Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>CN(C)C=O>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccccc1CBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1COc1ccccc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl α-bromo-2-toluate (53 g, 0.23 mole) was added to a mixture of 2-bromophenol (40 g, 0.23 mole) and potassium carbonate (42 g, 0.3 mole) in 250 mL of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours, then heated on a steam bath for 3.5 hours. The mixture was poured into ice water, and the solids were collected by filtration and washed with water to give the crude product. An analytical sample was obtained by recrystallization from hexane/ethyl acetate (38 g, mp 73°-74° C. pmr (CDCl3) δ: 6.58-8.05 (m, 8, aromatic H); 5.48 (s, 2H, ArCH2O); 3.80 (s, 3H, CO2CH3)
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.COC(=O)C1C=CC(C(OC)=O)=CC=1OC1C=CC=CC=1OC>>[CH3:11][O:10][C:8]([C:7]1[CH:12]=[CH:13][C:4]2[C:3](=[O:22])[C:16]3[C:15]([O:14][C:5]=2[CH:6]=1)=[CH:20][CH:19]=[C:18]([F:21])[CH:17]=3)=[O:9]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Oc2ccc(F)cc2)c1
Agent: COC(=O)c1ccc(C(=O)OC)c(Oc2ccccc2OC)c1
Product: COC(=O)c1ccc2c(=O)c3cc(F)ccc3oc2c1

Procedure:
Using an adaptation of the method described in Procedure 15, substituting 2-(4-fluorophenoxy)-terephthalic acid dimethyl ester, 1e for 2-(2-methoxyphenoxy)-terephthalic acid dimethyl ester, 1c, the title compound 7-fluoro-9-oxo-9H-xanthene-3-carboxylic acid methyl ester, 2e was obtained. MS m/z (MH+) 272.9.
Reaction SMILES: [CH2:1]([Zn]CC)C.S1CCCC1.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCCl.ClCCl>[CH2:1]1[O:18][CH:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CC[Zn]CC
Solvent: ClCCCl
Solvent: C1CCSC1
Solvent: ClCCl
Product: c1ccc(C2CO2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of diethyl zinc (18 ml of 1.1M solution in toluene, 20 mmol) in 1,2-dichloroethane (60 ml) was added chloroiododomethane (2.18 ml, 30 mmol) at -15° C. and the reaction mixture was stirred for 15 minutes. Tetrahydrothiophene (2.40 ml, 30 mmol) was added at -15° C. and the mixture was stirred for 25 minutes. During this time the temperature was allowed to rise to 19° C. Benzaldehyde (2.12 ml, 20 mmol) was added and the reaction mixture was stirred until it reached room temperature. The reaction mixture was stirred at room temperature for 1 hour after which it was diluted with dichloromethane (20 ml) and washed with a saturated solution of NH4Cl (3×5 ml). The organic layer was dried over MgSO4. The resulting solution was analysed by gas chromatography and the title compound was found to be present.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]2[N:5]([CH3:6])[CH2:4][CH2:3][N:2]2[CH3:1])=[CH:11][CH:10]=1
Reactant: CNCCNC
Reactant: COc1ccc(C=O)cc1
Solvent: c1ccccc1
Product: COc1ccc(C2N(C)CCN2C)cc1

Procedure:
Benzene (20 ml) and N,N'-dimethylethylenediamine (1.56 ml, 14.7 mmol) were added to 4-methoxybenzaldehyde (2 g, 14.7 mmol), and the m tture was refluxed under heating for 5 hours while removing the generated water. Benzene was evaporated to give a crude product of 2-(4-methoxyphenyl)-1,3-dimethylimidazolidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Li+].[Cl-].C[CH2:15][O:16]C(C)=O>FC(F)(F)C(O)=O.CO.Cl[Pd]Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]2[C:15](=[O:16])[O:10][CH2:9][C:4]=2[C:3]=1[CH3:11]
Reactant: CCOC(C)=O
Reactant: Cc1cc(Br)c(C)c(CO)c1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Br)c(C)c2c1C(=O)OC2
Reaction time: 8 h

