Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:12]([C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:18]=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=C1Cc2cc(-c3cccc([N+](=O)[O-])c3)ccc2N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6.5 %

Procedure:
5-bromo-2-indolinone (1.08 g, 5.09 mmol) and tetrakistriphenyl phosphine Pd (0) (0.273 g) were stirred under an atmosphere of nitrogen in ethylene glycol dimethyl ether (35 mL). After 15 minutes, 3-nitrophenyl boronic acid (1.70 g, 10.2 mmol) was added, followed by potassium carbonate (4.24 g, 30.7 mmol) in water (15 mL). The reaction was heated to reflux overnight, cooled to room temperature and then filtered. Saturated ammonium chloride was added. The water layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried MgSO4, filtered, and solvent removed in vacuo. Product purified by flash silica gel chromatography; eluted: 3:2 hexane; ethyl acetate, to give 5-(3-Nitro-phenyl)-1,3-dihydro-indol-2-one (0.084 g, 65%), Mp=269° C.; 1H NMR (DMSO) δ 10.5 (s, 1H), 8.38-8.36 (m, 1H) 8.17-8.14 (m, 1H), 8.10-8.07 (m, 1H), 7.75-7.60 (m, 3H), 6.95 (d, 1H, J=8.1 Hz), 3.57 (s, 2H); IR (KBr) 3420, 3190, 1700 cm−1; MS (EI) m/z 253 (M−H)−; CHN calculated for C14H10N2O: C, 66.14; H, 3.96; N, 11.02; Found: C, 64.59; H, 4.16; N, 9.43.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH2:10])=[N:7][CH:8]=1.[CH:11](O)=[O:12].[OH-].[NH4+]>O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:10][CH:11]=[O:12])=[N:7][CH:8]=1
Reactant: NCc1ccc(Cl)cn1
Reactant: O=CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=CNCc1ccc(Cl)cn1
Temperature: 0 °C

Procedure:
A solution of (5-chloropyridin-2-yl)methanamine hydrochloride (1.0 g, 5.31 mmol) in formic acid (5.09 g, 4.24 mL, 106 mmol) was refluxed at 110° C. After 20 h the reaction was cooled to 0° C. and 25% ammonium hydroxide in water was added until pH˜9 was reached. The mixture was diluted with water and then extracted into dichloromethane (3×). The organic layers were combined and dried (MgSO4), filtered and concentrated in vacuo. This was used directly in the next step without further purification. 1H NMR (CDCl3) δ: 8.53 (s, 1H), 8.35 (s, 1H), 7.69 (m, 1H), 7.65 (m, 1H), 4.64 (d, J=5.3 Hz, 2H), 4.0 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C@@H:4]([C:19]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:20])[CH2:3]1.O[Li].O>>[F:34][C:2]1([F:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C@@H:4]([C:19]([NH:21][C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[CH3:23])=[O:20])[CH2:3]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CCN2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CC(F)(F)CCN1Cc1ccc(C(F)(F)F)cc1)c1ccc(C(=O)O)cc1
Yield: 77.2 %

Procedure:
The title compound (E16) (15 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-((S)-1-((R)-4,4-difluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (D135) (20 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[NH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]=2[CH2:10]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:8][CH:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]=3[CH2:10]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(N)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc2c(c1)CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 84.9 %

Procedure:
2.99 g of potassium carbonate, 20 ml of ethyl acetate and 40 ml of water are added to 2.09 g of ethyl (+)-6-amino-5,6,7,8-tetrahydronaphthalene-2-acetate 1/2 (+)-D-dibenzoyltartrate, and a solution of 1.28 g of 4 -chlorophenylsulfonyl chloride in 20 ml of ethyl acetate is added thereto at room temperature under stirring. After the mixture is stirred at room temperature for 1.5 hour, the organic layer is separated therefrom, washed, dried and evaporated to revove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform) to give 2.10 g of ethyl (+)-6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate as colorless viscous oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([CH:16]=[O:17])=[CH:14][N:15]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([CH2:28][N+:29]#[C-:30])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[O:17]1[C:16]([C:13]2[N:10]3[CH:11]=[CH:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]3=[N:15][CH:14]=2)=[CH:30][N:29]=[CH:28]1
Reactant: O=Cc1cnc2cc(-c3ccccc3)ccn12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(-c2ccn3c(-c4cnco4)cnc3c2)cc1

