Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)[C@H:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Br[C:31]1[CH:32]=[C:33](I)[C:34](=[O:37])[NH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:33]3[C:34](=[O:37])[NH:35][CH:36]=[CH:31][CH:32]=3)=[CH:10][CH:9]=2)[C@H:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)OC(=O)N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@H]1c1ccccc1
Reactant: O=c1[nH]cc(Br)cc1I
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3ccc[nH]c3=O)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A resealable tube was charged with (S)-5,5-dimethyl-4-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2-one (Intermediate J)(0.100 g, 0.254 mmol), 5-bromo-3-iodopyridin-2(1H)-one (commercially available from Adesis, Inc., New Castle, Del.)(0.153 g, 0.509 mmol), sodium carbonate (0.108 g, 1.017 mmol), dioxane (2.0 mL), and water (0.40 mL). Tetrakis(triphenylphosphine)palladium(0) (0.147 g, 0.127 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture was then stirred at 100° C. for 16 hours. The reaction mixture was filtered through Celite® brand filter aid. The filtrate was then concentrated to afford a black oil. The oil thus obtained was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-100% EtOAc-hexane) to afford (S)-5,5-dimethyl-3-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)-4-phenyloxazolidin-2-one (0.021 g, 0.058 mmol, 23% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (s, 3H), 1.64 (s, 3H), 5.46 (s, 1H), 6.24 (t, J=6.70 Hz, 1H), 7.20-7.43 (m, 6H), 7.48 (d, J=8.90 Hz, 2H), 7.58 (dd, J=6.94, 2.05 Hz, 1H), 7.65 (d, J=8.80 Hz, 2H), 11.72 (br. s., 1H). m/z (ESI) 361 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: Cc1cc(C(F)(F)F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)ccc1Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[2-methyl-4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (315 mg) in THF (dry) (10 mL) and MeOH (10 ml.) and the mixture was stirred at room temperature under hydrogen for 4 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (206.1 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH:35]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:27]2[N:26]([CH3:25])[C:34]3[C:29]([CH:28]=2)=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:21]=[CH:22][CH:23]=1
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Cn1c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)cc2ccccc21

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 1-methyl-1H-indole-2-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 474.9.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([OH:3])=O.[F:12][C:13]([F:24])([F:23])[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[CH:7]([C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=1)[C:1]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][C:13]([F:12])([F:23])[F:24])=[CH:16][CH:17]=1)=[O:3])=[O:8]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=Cc1cccc(C(=O)NCc2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
to a solution of 300 mg of 3-carboxybenzaldehyde (2 mmoles) and 382 mg of 4-(trifluoromethoxy)benzylamine (2 mmoles) in 5 ml of DCM is successively added 540 mg of 1-hydroxybenzotriazole (HOBt) (4 mmoles) and 0.63 mg of diisopropylcarbodiimide (DIC) (4 mmoles). The reaction mixture is stirred overnight at room temperature and then poured into 20 ml of 10% KH2SO4 solution. The mixture is extracted twice with 15 ml of ethyl acetate. The combined organic extracts are washed with 20 ml of water and 20 ml of brine, dried over MgSO4 and concentrated giving 670 mg of 3-formyl-N-(4-trifluoromethoxy-benzyl)-benzamide (yield=85%). Analytical LC/MS method A: ([M+H]+): 324, RT: 5.24 min (gradient 5 to 85% acetonitrile in 7 min). Compound 60 is prepared as described for example 2 starting with 21.3 mg of of N-Boc-3,5-diketopiperidine (0.1 mmole), 8.3 mg 3-aminopyrazole (0.1 mmole) and 32.3 mg of 3-formyl-N-(4-trifluoromethoxy-benzyl)-benzamide (0.1 mmole) in a mixture of 0.5 ml of ethanol and 0.5 ml of DMF, resulting in 22.5 mg of product 60 after purification by preparative LC/MS. (method A, yield=38%). Analytical LC/MS method A: ([M+H]+): 484, RT: 2.51 min (gradient 2 to 80% acetonitrile in 7 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1>CC#N>[Br:19][C:5]1[C:6]([C:8]([F:11])([F:9])[F:10])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nccc(C(F)(F)F)n1
Solvent: CC#N
Product: Nc1ncc(Br)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 86 %

