Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8](S(C3C=CC=CC=3)(=O)=O)[CH:7]=[CH:6][C:5]=2[C:4]=1[CH:21]=O.[CH3:23][NH:24][CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl.[OH-].[Na+]>[CH3:1][O:2][C:3]1[C:4]([CH2:21][N:24]([CH3:25])[CH3:23])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1C=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2[nH]ccc2c1CN(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (366 mg, 1.16 mmol; Intermediate 75) was dissolved in DCE, dimethylamine (3.48 mmol as 2M in MeOH) and sodium triacetoxyborohydride (738 mg, 3.48 mmol) was added in sequence. The reaction mixture was left stirring at r.t. for 23 h, diluted with DCM, NaOH (2M aq) was added until sustained pH at 10. The organic phase was separated, and the water-phase extracted once DCM. The combined organic phases were dried over Na2SO4 and purified by preparative HPLC. Yield: 57 mg residue mauve color
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH2:30]([CH2:32][NH2:33])[OH:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:33][CH2:32][CH2:30][OH:31])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCCO
Reactant: Cc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1ccc(-c2cc3cc(CNCCO)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 80.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (54.0 mg, 0.138 mmol) was dissolved in acetonitrile (4.3 mL), and the solution was treated with ethanolamine (0.034 mL, 0.55 mmol), acetic acid (0.158 mL, 2.76 mmol) and sodium triacetoxyborohydride (58.0 mg, 0.276 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-methyl-7-{1-(tert-butoxycarbonyl)-5-[(2-hydroxyethylamino)methyl]indol-2-yl}isoindolinone (48.5 mg, yield 81%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.CO[CH2:12][CH2:13]OC>C([O-])([O-])=O.[K+].[K+].C(OCC)C.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>[Cl:9][C:4]1[N:3]=[C:2]([CH:12]=[CH2:13])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: COCCOC
Reactant: Cc1cc(Cl)nc(Cl)c1
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: CCOCC
Product: C=Cc1cc(C)cc(Cl)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2,6-dichloro-4-methyl-pyridine (2.34 g, 14.4 mmol) and 2,4,6-trivinyl-cyclotriboroxane pyridine complex (1.75 g, 7.26 mmol) in DME (27 mL), 2 M aq. K2CO3 solution (10 mL) is added. The mixture is degassed and put under argon before Pd(PPh3)4 (300 mg, 0.26 mmol) is added. The mixture is stirred at 80° C. for 3 h before it is cooled to rt, diluted with diethyl ether and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1. The thus obtained product is dissolved in EA, repeatedly washed with 5% aq. citric acid solution, dried over MgSO4, filtered and evaporated to give 6-chloro-4-methyl-2-vinyl-pyridine (1.24 g) as a colourless oil; LC-MS: tR=0.90 min, [M+1]+=154.03.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:42])[CH:40]=[CH2:41]>C(Cl)Cl>[C:39]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)(=[O:42])[CH:40]=[CH2:41]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(C2CCNc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.3 %

Procedure:
To a solution of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.071 mmol) in DCM (2 mL) was added pyridine (0.2 mL). Then acryloyl chloride (6 mg, 0.084 mmol) was added dropwise. The mixture was stirred at RT for 0.5 hr and partitioned between DCM (20 mL) and brine (20 mL). Organic layer was separated from aqueous layer, washed with brine (2×20 mL), dried over Na2SO4 and purified by Pre-TLC (DCM/CH3OH=10/1) to afford 1.82 mg (5.38%) of 7-(3-acrylamidophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.58 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.34-7.26 (m, 4H), 7.10 (t, J=7.6 Hz, 1H), 7.04-6.95 (m, 4H), 6.84 (d, J=7.6 Hz, 1H), 6.39-6.25 (m, 2H), 5.69 (dd, J=2.4, 9.6 Hz, 1H), 5.47-5.44 (m, 1H), 3.38-3.31 (m, 1H), 3.22-3.12 (m, 1H), 2.52-2.42 (m, 1H), 2.23-2.17 (m, 1H). MS (ESI) m/e [M+1]+ 480.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1.N([O-])=O.[Na+].CC#N.O.[ClH:41]>O.Cl[Cu]>[Cl:41][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1