Procedure:
7-Phenylimidazo[1,2-a]pyridine-3-carbaldehyde (7-1, 0.030 g, 0.14 mmol), tosylmethyl isocyanide (0.032 g, 0.16 mmol) and K2CO3 (0.022 g, 0.16 mmol) were dissolved in 1 ml MeOH and the resulting solution was heated to reflux. After 4 h the reaction was quenched by the addition of water. The resulting mixture was extracted 3× with EtOAc, and the combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of DCM to 95:5 DCM/MeOH. The product was further purified by reverse phase preparative HPLC to afford the title compound. 1H NMR (CDCl3) δ 8.63 (d, 1H, J=7.1 Hz), 8.52 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.78 (m, 2H), 7.74 (dd, 1H, J=1.4, 7.3 Hz), 7.67 (s, 1H), 7.58 (m, 3H). LCMS m/z (M+1) Calc: 262.1, found 262.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[NH:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and diethanolamine were converted to yield 2-[{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-hydroxy-ethyl)-amino]-ethanol as colorless oil, MS: 390 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([O:14][CH3:15])=[C:8]([CH3:16])[C:4]=1[C:5]([OH:7])=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:21]=[CH:22][C:23]=1[OH:24]>>[OH:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:19][C:18]=1[NH:17][C:5](=[O:7])[C:4]1[C:8]([CH3:16])=[C:9]([O:14][CH3:15])[C:10]([CH3:13])=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Reactant: COc1c(C)c(C)c(OC)c(C(=O)O)c1C
Product: COC(=O)Cc1ccc(O)c(NC(=O)c2c(C)c(OC)c(C)c(C)c2OC)c1

Procedure:
2,5-Dimethoxy-3,4,6-trimethylbenzoic acid (m.p. 98°-100° C. was reacted with methyl 3-amino-4-hydroxyphenylacetate to give methyl 4-hydroxy-3-(2,5-dimethoxy-3,4,6-trimethylbenzoylamino)phenylacetate [m.p. 159°-160° C., δ 2.14 (3H), 2.20 (3H), 2.32 (3H), 3.48 (2H), 3.65 (6H), 3.70 (3H), 7.02 (3H), 8.30 (1H), 8.87 (1H)] (11.0 g, 28.4 mmol), which was dehydrated with phosphorus oxychloride (13.1 g) to give methyl 2-[6-(2,5-dimethoxy-3,4,6-trimethylphenyl)benzoxazol-6-yl]acetate m.p. 68°-69° C., δ 2.22 (3H), 2.27 (3H), 3.58 (3H), 3.70(3H), 3.72 (3H), 3.76 (2H), 7.32 (1H), 7.55 (1H), 7.76 (1H)] .
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:19])[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:19])[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=O)cc(-c3ccccc3)oc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reaction time: 1 h
Yield: 64 %

Procedure:
100 mg (0.4 mmol) of compound 7-methoxy-2-phenyl-chromen-4-one obtained in Example 2 was dissolved in methylenechloride, and 2.0 molar equivalents of BBr3 was added thereto. The mixture was stirred for 1 hour. Methanol was added to the mixture, and then solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylenechloride/methanol=5/95, v/v) to give the title compound in a yield of 64%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])[CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CCCC[C@H]1O
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)cc1O[C@@H]1CCCC[C@H]1O

Procedure:
(R,R)-4-Fluoro-2-(2-hydroxycyclohexyloxy)-nitrobenzene (1.99 g) in methanol (20.0 ml) was hydrogenated under 50 psi hydrogen for 5 h at rt using palladium on charcoal (5%) (200 mg) as catalyst. The catalyst was filtered off; the resulting solution was evaporated to dryness to yield an oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:6]=2[CH:5]=[CH:4]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O1CCCC1>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([N:3]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:13])[C:6]=3[CH:5]=[CH:4]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)c1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)OCc4ccccc4)cccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a suspension of sodium hydride (133 mg) in tetrahydrofuran (5.0 ml) was added dropwise a solution of benzyl indole-4-carboxylate (580 mg) in tetrahydrofuran (5.0 ml) at 0° C. and the mixture was stirred at 0° C. for 1 hour. 4-Toluenesulfonyl chloride (440 mg) was added to the mixture and the solution was stirred at ambient temperature for 1 hour. The reaction was quenched with 1 N hydrochloric acid and then the aqueous solution was extracted with ethyl acetate. Drying, filtering and removal of solvents afforded a crude product. The crude product was purified by column chromatography (eluent; n-hexane:ethyl acetate=15:1) to give benzyl 1-(4-toluenesulfonyl)indole-4-carboxylate (560 mg) as a colorless syrup.
Reaction SMILES: [N:1]1([C:6]2[CH:17]=[CH:16][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>ClCCl>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:16]=[CH:17][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: NCCCCOc1ccc(-n2ccnc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)NCCCCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: -10 °C
Reaction time: 18 h