Procedure:
To a solution of 2-amino-4-trifluoromethylpyrimidine (25 g, 0.15 mol) in CH3CN (800 mL) was added dropwise (over 2.5 hours) NBS (34.8 g, 0.195 mol) dissolved in 200 mL of CH3CN in the dark. The mixture was stirred 4.5 h at RT in the dark and then the solvent was evaporated. The residue was dissolved in EtOAc and H2O and the binary mixture was transferred into a separating funnel. The aqueous layer was separated and extracted with EtOAc. The organic layers were washed with H2O and brine, dried with Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel using a gradient of hexane/EtOAc 9:1 to 3:2. The combined pure fractions were evaporated and the residue suspended in 40 mL hexane, stirred for 10 min., filtered and washed with 2×20 mL of hexane to give the title product as a beige solid (31.2 g, 85%). tR: 0.82 min (LC-MS 1).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][OH:9])[NH:5][C:4](=[O:6])[CH2:3]1.CO[C:12](OC)([CH3:14])[CH3:13].B(F)(F)F.CCOCC>C(Cl)Cl>[O:6]=[C:4]1[N:5]2[C:2]([CH3:1])([CH2:7][CH2:8][O:9][C:12]2([CH3:14])[CH3:13])[CH2:3]1
Reactant: CC1(CCO)CC(=O)N1
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC12CCOC(C)(C)N1C(=O)C2

Procedure:
A solution of 4-methyl-4-(2-hydroxyethyl)-2-azetidinone (0.016 mole) and 2,2-dimethoxypropane (1.69 g, 0.016 mole) in 25 ml anhydrous methylene chloride is treated with boron trifluoride etherate (0.201 ml, 0.002 mole) at 25° C. The resulting solution is stirred for ten minutes. After removal of the solvent under reduced pressure, chromatography of the crude product on silica gel gives 8-oxo-2,2,6-trimethyl-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]1([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]([CH2:38][C:39]#[CH:40])[C:30]2=[O:41])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:40]#[C:39][CH2:38][N:31]3[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:30]3=[O:41])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCn1c(=O)n(-c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1sc(C#CCn3c(=O)n(-c4ccccc4)c4ccccc43)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was prepared by reacting 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 1,3-dihydro-1-phenyl 3-(2-propynyl)-2H-benzimidazol-2-one under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The clean fractions were combined and evaporated and the residue was crystallized from methanol/ethyl acetate and recrystallized from methanol to yield off white crystals of 1-{3-[4-(2-chlorophenyl)-9-methyl-6H thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl }-1,3-dihydro-3-phenyl-2H-benzimidazol-2-one with m.p.176°-179°. These crystals contained 0.66 mol of water according the analytical data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10].CCOC(C)=O.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]#[N:18])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1C#N
Temperature: 100 °C

Procedure:
To a solution of 1-bromo-4-fluoro-2-methoxybenzene (25 g, 0.12 mol) in 250 mL of DMF was added Zn(CN)2 (28.6 g, 0.240 mol) and Pd(PPh3)4 (7.05 g, 6.10 mmol) at one portion and the reaction was charged with Ar and heated to 100° C. for 10 hours. Then the reaction was poured into 1 L of EtOAc and filtered through a kieselguhr pad. The filtrate was washed with water, brine, dried and concentrated to solid, which was purified by silica gel column to give 4-fluoro-2-methoxybenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH2:22][CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Reactant: CCCCCN
Product: CCCCCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(Cl)c1
Yield: 64.5 %

Procedure:
Using a method similar to Example 405, using 5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140 mmol) and amylamine (0.012 g, 0.140 mmol) gives the title compound (0.0314 g, 64.3%): TOF MS ES+ 348.1 (M+H)+, HRMS calcd for C18H23N3O2Cl 348.1479 (M+H)+, found 348.1456, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.6 min, 100% purity.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:19][CH2:20]Cl)[C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16].[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1>>[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:20][CH2:19][N:4]([C:5]3[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]4[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=4[C:15]=3[CH3:16])[CH2:3][CH2:2]2)=[N:24]1
Reactant: Cn1ccc(N)n1
Reactant: Cc1c(C)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Product: Cc1c(C)c(N2CCN(c3ccn(C)n3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 48.1 %

Procedure:
By using N,N-bis(2-chloroethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (660 mg, 2.0 mmol) synthesized in Reference Example 146 and 1-methyl-1H-pyrazole-3-amine (291 mg, 3.0 mmol), the reaction was carried out in the same manner as Example 117 to obtain 341 mg of the title compound as a colorless solid (yield 48%). Melting point was 147 to 149° C. (ethanol-water).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:9][S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:16][C:17]([Cl:23])([S:21]Cl)[CH:18]([Cl:20])[Cl:19]>ClCCl>[CH2:3]([N:9]([S:21][C:17]([Cl:23])([Cl:16])[CH:18]([Cl:20])[Cl:19])[S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: CCCCCCNS(=O)(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCN(SC(Cl)(Cl)C(Cl)Cl)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.2 %