Procedure:
To a solution of (3-bromo-2,5-dimethylphenyl)methanol (1.6 g, 7.4 mmol) in trifluoroacetic acid (20 mL) was added Tl(OOCF3)3 (4 g, 7.4 mmol) at r.t, then the reaction was stirred at r.t overnight under N2. The mixture was concentrated under pressure. The residue solids, LiCl (0.6 g, 14.9 mmol), MgO (0.6 g, 14.9 mmol) and PdCl2 (0.13 g, 0.74 mmol) in MeOH were stirred under CO at 1 Mpa over night. EtOAc was added to the mixture and filtered. The organic phase was concentrated to afford 5-bromo-4,7-dimethyl-2-benzofuran-1(3H)-one.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH2:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[CH:31])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[C:13]#[CH:14]>O>[CH:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH:12]=[C:13]=[CH2:14])=[CH:21][CH:20]=2)=[CH:23][CH:24]=1)=[C:30]=[CH2:31]
Reactant: C#CCOc1ccc(-c2ccc(OCC#C)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C=COc1ccc(-c2ccc(OC=C=C)cc2)cc1
Yield: 35.3 %

Procedure:
Into a similar reaction vessel, as used in the abovementioned reaction, were placed 2.124 parts of t-BuOK and 12.036 parts of THF and to this, a mixture of 10.000 parts of 4,4'-dipropargyloxybiphenyl and 23.333 parts of THF was added dropwise. The content was reacted at 50° C. for 60 minutes and then a deionized water was added to stop the reaction. THF layer and water layer were removed by using an evaporator, and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 4,4'-diallenyloxy biphenyl as pale yellow crystals (M.P.135.2°-138.5° C.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:6]([CH2:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1)[Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cccc(Br)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 111.2 %

Procedure:
A stirred solution of 3-bromobenzyl alcohol (21) (10.0 g, 53.5 mmol), 4-dimethylaminopyridine (0.33 g, 2.7 mmol), and t-butylchlorodiphenylsilane (17.6 g, 64.2 mmol) in anhydrous CH2Cl2 (240 mL) was cooled to 0° C. under argon. Triethylamine (8.1 g, 80.2 mmol) was added dropwise via syringe and the reaction mixture was allowed to warm to room temperature over 3.5 h. The reaction solution was washed with water, and the aqueous portion was extracted again with CH2Cl2. The organic layers were combined, washed sequentially with 1N HCI solution, water, and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 25.3 g of 22 as a clear, pale yellow oil. Purification by column chromatography (20:1 ratio silica gel/crude product; elution with 5% to 7.5% ethyl acetate/hexanes) yielded 21.2 g (93%) of 22 as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ7.63-7.65 (m, 4H, ArH), 7.35-7.48 (m, 8 H, ArH), 7.18-7.28 (m, 2H, ArH), 4.72 (s, 2H, CH2OSi), and 1.05 (s, 9H, SiC(CH3)3).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[C:14](=[O:43])[N:15]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C2CCCCO2)=[O:29])[CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[F:12][C:13]1[C:14](=[O:43])[N:15]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:39])=[O:40])[C:28]([NH:30][OH:31])=[O:29])[CH:16]=[CH:17][C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@](CCn1ccc(-c2ccccc2)c(F)c1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C[C@@](CCn1ccc(-c2ccccc2)c(F)c1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
Pyrinium p-toluenesulfonate (20 mg, 0.080 mmol) was added to a solution of (2R)-4-(3-fluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (110 mg, 0.236 mmol) in ethanol (5 ml) and heated at reflux for 3 hours. The solution was cooled to RT, and upon cooling, a solid precipitated. The solid was collected via filtration and washed with ethanol (5 mL), heptane (10 mL), and ether (10 mL). The solid was dried under vacuum to afford the title compound as a yellow solid (38.4 mg, 42.6%). LC-MS m/z 383.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (s, 3 H) 2.10-2.26 (m, 1 H) 3.11 (s, 3 H) 3.70-3.94 (m, 1 H) 4.07-4.30 (m, 1 H) 6.46 (t, J=6.93 Hz, 1 H) 7.46-7.57 (m, 3 H) 7.59-7.65 (m, 3 H)
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[K+].[Cl-].[NH4+]>C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:2]2[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1c(Cl)ncnc1Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 94.8 %