Reactant: CCOC(=O)C1(c2cc(OCC3CC3)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(c2cc(OCC3CC3)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H2O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude black oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate as yellow oil (1.1 g).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1)=O.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16].C[O-].[Na+].Cl>C(O)C.CO>[CH3:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:5]2[CH:4]=[CH:3][N:20]=[C:18]([NH:17][C:15]#[N:16])[N:19]=2)[CH:12]=1
Reactant: Cc1ccnc(C(=O)C=CN(C)C)c1
Reactant: N#CNC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cc1ccnc(-c2ccnc(NC#N)n2)c1
Yield: 37.5 %

Procedure:
To a suspension of 3-dimethylamino-1-(4-methylpyridin-2-yl)prop-2-en-1-one (0.78 g) and cyanoguanidine (1.38 g) in ethanol (8 ml) was added a solution of sodium methoxide in methanol (28%, 1.49 ml), and the mixture was refluxed for 2 hours. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate and tetrahydrofuran (3:1). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 75 g, 10% methanol in dichloromethane). The solid obtained was triturated with 2-propanol, filtered and dried to give N-(4-(4-methylpyridin-2-yl)-pyrimidin-2-yl)cyanamide (325 mg).
Reaction SMILES: [OH:1][OH:2].FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C([O:10][C:11](=O)[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=O>FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(O)=O>[F:19][C:14]([F:20])([C:15]([F:16])([F:17])[F:18])[C:13]([F:21])([F:22])[C:12]([F:24])([F:23])[C:11]([O:1][O:2][C:11](=[O:10])[C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:19])([F:20])[C:15]([F:18])([F:17])[F:16])=[O:10]
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OO
Agent: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(OOC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
In a manner similar to that of Example 1, H2O2 (>95%) was combined with nonafluorovaleric anhydride to give bis(nonafluoropentanoyl) peroxide (δ−83.2, −117.9, −124.8, −127.5) in nonafluorovaleric acid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[O:8][CH2:7]1)[CH:2]=[CH2:3].[CH2:9]([SiH:12]([O:15][CH3:16])[O:13][CH3:14])[CH:10]=[CH2:11]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:14][O:13][Si:12]([O:15][CH3:16])([CH2:3][CH2:2][CH2:1][O:4][CH2:5][CH:6]1[O:8][CH2:7]1)[CH2:9][CH:10]=[CH2:11]
Reactant: C=CCOCC1CO1
Reactant: C=CC[SiH](OC)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C=CC[Si](CCCOCC1CO1)(OC)OC
Yield: 43023.8 %

Procedure:
Using the same apparatus and procedure described in EXAMPLE 1, 12.1 g (0.11 mmol) of allylglycidyl ether and 60 μl of 1% chloroplatinic acid in isopropanol were added to the flask. Through the dropping funnel was added dropwise 6.6 g (0.05 mmol) of allyldimethoxysilane at 80° C. and the solution was further reacted for 2 hrs to complete the reaction. Vacuum distillation (83°-85° C.) of the product mixture gave 5.3 g (43.5%) of 4,4-dimethoxy-7-glycidoxy-4-sila-1-heptene.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.O[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH:7]1[CH:8]=[C:4]([CH2:3][O:2][N:10]2[C:14](=[O:15])[C:13]3[C:12](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:20])[N:5]=[CH:6]1
Reactant: OCc1c[nH]cn1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
To an ice-cold solution of 4-(hydroxymethyl)imidazole hydrochloride (2.0 g, 15 mmol), N-hydroxyphthalimide (2.4 g, 15 mmol) and triphenylphosphine (4.0 g, 15 mmol) in THF (65 mL) was added a solution of diethyl azodicarboxylate (2.6 mL, 16 mmol) in THF (10 mL) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 18 h, the resultant precipitate was collected by vacuum filtration. The solid was partitioned between EtOAc (75 ml) and saturated NaHCO3 (75 mL). The aqueous layer was separated and extracted again with EtOAc (75 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, CH2Cl2 to 90:10 CH2Cl2/MeOH) gave 2-(1H-imidazol-4-ylmethoxy)-1,3-dihydro-2H-isoindole-1,3-dione (800 mg, 22%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ5.03 (2H, s), 7.30 (1H, s), 7.55 (1H, s), 7.81-7.86 (4H, m), 12.08 (1H, br s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=1.[NH2:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([OH:32])=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:18][C:17]=2[F:33])=[CH:12][N:11]=1>>[NH2:9][C:10]1[N:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:23]=3[O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=3)=[CH:18][C:17]=2[F:33])=[CH:14][N:15]=1
