:20]C=C)=[CH:13][CH:12]=2)=[C:9]([Cl:27])[S:8][C:7]=1[NH:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])=[O:5])[CH3:2]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3([OH:23])[CH2:20][CH:26]=[CH:25][CH2:24]3)=[CH:15][CH:16]=2)=[C:9]([Cl:27])[S:8][C:7]=1[NH:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])=[O:5])[CH3:2]
Reactant: C=CCC(O)(CC=C)COc1ccc(-c2c(Cl)sc(NC(=O)CC#N)c2C(=O)OCC)cc1
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(=O)CC#N)sc(Cl)c1-c1ccc(OCC2(O)CC=CC2)cc1
Reaction time: 8 h

Procedure:
To an ambient solution of 4-[4-(2-allyl-2-hydroxy-pent-4-enyloxy)-phenyl]-5-chloro-2-(2-cyano-acetylamino)-thiophene-3-carboxylic acid ethyl ester (300 mg, 0.613 mmol) in DCM (12.3 mL) was added [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinynlidene)dichloro(phenylmethylene)-(tricyclohexylphoshine)ruthenium] (29 mg, 0.034 mmol) in a single portion. The reaction was stirred overnight and then concentrated under reduced pressure to a dark oil. The residue was purified by MPLC (SiO2 gel, 1:1 Hx:EtOAc) to yield the title compound as an oil. MS (ESI) m/e 459 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (m, 3H), 2.32 (d, J=15.60 Hz, 2H), 2.56 (d, J=15.60 Hz, 2H), 3.91 (s, 2H), 4.01 (m, 2H), 4.31 (m, 2H), 4.90 (s, 1H), 5.67 (s, 2H), 6.98 (m, 2H), 7.14 (m, 2H), 11.37 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21](Cl)=[O:22].Cl>O.CC(C)=O>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)=[O:22]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O)c1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To 13 mL of acetone, there were added 10.04 g of p-nitro-L-phenylalanine and 28 mL of water to thus form a suspension and the latter was cooled in an ice-bath. To this suspension, there were alternatively dropwise added 18.4 mL of a 6M sodium hydroxide solution and 10.05 g of 2,6-dichlorobenzoyl chloride in such a manner that the pH value of the suspension was maintained at a level of not less than 13 at a temperature of not more than 15° C. After the completion of the dropwise addition, the suspension was further stirred for 2 hours with cooling in an ice-bath, then the progress of the reaction was confirmed by HPLC and 36 mL of a 2M hydrochloric acid solution was dropwise added while taking care to prevent any excess generation of heat. The suspension containing separated solid matter was stirred at 10° C. overnight, the precipitates were isolated through filtration and then dried under reduced pressure at 60° C. to thus obtain 17.32 g of the title compound as a white crystalline solid (yield: 95%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][OH:11]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH:10][OH:11])=[NH:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NO
Solvent: CCO
Product: N=C(NO)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
In a 50 ml round bottom flask, 3.0 g (24.8 mmol) of 4-fluoro-benzonitrile are suspended in 50 ml of ethanol and 1.46 ml of aqueous hydroxylamine (50%, 24.8 mmol) are added. The mixture is heated to 90° C. and the resulting solution stirred at this temperature for 16 h. After cooling to room temperature, the solvent is removed in vacuo and the resulting residue recrystallised from 25 ml of ethanol/water (1:5) which yields a white solid. Mass spectrum: m/z (M+H)+: 155.0
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([CH:5]1[O:7][CH2:6]1)Cl>>[CH2:3]([O:1][CH2:3][CH:5]1[O:7][CH2:6]1)[CH:5]1[O:7][CH2:6]1
Reactant: ClCC1CO1
Reactant: [OH-]
Agent: [Na+]
Product: C(OCC1CO1)C1CO1
Temperature: 118 °C
Reaction time: 0.5 h
Yield: 651.6 %

Procedure:
To a 5-liter, 4-necked round-bottomed flask fitted with a condenser, addition funnel, stirrer, and thermometer were charged 1260 g (1.71 moles) above polyisopropylphenol. A 50% NaOH solution (137.3 g, 1.71 moles) was then added and the mixture heated with stirring to reflux (118° C.) and held there for 0.5 hours. The mixture was vacuum stripped at 100° (0.5 mm) to remove water, recharged with 50 g toluene, and restripped (105°, 0.2 mm) to azeotropically remove the last traces of water. The reaction was then cooled to 65° C. and 792 g (8.55 moles) epichlorohydrin was added and the reaction heated to reflux (~120° C.) for three hours. The excess epichlorohydrin was then vacuum stripped at 120° (0.05 mm) to yield ~1450 g of the crude glycidyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:59])[CH:5]=[C:6]([Cl:58])[C:7]=1[CH2:8][C@@H:9]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH:50]([F:52])[F:51])=[C:45]([O:53][CH2:54][CH:55]2[CH2:57][CH2:56]2)[CH:44]=1)[O:10][C:11]([C@H:13]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:42])[NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=3)[CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][S:14]1)=[O:12].[NH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:59])[CH:5]=[C:6]([Cl:58])[C:7]=1[CH2:8][C@@H:9]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH:50]([F:51])[F:52])=[C:45]([O:53][CH2:54][CH:55]2[CH2:57][CH2:56]2)[CH:44]=1)[O:10][C:11]([C@H:13]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:42])[NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[CH:34]=3)[CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][S:14]1)=[O:12]
Reactant: O=Cc1cccc(C(=O)NCCNC(=O)c2cccc(S(=O)(=O)N3CCS[C@H]3C(=O)O[C@@H](Cc3c(Cl)c[n+]([O-])cc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)c2)c1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NCCNC(=O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1)c1cccc(CNc2ccccc2)c1
Temperature: 25 °C
Yield: 105.9 %