Procedure:
A solution of 4,6-dichloro-5-methoxy-pyrimidine (5.62 g, 27.9 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.02 g, 27.9 mmol) in 200 mL THF was chilled to 0° C. A 1.0 M solution of potassium t-butoxide (30.7 mL, 30.7 mmol) was added drop-wise with stirring and the resulting mixture then was allowed to stir at 0° C. for one hour. Saturated ammonium chloride (100 mL) was added and the solution extracted with ethyl acetate. The organic phase was washed with brine and dried with magnesium sulfate, solvent removed to yield 9.10 g (94.8% yield). 1HNMR (CDCl3, 400 MHz) a 1.48 (s, 2H), 1.79-1.83 (m, 2H), 1.99-2.04 (m, 2H), 3.33-3.39 (m, 2H), 3.72-3.77 (m, 2H), 3.91 (s, 3H), 5.30-5.38 (m, 1H), 8.26 (s, 1H). Exact mass calculated for C15H22ClN3O4: 343.13. found: 344.3 (MH+).
Reaction SMILES: C(OCC(C)C)(=[O:3])C.[F:9][CH:10]([F:33])[O:11][C:12]1[CH:32]=[CH:31][C:15]2[NH:16][C:17]([S:19][CH2:20][C:21]3[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][N:22]=3)=[N:18][C:14]=2[CH:13]=1.[OH-].[Na+].[O-]Cl.[Na+]>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[CH3:30][O:29][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([CH2:20][S+:19]([O-:3])[C:17]2[NH:16][C:15]3[CH:31]=[CH:32][C:12]([O:11][CH:10]([F:9])[F:33])=[CH:13][C:14]=3[N:18]=2)[C:26]=1[O:27][CH3:28]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: CC(=O)OCC(C)C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: -7 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A flask is charged with isobutyl acetate (0.1 L). Under mixing, compound VI (5 g) is added, followed by 18.8% NaOH (11.5 ml, 4.9 eq.). The flask is cooled to −7° C. Then, aqueous 9.4% active NaOCl (11.5 ml, 1.24 eq.) is added dropwise over 15 min. The two-phase mixture is stirred at room temperature overnight, over which time a precipitate forms. Aqueous Na2S2O5 (20 ml) is then added and the precipitate is redissolved. On standing, another precipitate forms in the mixture which is separated by filtration and dried to give pantoprazole (4.33 g, 83%) containing 0.4% compound VI and free of sulfone within the limit of UV detection.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][C:9]1([CH3:15])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC1(C)CNCCN1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CC1(C)CN(c2ccc(F)cc2)CCN1Cc1ccccc1
Temperature: 100 °C
Yield: 62.8 %

Procedure:
To a stirred solution of 1-benzyl-2,2-dimethylpiperazine (1.2 g, 5.87 mmol) in 1,4-dioxane (50 ml) at 25° C. was added 1-bromo-4-fluorobenzene (1.233 g, 7.05 mmol), 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.366 g, 0.587 mmol), sodium tert-butoxide (1.129 g, 11.75 mmol), and tris(dibenzyllideneacetone)dipalladium (0) [Pd2(dba)3] (0.269 g, 0.294 mmol). The reaction mixture was purged with nitrogen for 10 min in sealed tube and then heated at 100° C. for 5 h. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C., filtered through celite, washed with ethyl acetate (2×50 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified over silica gel (100-200 mesh) by flash chromatography using 10% ethyl acetate in hexane as eluent to obtain the title compound (1.1 g, 62.8%)
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH3:24][CH:25]([N:28]=[C:29]=[O:30])[CH2:26][CH3:27]>>[CH:25]([N:28]1[C:4](=[O:5])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:29]1=[O:30])([CH2:26][CH3:27])[CH3:24]
Reactant: CCC(C)N=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: CCC(C)n1c(=O)c2cnc3c(OC)cccc3c2n(C2CCCC2)c1=O
Yield: 68 %