Reactant: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3O)cc2F)cn1
Reactant: Nc1nccc(Cl)n1
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3Oc3ccnc(N)n3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 555 using 4-chloropyrimidin-2-amine and 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol. MS (ESI): mass calcd. for C21H14F4N6O, 442.12; m/z found, 443.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.51-8.43 (d, J=1.3, 2H), 8.06-7.94 (d, J=5.7, 1H), 7.72-7.69 (m, 1H), 7.69-7.66 (m, 1H), 7.55 (s, 1H), 7.52-7.47 (m, 1H), 7.39-7.31 (m, 2H), 6.31-6.03 (d, J=5.7, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>C1COCC1.[Cl-].[NH4+]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)([OH:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCCN(Cc3ccccc3)C2)cc1
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a solution of 1-benzylpiperidin-3-one (5 g, 26 mmol) in THF (30 mL) was added (4-methoxyphenyl)magnesium bromide (0.5 M in ether) (66 mL, 33 mmol) at rt under a nitrogen atmosphere. The reaction was stirred for 2 h and then diluted with sat. ammonium chloride solution and extracted with ethyl acetate (200 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give crude 1-benzyl-3-(4-methoxyphenyl)piperidin-3-ol (5.1 g, 10.29 mmol, 38.9% yield) with was used in the next step without further purification. LCMS (Method 107): (ES-API), m/z 298.2 (M+H) RT=1.703 min.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CCN(CC)CC.[F:27][C:28]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[F:27][C:28]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[CH:33][C:29]=1[C:30]([NH:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])=[O:31]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(F)c(F)c(F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To an ice-cold solution of di-tert-butyl L-glutamate hydrochloride (6.6 g, 22.4 mmol) and Et3N (6.9 ml, 50 mmol) in dry CH2Cl2 (70 ml) was added, over a period of 1.5 hr, 2,3,4,5-tetrafluorobenzoyl chloride (5.0 g, 23.5 mmol) in dry CH2Cl2 (20 ml) and thirty minutes later the solution was allowed to warm to room temperature. Sixteen hours later the solution was washed with H2O, dried (MgSO4) and evaporated to dryness. 1H NMR δ 1.40+1.42 (2s, 18H, t-butyl), 1.85+1.95 (2m, 2H, CH2CH), 2.34 (t, 2H, CH2CO, J=7.5 Hz), 4.3 (m, 1H, CH), 7.57 (m, 1H, H6), 8.80 (d, 1H, NH, J=7.5 Hz); 19F NMR δ −138.6+139.0 (2m, 2F, F2+5), −152.4 (m, 1H, F4), −154.9 (t, 1F, F3, J=20 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:36][CH2:35]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(OC)c(OC)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 63 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate (28 mg, 0.091 mmol) and 1-(3-methoxy phenyl)piperazine (27 mg, 0.18 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (27 mg, 0.18 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (1:2) mixture and concentration gave 26 mg of the titled compound (yield, 64%). 1H NMR (300 MHz, CDCl3) δ 3.27-3.29 (m, 4H), 3.78-3.81 (m, 7H), 3.94 (s, 3H), 3.97-3.98 (m, 1H), 4.00 (s, 3H), 4.15 (s, 3H), 6.47-6.49 (m, 2H), 6.56-6.58 (m, 1H), 7.11 (s, 1H), 7.14-7.27 (m, 3H).