Procedure:
3,5-Dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-3-((3-((2-(3-formylbenzamido)ethyl)carbamoyl)phenyl)sulfonyl)thiazolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide (30 mg, 0.034 mmol) was dissolved in DCM (300 μl, 4.66 mmol). Aniline (3.75 mg, 0.040 mmol) and acetic Acid (2.306 μl, 0.040 mmol) were added, and the mixture was stirred at RT for 30′. Sodium triacetoxyborohydride (8.54 mg, 0.040 mmol) was added, and the mixture was stirred at room temperature for 8 hrs to achieve completion. The reaction mixture was diluted with DCM and extracted with water. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-3-((3-((2-(3-((phenylamino)methyl)benzamido)ethyl)carbamoyl)phenyl)-sulfonyl)thiazolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide (35 mg, 0.036 mmol, 107% yield).
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(OC([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([NH:26][CH:27]([CH3:29])[CH3:28])=[CH:24][N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=O)C>ClCCl.[OH-].[Na+]>[CH3:29][CH:27]([NH:26][C:25]1[C:20]([N:17]2[CH2:16][CH2:15][NH:14][CH2:19][CH2:18]2)=[N:21][CH:22]=[N:23][CH:24]=1)[CH3:28]
Reactant: CC(C)Nc1cncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Nc1cncnc1N1CCNCC1

Procedure:
Trifluoroacetic acid (5 ml) is added to a solution of 1-[1,1-dimethylethoxy- carbonyl]-4-[5-(1-methylethylamino)-4-pyrimidinyl]piperazine (PREPARATION 11, 0.37 g) in dichloromethane (20 ml) at -78°. The reaction is allowed to warm to 20°-25° overnight, and then diluted with excess aqueous sodium hydroxide solution (10%). The phases are separated. The aqueous phase is extracted twice again with dichloromethane. The combined organic extracts are washed with saline, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound, NMR (CDCl3) 1.25, 1.7, 3.01, 3.21, 3.45, 3.5, 7.86 and 8.34 δ.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:9]([CH:10]=[O:11])=[C:8]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)[CH:7]=[CH:6][CH:5]=1.[Mn]([O-])(=O)(=O)=[O:25].[K+]>CC(C)=O>[F:23][CH:2]([F:1])[O:3][C:4]1[C:9]([C:10]([OH:25])=[O:11])=[C:8]([O:12][C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(OC)nc(Oc2cccc(OC(F)F)c2C=O)n1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)nc(Oc2cccc(OC(F)F)c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-difluoromethoxy-2-(4,6-dimethoxypyrimidin-2-yl)oxybenzaldehyde (3 g) was dissolved in acetone (30 ml). Then, an equimolar amount of an aqueous potassium permanganate solution (10 ml) was dropwise added thereto. The mixture was stirred at room temperature for 3 hours. Then, the precipitate was filtered. A large amount of water was added to the filtrate, and unreacted material was removed by extraction with ethyl ether. The aqueous phase was acidified with a 5% hydrochloric acid aqueous solution, and extracted with ethyl ether. The extract was washed with water and dried. Then, ethyl ether was distilled off under reduced pressure to obtain the above identified compound as white crystals (1.9 g). Melting point: 113°-115° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([CH:7]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:8]([O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[O:4][NH:3]1.[N+](=[CH2:37])=[N-].CCOCC>C(Cl)Cl>[CH3:37][O:1][C:2]1[CH2:6][CH:5]([CH:7]([N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[C:8]([O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[O:4][N:3]=1
Reactant: O=C1CC(C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)c3ccccc3C2=O)ON1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOCC
Product: COC1=NOC(C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)c3ccccc3C2=O)C1

Procedure:
To 90 mg. (0.2 mmole) of 3-oxo-α-phthalimido 5-isoxazolidine acetic acid, benzhydryl ester (IIa) in 5 ml of methylene chloride is added a 50% molar excess of a standard etheral diazomethane solution. A 5 μl. amount of βF3.Et2O is added and, after 30 minutes, the reaction is concentrated and the residue chromatographed on preparative TLC (AIX eluent) to yield (45 mg.) of 3-methoxy-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid, benzhydryl ester.
Reaction SMILES: C(OC([NH:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:29][CH:28]=3)[N:19]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])=O)(C)(C)C.C(Cl)Cl.FC(C(O)=O)(F)F>>[NH2:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:31][CH:32]=3)[N:19]=2)=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(CCN4CCCCC4)cc3)ncc2C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)c1ccc(-c2nc(Nc3ccc(CCN4CCCCC4)cc3)ncc2C#N)cc1
Yield: 77.5 %

Procedure:
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-piperidin-1-ylethyl)phenyl]pyrimidine-2-amine (380 mg) was stirred in 50% v/v CH2Cl2-TFA (5 mL) at room temperature for 30 min. The solvent was removed under reduced pressure and the resulting residue was redissolved in CH2Cl2, washed with saturated aqueous NaHCO3, dried (MgSO4) and evaporated to give the title compound (240 mg) as a yellow solid, m.p. 150°. δH (CDCl3) 8.70 (1H, s), 8.01 (2H, d, J 8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 7.55 (2H, d, J 8.0 Hz), 7.22 (2H, d, J 8.0 Hz), 2.84 (2H, m), 2.63 (2H, m), 2.52 (4H, m) and 1.51 (6H, s).