Procedure:
3-sec-Butyl-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (25 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and 2-butyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 368 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[C:28]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([CH2:41][CH2:42]Br)[CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CC(=O)CC.CC(C)=O>[O:21]=[C:2]1[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:42][CH2:41][CH:37]1[CH2:38][CH2:39][CH2:40][N:35]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCBr)C1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(CCN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.96 g, 3.41 mmol) in 2-butanone (17 mL) and acetone (17 mL) were added cesium carbonate (3.79 g, 11.6 mmol) and N-Boc-3-(2-bromoethyl)piperidine (1.00 g, 3.42 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 16 h. The reaction mixture was filtered and washed with acetone (2×50 mL). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 30% gradient) to give tert-butyl 3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate (1.48 g, 88%) as a white powder: mp 64-67° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.30 (dt, J=7.8, 0.9 Hz, 1H), 7.16 (d, J=7.3 Hz, 1H), 7.50 (dt, J=7.5, 0.7 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.10 (d, J=1.7 Hz, 1H), 5.86 (dd, J=6.0, 1.0 Hz, 2H), 4.90 (dd, J=9.0, 0.6 Hz, 1H), 4.65 (dd, J=9.0, 3.0 Hz, 1H), 3.90-3.69 (m, 4H), 2.97-2.86 (m, 1H), 2.77-2.68 (m, 1H), 1.96-1.92 (m, 1H), 1.76-1.16 (m, 15H); 13C NMR (75 MHz, CDCl3) δ 177.2, 155.8, 154.8, 148.8, 142.3, 142.2, 142.1, 132.4 (2), 128.9, 124.0, 123.2, 119.4 (2), 108.5, 102.9, 101.4, 93.6, 80.4, 79.4, 58.1, 38.2, 33.5, 30.7, 30.7, 30.6, 30.5, 28.4, 24.3; MS (ES+) m/z 515.4 (M+23).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[Cl:11][C:9]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]([NH2:8])[N:6]=[C:5]([N:2]([CH3:3])[CH3:1])[CH:10]=1
Reactant: CNC
Reactant: Clc1cc(Cl)nc(Nc2ccccc2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1=NC(N)N(c2ccccc2)C(Cl)=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Dimethylamine in tetrahydrofuran (2M, 15 mL) was added to a solution of 4,6-dichloro-N-phenyl-2-pyrimidinamine (0.715 g, 2.97 mmol) in tetrahydrofuran (30 mL) and N,N-diisopropylethylamine (0.52 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the crude material was purified by flash chromatography on silica gel, eluting with ethyl acetate/hexane (1:9). The eluent was removed, giving 6-chloro-N4, N4-dimethyl-1-phenyl-2,4-pyrimidinediamine (0.592 g, 2.39 mmol, 80%, Rf=0.3).
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([OH:13])=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1[CH:18]=CC2N(O)N=[N:23][C:21]=2[CH:22]=1.CN1CCOCC1.N1CCCC1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:2]1([CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([N:23]2[CH2:18][CH2:17][CH2:22][CH2:21]2)=[O:13])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C([C@@H]1CCCN1Cc1ccccc1)N1CCCC1
Reaction time: 8 h
Yield: 76 %