Procedure:
A 3.8 g (0.047 mol) sample of 50% weight aqueous sodium hydroxide solution was added dropwise to a cooled (8° C.) solution of 9.0 g (0.043 mol) N-hexyl propanesulfonamide and 11.0 g (0.047 mol) 1,1,2,2-tetrachloroethylsulfenyl chloride in 150 ml dichloromethane. After the addition was completed, the reaction was stirred at about 25° C. for 4 hours during which time a precipitate formed. The reaction mixture was then washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give an oily residue. The residue was chromatographed through 250 g silica gel with 10% ethylether/90% hexane elution to give 7 g of the product as a yellow oil. The elemental analysis for the product showed: %S, calc. 15.8, found 16.2; %Cl, calc. 35.0, found 33.5. The product is tabulated in Table I as Compound No. 1.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH3:30])[C:26](=[O:31])[CH:25]=2)=[CH:18][N:17]=1)([O-])=O>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH3:30])[C:26](=[O:31])[CH:25]=2)=[CH:18][N:17]=1
Reactant: Cn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccn(C)c(=O)c2)c(=O)[nH]1
Yield: 55.5 %

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethylamine (1.37 g) and 2-nitroamino-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (2.08 g) were refluxed in ethanol (10 ml) for 24 hours. The reaction mixture was cooled and evaporated under reduced pressure to afford a glassy residue which was washed with hot water yielding a white solid. This solid was filtered off, washed with water and recrystallised from methanol to yield 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (1.61 g); recrystallisation from aqueous methanol afforded the title compound, m.p. 202.5°-203.5° C.
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:2]([C:10]([O:12]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[CH3:36]>C1COCC1.O>[NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:2]([C:10]([NH:34][C@@H:35]([C:37]([OH:39])=[O:38])[CH3:36])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Reactant: C[C@@H](N)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.68 g (20.0 mmol) of Z-Phe-OPfp was dissolved in 20 ml of THF and to this was added 2.3 g (25.6 mmol) of H-D-Ala-OH dissolved in 5 ml water, pH 8.5. The reaction mixture was stirred for one day and one night at room temperature. The solvents were removed by evaporation under vacuum, 70 ml ethyl acetate was added, and the mixture was acidified to pH 2-3 by the addition of 70 ml of 2% sulfuric acid. The peptide was extracted twice with 70 ml ethyl acetate, washed with saturated sodium chloride solution to neutral pH, then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum, leaving a thick oil. The product was crystallized from ether/hexane. The yield was 7.6 g (97.7%), melting point was 153-154° C. Rf=0.40 in chloroform:ethyl acetate:methanol:acetic acid=6:3:1:0.1. Rf=0.53 in acetic acid:chloroform:methanol=0.5:16:1. Rf=0.58 in acetic acid:chloroform:methanol=0.5:9:1. [α]20D=+3.2(C=1, CH3OH).
Reaction SMILES: C(N[C:6]([C:8]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])([CH2:20][CH2:21][CH2:22][CH2:23][B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)[CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[O:7])(C)(C)C.[ClH:38].[C:39](OCC)(=[O:41])[CH3:40]>>[ClH:38].[NH2:12][CH2:11][CH2:10][CH2:9][C:8]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])([CH2:20][CH2:21][CH2:22][CH2:23][B:24]1[O:25][C:26]([CH3:31])([CH3:32])[C:27]([CH3:29])([CH3:30])[O:28]1)[C:6]([O:41][CH2:39][CH3:40])=[O:7]
Reactant: CC(=O)N(C)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCCNC(=O)OC(C)(C)C)C(=O)NC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CCOC(=O)C(CCCN)(CCCCB1OC(C)(C)C(C)(C)O1)N(C)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 4-(tert-butylcarbamoyl)-4-(N-methylacetamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)octylcarbamate (140 mg, 0.266 mmol) in ethyl acetate (2 mL) was treated with anh HCl (2 N in ethyl acetate, 10 mL) and stirred at room temp. After 30 min, the solution was concentrated to give crude ethyl 2-(3-aminopropyl)-2-(N-methylacetamido)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate hydrochloride as a white solid (130 mg). ESI MS found for C20H39BN2O5 m/z [399.5 (M+1)]. This material was used without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:27])[CH:22]([CH2:23][CH2:24][OH:25])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:26])[CH:19]=2)[O:14]1>N1C=CC=CC=1>[CH3:12][C:13]1([CH3:27])[CH:22]([CH2:23][CH2:24][O:25][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:26])[CH:19]=2)[O:14]1
Reactant: CC1(C)Oc2ccc(F)cc2CC1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2Cc3cc(F)ccc3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.01 g (21 mmol) of 4-toluenesulfonyl chloride are added while stirring at room temperature to a solution of 4.48 g (20 mmol) of 2,2-dimethyl-6-fluoro-3-(2-hydroxyethyl)-chroman in 30 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature with an ice bath. The reaction mixture is then stirred at room temperature for 2 hours, then poured onto ice-water and the mixture is extracted with diethyl ether. The combined organic phases are washed while cold with 2N hydrochloric acid and then with water, dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 6.5 g (85.8% of the theoretical yield) of 2,2-dimethyl-6-fluoro-3-[2-(4-toluenesulfonyloxy)ethyl]-chroman in the form of a light-yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CS(C)=O.[Cl-]>C1COCC1>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=3)[CH:5]=[CH:4][N:3]=2)=[CH:18][CH:17]=1
Reactant: Nc1ncc(-c2ccnc(Cl)n2)cn1
Reactant: Nc1ccc(F)cc1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccnc(Nc3ccc(F)cc3)n2)cn1
Temperature: 150 °C
Yield: 12.7 %