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[Cl:41][C:42]1[CH:50]=[CH:49][C:45](C(Cl)=O)=[CH:44][CH:43]=1>>[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C@:2]3([CH3:1])[O:6][C:5]4=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]4[CH2:3]3)[CH2:19][CH2:18]2)=[O:21])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCN(C(=O)c3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (300 mg, 0.82 mmol) and trifluoroacetic acid (6 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (15 ml), and the solution was added triethylamine (2 ml, 14.35 mmol). To the solution, 4-chlorobenzoyl chloride (150.7 mg, 0.86 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 1 hour. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution, water and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether-ethyl acetate to afford (S)-(4-chlorophenyl)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]methanone (282 mg, yield 85%) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH2:9][C:10]1[C:11]([C:15](Cl)=[N:16][OH:17])=[N:12][O:13][N:14]=1.C(N(CC)CC)C>C(O)C>[NH2:9][C:10]1[C:11]([C:15](=[N:16][OH:17])[NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)=[N:12][O:13][N:14]=1
Reactant: Nc1cccc(F)c1
Reactant: Nc1nonc1C(Cl)=NO
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nonc1C(=NO)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
A solution of 3-fluoroaniline (36 μL, 0.37 mmol) in ethanol (0.5 mL) was treated with a solution of 4-amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (50 mg, 0.31 mmol) in ethanol (1.5 mL) followed by triethylamine (51 μL, 0.37 mmol) dropwise. The reaction mixture was stirred at 25° C. for 1 h and purified by preparative LCMS to give the desired product (21 mg, 29%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[C:9]=2[C:8](=[O:17])[N:7]([CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[CH2:24]([N:27]([CH2:31][C:32]#[CH:33])[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[C:9]=2[C:8](=[O:17])[N:7]([CH2:18][CH2:19][C:20]([OH:22])([CH3:21])[C:33]#[C:32][CH2:31][N:27]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26])[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: C#CCN(CCC)CCC
Reactant: CCCCn1c(=O)n(CCC(C)=O)c(=O)c2c1ncn2CCC
Product: CCCCn1c(=O)n(CCC(C)(O)C#CCN(CCC)CCC)c(=O)c2c1ncn2CCC
Yield: 28 %

Procedure:
3-Butyl-1-(6-dipropylamino-3-hydroxy-3-methyl-4-hexynyl)-7-propylxanthine was prepared in 28% yield using 3-butyl-1-(3-oxobutyl)-7-propylxanthine and N,N-dipropyl-2-propynylamine as as in Example 6C1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>O1CCCC1>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[CH:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH2:20][CH2:21]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(N3CCNCC3)cccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(N3CCN(Cc4ccccc4)CC3)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(phenylsulfonyl)-4-piperazin-1-yl-1H-indole (71 mg, 0.18 mmol) in tetrahydrofuran is treated sequentially with benzyl bromide (21 μl) and triethyl-amine (75 μl), shaken at room temperature for 16 hr and concentrated in vacuo to give a residue. The residue is purified by RP-HPLC to give the title product, 37 mg, identfied by HPLC and mass spectral analyses (2.81 min; 432 M+H) using the LCMS conditions described in Table I.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:9]2[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([C@@H:13]([NH2:15])[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:3][C:4]1[C:9]2[N:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]([C@@H:13]([NH:15][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2cccc(Br)c2n1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2cccc(Br)c2n1-c1ccccc1
Yield: 67.1 %

Procedure:
(S)-1-(7-Bromo-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (1 g, 2.5 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.736 g, 3.1 mmol) and DIPEA (2.26 mL, 13 mmol) in IPA (4 mL) were heated in a sealed tube for 4 h. The cooled reaction mixture was concentrated in vacuo; the residue dissolved in EtOAc and the resulting solution washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified on silica (Si—PCC, 0-10% MeOH in DCM) to give the product as a white solid (870 mg, 67%). LCMS (Method B): RT 3.48 min; m/z [M+H]+ 518/520