Procedure:
1-(Phenylmethyl)-L-proline hydrochloride (2.0 g, 8.247 mmol) and HOBt (1.34 g, 9.928 mmol) were dissolved in CH2Cl2 (50 mL), and 4-methylmorpholine (3.63 mL, 33.09 mmol), pyrrolidine (0.760 mL, 9.101 mmol), and EDCI (1.906 g, 9.928 mmol) were added. The solution was stirred overnight, and was then washed with water (50 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL), and the combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-100% ethyl acetate/hexanes, 1% triethylamine) to provide (2S)-1-(phenylmethyl)-2-(1-pyrrolidinylcarbonyl)pyrrolidine (1.619 g, 76%). LCMS: (M+H)+: 259.2
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)(=O)C>C(Cl)Cl>[CH2:29]([O:28][C:26]([CH:25]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:27])[CH3:30]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N)C1=O
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
0.22 g of the isomer of t-butyl α-[6-amino-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (h) above] was subjected to N-alkylation with 0.28 g of ethyl 2-bromo-4-phenylbutyrate in the same manner as described in Example 1(h). The resulting product was subjected to silica gel column chromatography, using a 1:20 by volume mixture of ethyl acetate and methylene chloride as the eluent. From the fraction first eluted was obtained 0.14 g of t-butyl α-{6-[1-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl}acetate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:19]3[CH:20]=[C:21]4[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]4[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(Oc2cncc(Cl)c2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cncc(Cl)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((5-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH2:11][C:12]#[CH:13])[CH:3]=1.[CH:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:16]/[CH:14]=[O:15])=[C:4]([O:10][CH2:11][C:12]#[CH:13])[CH:3]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CCOc1cc(Br)ccc1C=O
Solvent: C1CCOC1
Product: C#CCOc1cc(Br)ccc1/C=C/C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
A mixture of 4-bromo-2-(prop-2-ynyloxy)benzaldehyde (0.852 g, 3.56 mmol) and formylmethylenetriphenylphosphorane (2.2 g, 7.12 mmol, 2 equiv) suspended in THF (20 mL) under nitrogen was stirred at ambient temperature for 18 h and then at 50° C. for another 24 h. The reaction mixture was filtered through a bed of silica gel (˜25 g) eluting with EtOAc:hexane (1:4, 300 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a linear gradient of EtOAc:hexane (1:19 to 1:9). Pooled fractions containing the title compound and its Z-isomer in the ratio of (39:11, by NMR) was concentrated under reduced pressure to give (E)-3-(4-bromo-2-(prop-2-ynyloxy)phenyl)acrylaldehyde (0.69 g, 2.6 mmol, 57% yield). 1H NMR (500 MHz, CDCl3) δ 9.71 (d, J=7.6 Hz, 1H), 7.77 (d, J=16.2 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.26-7.17 (m, 2H), 6.77 (dd, J=16.2, 7.6 Hz, 1H), 4.82 (d, J=2.4 Hz, 1H), 4.80-4.75 (m, 1H), 2.62 (t, J=2.4 Hz, 1H). The Z-isomer showed the aldehydic proton at δ 9.87 (d, J=7.9 Hz) and a smaller cis-coupling (J=11.4 Hz) for the olefinic proton at δ 6.22; LCMS (Method B) (ESI) m/e 265.0, 267.0 Br pattern [(M+H)+, calcd for C12H9BrO2 265.0].
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[C:7](=[O:18])[CH:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.IC.[CH3:25]C([O-])(C)C.[Na+]>CS(C)=O.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[C:7](=[O:18])[C:6]3([CH3:25])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: CC12COCCN1c1nc(Cl)ncc1N(CC1CCOC1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.9 %

Procedure:
2-Chloro-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (320 mg, 0.985 mmol) and iodomethane (0.307 ml, 4.93 mmol) were frozen in DMSO (2 ml). Sodium 2-methylpropan-2-olate (284 mg, 2.96 mmol) was added and covered by a layer of DMSO. The mixture was allowed to warm to room temperature and stir for 1 hour, then was diluted with water then extracted twice with EtOAc. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 390 mg of 2-chloro-6a-methyl-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a tan oil. [M+H] found 339.