Procedure:
To a suspension of 2-chloro-4,5′-bipyrimidin-2′-amine (30) (110 mg, 0.530 mmol) in THF (5298 μl), 4-Fluoroaniline (100 μl, 1.060 mmol) was added. DMSO (1 mL) was added to dissolve the starting chloride, and the suspension was heated to 150° C. in the microwave for 2 hours. The crude reaction mixture was filtered through a syringe filter, then purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] to obtain a reddish purple product. The product was triturated with acetone and acetonitrile, then filtered to obtain a slightly gray solid as the desired product (19 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.15 (t, J=9.09 Hz, 2H) 7.22 (s, 2H) 7.31 (d, J=5.05 Hz, 1H) 7.79 (dd, J=9.09, 5.05 Hz, 2H) 8.44 (d, J=5.05 Hz, 1H) 8.99 (s, 2H) 9.59 (s, 1H). HRMS (ES+) for C14H11FN6.H+ [MH+]: calcd, 283.1107; found, 283.1108. UV-LC: 100/100% UV purity at 214/254 nm; tR=1.07 minutes over 7.75 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]([C:12]2[C:21]3[C:16](=[C:17]([CH3:25])[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[CH:14][C:13]=2[C:26]#[N:27])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:28]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.S(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:28][CH2:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[C:21]2[C:16]=1[N:15]=[CH:14][C:13]([C:26]#[N:27])=[C:12]2[N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2c(C)cc([N+](=O)[O-])cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2c(CBr)cc([N+](=O)[O-])cc12
Yield: 119 %

Procedure:
A stirred mixture of 4-[(3-bromophenyl)-N-acetylamino]-8-methyl-6-nitro-3-quinolinecarbonitrile (10.6 g, 25 mmol), N-bromosuccinimide (6.68 g, 37.5 mmol), 0.30 g of dibenzoyl peroxide, and 200 ml of carbon tetrachloride was refluxed for 2 h, treated with an additional 0.30 g of dibenzoyl peroxide, and refluxed an additional 2.5 h, cooled, diluted with methylene chloride, and stirred with aqueous sodium bisulfite. The organic layer was separated and washed successively with water, sodium bicarbonate solution, and water. The solution was dried and evaporated to give 15 g of a white foam, NMR (CDCl3) δ 5.19 (dd, CH2Br).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH3:12].C([Li])CCC.[C:18](=[O:20])=[O:19].O>O1CCCC1>[CH3:12][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[CH:10]=[CH:11][C:2]=1[C:18]([OH:20])=[O:19]
Reactant: Cc1c(Br)ccc2c1OCCO2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc2c1OCCO2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
In 300 ml of dry tetrahydrofuran, was dissolved 32.0 g of 6-bromo-5-methyl-1,4-benzodioxane and after cooling the solution to -78° C., 96.7 ml of n-butyl lithium (n-hexane solution) was added dropwise over 20 minutes or more. After stirring at the same temperature for 1.5 hours, the reaction mixture was poured onto crushed dry ice and dry ice was sublimated while stirring. Water was added to the mixture and the tetrahydrofuran was removed under reduced pressure. The resulting alkaline aqueous solution was washed with methylene chloride and adjusted to pH 3 with a 5% hydrochloric acid, and the precipitated crystals were collected by filtration and dried to obtain 20.9 g of 5-methyl-1, 4-benzodioxan-6-carboxylic acid (yield: 77%).