Procedure:
A solution of 2.3 g of 4-[4-(1H-imidazol-1-yl)phenoxy]butaneamine (Example 2) in 50 ml of dichloromethane containing 2 ml of pyridine is treated with 2.0 g of 4-methoxybenzoyl chloride. The reaction mixture is allowed to stand at room temperature for 18 hours, and is then heated at reflux for one hour. The volatiles are removed in vacuo. The residue is partitioned between 100 ml of dichloromethane and 100 ml of water. The dichloromethane layer is dried over Na2SO4, and then heated to gentle boiling. Hexane is then added to turbidity and the mixture cooled at -10° C. A tacky precipitate results and crystals develop in the supernatant solvent. These are collected, washed with hexane, and dried in vacuo at room temperature; m.p. 125°-126° C.; yield, 0.4 g.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[CH3:19])=[CH:5][C:4]=1[N+:20]([O-])=O.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:5]=[C:4]([NH2:20])[C:3]([NH:2][CH3:1])=[CH:8][CH:7]=2)=[C:11]([CH3:19])[CH:12]=1
Reactant: [H][H]
Reactant: CNc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ccc(Oc2ccc(N)cc2C)cc1N

Procedure:
To a solution of N-methyl-4-(2-methyl-4-nitrophenoxy)-2-nitrobenzenamine (1.90 g, 6.27 mmol) in ethyl acetate (10 mL) and ethanol (20 mL) was added 10% Pd/C (0.342 g, 0.321 mmol). After shaking under 50 psi of hydrogen for 1 hour, the mixture was filtered and the filtrate was concentrated under reduced pressure to provide the product as clear oil.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1)(C)(C)C.Cl.[CH2:24](N(CC)CC)C.C(Cl)(=O)C>ClCCl>[CH:20]([C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:5])[CH3:24])[CH:12]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)NCCCn1cc(C=O)c2ccccc21
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)NCCCn1cc(C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred dichloromethane (0.09 M) solution of tert-butyl[3-(3-formyl-1H-indol-1-yl)propyl]carbamate from the previous step was added HCl (4 N solution in dioxane, 45 eq.). The resulting solution was stirred at RT for 1 h before the volatiles were removed in vacuo. Dichloromethane was then added to the red residue and the volatiles were again removed in vacuo to afford a red gum. To the crude amine thus obtained was then added dichloromethane (0.09 M) and triethylamine (2.2 eq.). When the reaction solution became homogeneous, acetyl chloride (1.05 eq.) was added and the resulting mixture was allowed to stir at RT for another 2 h. The reaction was finally quenched with 1 N aq. NaOH and extracted with dichloromethane. The combined organic extracts were dried over MgSO4, filtered and concentration of the filtrate in vacuo afforded the crude title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:26][C:27]([O:29]CC)=[O:28])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>COCCOC.C(OCC)(=O)C.Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:13]1=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(CC)c2cccc(C)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)O)c2c(C)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-ethyl-1-ethoxycarbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-one (1.55 g) and 1N sodium hydroxide (7.0 ml) in 1,2-dimethoxyethane (10 ml) was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo to afford a residue, which was dissolved in a mixture of ethyl acetate and 1N aqueous hydrochloric acid. The separated organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a residue, which was triturated in diisopropyl ether and collected by filtration to give (3RS)-3-benzyloxycarbonylamino-5-ethyl-1-carboxymethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one (1.22 g, 84.2% yield) as a white crystalline powder.
Reaction SMILES: C(OC(N1CCC[C@H]1/C=C(/[C:15]1[CH2:21][C@H:20]2N([C:18](=O)[C@@H:19]2[C@H:22]([OH:24])C)[C:16]=1[C:26](OCC=C)=O)\C)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=[O:58])CC(=O)C1>O1CCCC1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][C:19]([C:22]([OH:58])=[O:24])=[CH:20][CH2:21][CH2:15][CH2:16][CH3:26]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: C=CCOC(=O)C1=C(/C(C)=C/[C@@H]2CCCN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCC=C(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 163.2 %

