Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1.[CH:22]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][C:26]=2[C:25]([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)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>[CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:38]2[CH:39]=[CH:40][C:35]([C:25]3[C:26]4[O:27][C:28]5[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=5[C:30]=4[CH:22]=[CH:23][CH:24]=3)=[CH:36][CH:37]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: COC(=O)C(Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
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: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A solution of 2-tert-Butoxycarbonylamino-3-(4-iodophenyl)-propanoic acid methyl ester (1.22 g, 3 mmol), 4-(4-dibenzofuranyl)benzeneboronic acid (0.906 g, 3.15 mmol) and Pd(PPh3)4 (160 mg, 5 mol %) in toluene (25 mL) and ethanol (6.0 mL) was treated with 2 M K2CO3 (4.5 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) gave 2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoic acid methyl ester (1.1 g, 70%) as an oil. 1H NMR (CDCl3), δ 7.98 (d, J=9 Hz, 2H), 7.96 (d, J=8 Hz, 2H), 7.74 (d, J=9, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 5.04 (d, J=9 Hz, 1H), 4.66 (m, 1H), 3.73 (s, 3H), 3.15 (m, 2H), 1.57 (s, 9H). LCMS 422 (M+−100).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:23]([NH2:25])=[O:24])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][O:20][S:21][NH2:22])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.CN1C(=O)CCC1>C1(C(C)C)C=CC=CC=1.[Pd]>[NH2:1][C:2]1[CH:27]=[CH:26][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][O:20][S:21][NH2:22])=[CH:15][CH:14]=4)[N:10]=[C:9]3[C:23]([NH2:25])=[O:24])=[C:4]2[CH:3]=1
Reactant: NSOOc1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Agent: [Pd]
Solvent: CN1CCCC1=O
Solvent: CC(C)c1ccccc1
Product: NSOOc1ccc(-n2nc(C(N)=O)c3ccc4ccc(N)cc4c32)cc1
Yield: 90.5 %

Procedure:
The product of Example 4b (1 g) and 5% Pd/C (300 mg) suspended in cumene (50 mL) and NMP (5 mL) was heated at reflux for 16 h. The mixture was then filtered and concentrated. The residue was diluted with methanol (10 mL) and added to water, after 1 h the resulting precipitate was collected by filtration and dried to yield the title compound (0.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cncc(Br)c1
Yield: 66 %

Procedure:
A solution of 5-bromonicotinic acid (10 g, 49.5 mmol) in MeOH (200 mL) was cooled to 0° C. and conc. H2SO4 (5 mL) was added dropwise. The reaction mixture was heated to reflux for 12 h. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water and the aqueous layer was washed with EtOAc. The resulting mixture was poured over an aqueous saturated NaHCO3 solution to adjust the pH 7-8, it was then extracted with EtOAc and the organic layer was dried over anhydrous Na2SO4. Solvent was evaporated under reduced pressure to get the solid product methyl 5-bromonicotinate as an off-white solid (7 g, yield 66%): 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.86 (s, 1H), 8.45 (s, 1H), 3.98 (s, 3H)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][C:19]1([CH:31]=[CH:30][CH:29]=[CH:28][CH2:27]1)[CH2:20][P:21](=[O:26])([O:24][CH3:25])[O:22][CH3:23]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:18][C@@:19]1([CH:27]=[CH:28][CH:29]=[CH:30][CH2:31]1)[CH2:20][P:21](=[O:26])([O:22][CH3:23])[O:24][CH3:25])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COP(=O)(CC1(N)C=CC=CC1)OC
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: COP(=O)(C[C@@]1(NC(=O)[C@H](C)NC(=O)OCc2ccccc2)C=CC=CC1)OC

Procedure:
In a manner analogous to that given in Example 13 (a), from the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine and dimethyl 1-aminobenzylphosphonate hydrochloride, there was obtained an isomeric mixture. After chromatography on silica gel with an isopropanol/ethyl acetate eluant, followed by recrystallization from ethyl acetate/ether, there were isolated dimethyl (1S)-1-[(N-benzyloxycarbonyl-L-alanyl)-amino] -benzylphosphonate of melting point 103°-105° C [[α]D20 =- 46.6°(c = 1% in methanol)]and dimethyl (1R)-1-[(N-benzyl-oxycarbonyl-L-alanyl)]-benzylphosphonate of melting point 120°-122° C [[α]D20 =+ 12.3°(c = 1% in methanol)]
Reaction SMILES: C([N:3](CC)CC)C.[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:21]([OH:23])=O)[CH3:20])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.N[CH2:33][P:34](=[O:37])([OH:36])[OH:35].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:21]([NH:3][O:35][P:34]([CH3:33])(=[O:37])[OH:36])=[O:23])[CH3:20])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCP(=O)(O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)NOP(C)(=O)O
Temperature: -5 °C
Reaction time: 3 h

Procedure:
24.2 g (0.24 mol) of triethylamine were added to 53.5 g (0.24 mol) of N-benzyloxycarbonyl-L-alanine in 2 liters of dry toluene and the mixture was cooled to -5° C. 32.8 g (0.24 mol) of isobutyl chloroformate were added dropwise while stirring and the mixture was maintained at -5° C for a further 25 minutes. While stirring this mixture at -5° C, there was added dropwise a solution of 6.66 g (0.060 mol) of aminomethylphosphonic acid in 60 ml of 2-N sodium hydroxide and the stirring continued for a further 3 hours at -5° C. The mixture was then allowed to warm to room temperature and stirred overnight. The aqueous layer was separated, back-extracted with toluene and adjusted to pH 9.5 with 45 ml of 2-N sodium hydroxide. The solution was evaporated at room temperature to remove triethylamine. The residue was dissolved in 200 ml of water three times and re-evaporated each time. The final residue was dissolved in 500 ml of water and the resulting solution extracted three times with 350 ml portions of chloroform. The aqueous layer was adjusted to pH 2.5 with 50 ml of 2-N hydrochloric acid and then extracted successively with three 350 ml portions of ether and three 350 ml portions of chloroform. The aqueous layer was evaporated at room temperature and the resulting white solid dissolved in 50 ml of water and 20 ml of 2-N ammonium hydroxide and then passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 250 g; freshly regenerated in the acid cycle). The column was eluted with water and the acid eluate evaporated. The residue was evaporated at room temperature three times with 100 ml of water each time to remove hydrogen chloride. There was obtained a final residue of [(N-benzyloxycarbonyl-L-alanyl)amino]-methylphosphonic acid, which was converted to its benzylamine salt as follows:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14](=[O:21])OCC(Cl)(Cl)Cl)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:22]1([C:28]2[N:29]=[C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[S:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([N:36]3[CH2:37][CH2:38][N:33]([C:30]4[S:31][CH:32]=[C:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:29]=4)[CH2:34][CH2:35]3)=[O:21])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(NC(=O)OCC(Cl)(Cl)Cl)ccc21
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2cc(NC(=O)N3CCN(c4nc(-c5ccccc5)cs4)CC3)ccc21

Procedure:
A solution of 2,2,2-trichloroethyl (1-acetyl-2,3-dihydro-1H-indol-5-yl)carbamate (200 mg, 0.569 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (140 mg, 0.569 mmol), diisopropylethylamine (0.198 ml, 1.14 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 48 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (92.0 mg, 36.1%) as a solid.
Reaction SMILES: [C:1]([C:5]1([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>CN(C)C=O>[C:1]([C:5]([OH:6])([CH2:7][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1(COC2CCCCO2)CO1
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)(COC1CCCCO1)Cn1cncn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 50.5 %

Procedure:
A solution of 160 g (0.75 mol) of 2-tert.-butyl-2-(tetrahydro-2H-pyran-2-yloxymethyl)-oxirane in 180 ml of absolute dimethylformamide is added dropwise to a mixture of 168 g (2.45 mols) of 1,2,4-triazole, 18.2 g (0.16 mol) of potassium tert.-butylate and 350 ml of absolute dimethylformamide at 80° C. under a nitrogen atmosphere. The reaction mixture is stirred at 80° C. for 6 hours and is then concentrated by stripping off the diluent under reduced pressure. The residue which remains is taken up in ethyl acetate and the organic solution formed is washed with water and then dried over sodium sulphate, and concentrated by stripping off the solvent under reduced pressure. The product thus obtained is purified chromatographically over silica gel with chloroform as the mobile phase. 107.3 g (51% of theory) of 2-tert.-butyl-1-(tetrahydro-2H-pyran-2-yl-oxy)-3-(1,2,4-triazol-1-yl)-propan-2-ol (mixture of diastereomers) are obtained in this manner.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[CH3:17][CH:18]([CH3:23])[CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl.CCOC(C)=O>[CH3:17][CH:18]([CH3:23])[CH2:19][C:20]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:21]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 113914.3 %