Procedure:
To a solution of allyl (5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.82 g) in a mixture of tetrahydrofuran (28 ml) and ethanol (14 ml) were added successively triphenylphosphine (0.51 g), 5,5-dimethyl-1,3cyclohexanedione (dimedone) (1.79 g), and tetrakis-(triphenylphosphine) palladium (0) (220 mg). Stirring at ambient temperature for 1 hour gave a precipitate, which was collected by filtration, washed with tetrahydrofuran (40 ml) and dissolved in water (150 ml). The solution was washed with ethyl acetate (50 ml×2), concentrated in vacuo and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(E)-2-(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo[b 3.2.0]hept-2-ene-2-carboxylic acid (1.52 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41](O)[CH:42]=[CH:43][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.CCOCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([F:38])[CH:44]=2)[C@H:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Reactant: Oc1cccc(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)N1CC[C@H](Oc2cccc(F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6.23 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine and 2.49 ml of m-fluorophenol in 250 ml of anhydrous benzene is added dropwise under nitrogen at 5° C. over a 90 minute period a solution of 4.79 g of diethyl azodicarboxylate in 250 ml of benzene. After the addition is complete the mixture is stirred overnight at room temperature. The solid is filtered, washed with benzene, and the filtrate is concentrated in vacuo to a gum. The gum is triturated overnight in a stoppered flask with 250 ml of hexane. The solid is filtered and washed with hexane. The filtrate is washed with 10% aqueous sodium hydroxide solution (3×75 ml), water (2×100 ml), saturated sodium chloride solution (100 ml) and dried overnight over anhydrous sodium sulfate. Filtration and concentration in vacuo affords a light yellow oil. Chromatography of the oil on 430 g of silica gel, using 2:1 (petroleum ether:ether), affords a colorless, cloudy gum. Trituration of the gum with petroleum ether yields product as a colorless crystalline solid, mp 74°-76.5° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:15]([C:16]([OH:19])([CH3:18])[CH3:17])=[N:14][C:13]2[C:8]1=[N:9][C:10](Cl)=[N:11][C:12]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=O)C.[CH3:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=[C:30]([NH2:43])[N:29]=1>>[NH2:43][C:30]1[N:29]=[C:28]([CH3:27])[C:33]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:15]([C:16]([OH:19])([CH3:17])[CH3:18])[N:7]3[CH2:6][CH2:5][OH:4])=[C:12]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:11]=2)=[CH:32][N:31]=1
Reactant: CC(=O)OCCn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(C(C)(C)O)n(CCO)c2n1

Procedure:
2-(2-Chloro-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purin-9-yl)ethyl acetate (300 mg) was treated with 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A and was purified via reverse phase HPLC to give 107 mg of 102 as a white solid. MS (Q1) 415.2 (M)+
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH:34]([C:37]([C:39]1[CH:52]=[CH:51][C:42]2[O:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[O:46][C:41]=2[CH:40]=1)=[O:38])([CH3:36])[CH3:35]>O1CCCC1>[F:50][C:44]1([F:49])[O:43][C:42]2[CH:51]=[CH:52][C:39]([C:37]([C:34]([Br:1])([CH3:36])[CH3:35])=[O:38])=[CH:40][C:41]=2[O:46][C:45]1([F:48])[F:47]
Reactant: [Br-]
Reactant: CC(C)C(=O)c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Yield: 171 %

Procedure:
1.89 g of phenyltrimethylammonium tribromide was added to a mixture comprising 1.40 g of 2,2,3,3-tetrafluoro-1,4-benzodioxan-6-yl isopropyl ketone and 19.7 ml of tetrahydrofuran, followed by a reaction for two hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.78 g of oily α-bromoisopropyl 2,2,3,3-tetrafluoro-1,4-benzodioxan-6-yl ketone.
Reaction SMILES: [CH2:1]([C:4]1[S:13][C:7]2[N:8]=[CH:9][N:10]=[C:11](O)[C:6]=2[CH:5]=1)[CH2:2][CH3:3].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:11]1[C:6]2[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[S:13][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CCCc1cc2c(O)ncnc2s1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1cc2c(Cl)ncnc2s1
Reaction time: 16 h

Procedure:
The product of Example 3b was reacted with excess POCl3 at reflux for 3 h then at room temperature for 16 h. The reaction was poured over ice and partitioned between water and ethyl acetate. The organic layer was concentrated to provide the title compound.