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (14.4 g, 0.1 mol) and pyridine (19.4 mL) in CH2Cl2 (150 mL) at 0° C., a solution of 3-methylbutyryl chloride (12 g, 0.1 mmol) in CH2Cl2 (140 mL) was added slowly. The reaction mixture was stirred for 1 h at 0° C. and for a further 1 h at rt. The mixture was concentrated to give a residue, which was diluted with EtOAc (500 mL) and filtered. The filtrate was washed with 10% aq Na2CO3 (200 mL) and water (200 mL). The combined aqueous layers were extracted with EtOAc (100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4 and concentrated to give crude 5-(3-methylbutanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (26 g), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].ClC(Cl)CCCCCN=C=N.O>C(Cl)Cl>[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([NH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: N=C=NCCCCCC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 1 h
Yield: 143.9 %

Procedure:
A portion (200 mg) of the compound obtained in Example 81 and N-t-butoxycarbonylglycine (170 mg) were suspended in methylene chloride (15 ml) and to the suspension was added dichlorohexylcarbodiimide (216 mg) under cooling with ice. The mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield the titled compound (470 mg) as a crude yellow solid. The compound was used in the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:13](=[O:26])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[C:4]([F:29])[CH:3]=1.[Cl:30][C:31]1[C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]([Cl:40])=[CH:33][N:32]=1>N1C=CC=CC=1>[Cl:30][C:31]1[N:32]=[CH:33][C:34]([Cl:40])=[CH:35][C:36]=1[C:37]([NH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:13](=[O:26])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[C:4]([F:29])[CH:3]=1)=[O:38]
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)cc4F)ccnc3NC2=O)cc1
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Solvent: c1ccncc1
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)c5cc(Cl)cnc5Cl)cc4F)ccnc3NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
57 (50 mg, 0.13 mmol) and 2,5-dichloropyridine-3-carbonyl chloride (29 mg, 0.14 mmol) were suspended in pyridine (1 mL), and stirred overnight at room temperature. The crude product was purified directly via HPLC. LC-MS (M+H=568, obsd.=568).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.[Br:17][C:18]1[N:23]=[C:22](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([F:32])=[CH:20][CH:19]=1>C(O)CC.O>[Br:17][C:18]1[N:23]=[C:22]([C@@H:24]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@H:25]([OH:12])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:21]([F:32])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OCl
Reactant: Fc1ccc(Br)nc1/C=C/c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: CC(C)(C)OC(=O)N[C@H](c1nc(Br)ccc1F)[C@H](O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To tert-butyl carbamate (214 mg, 1.827 mmol) in n-propanol (1.75 mL) was added sodium hydroxide (71.3 mg, 1.784 mmol) in water (3.5 mL) followed by tert-butyl hypochlorite (0.201 mL, 1.78 mmol). After 5 min, the solution was cooled to 0° C. and treated with a solution of DHQD2(PHAL) (23.7 mg, 0.030 mmol) in n-propanol (1.75 mL). The reaction was diluted with n-propanol (3.5 mL), and treated with (E)-6-bromo-3-fluoro-2-styrylpyridine (121 mg, 0.435 mmol) as a solid in one portion. To this was added potassium osmate dihydrate (8.01 mg, 0.022 mmol) as a solid in one portion. The reaction was allowed to gradually warm to room temperature in the dewar overnight. The reaction was cooled to 0° C. and quenched by addition of sodium thiosulfate (150 mg) in water (3 mL). The ice bath was removed and stirring continued for 30 min. The reaction was diluted with ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25% EtOAc/Hex) gave 208 mg (quant.). Mass spec.: 411.1 (MH)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:32]5[CH2:33][CH2:34][CH2:35][N:29]([C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=6)[CH2:30][CH2:31]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: c1ccc(N2CCCNCC2)nc1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCN(c2ccccn2)CC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 1-(pyridin-2-yl)-1,4-diazepane to give 227. MS: (ESI+)=473.1
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:31])[C:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.C(N(CC)CC)C.[C:39]1([C:45](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCCCCC>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([CH3:31])[C:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[N:27]([C:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=5)[C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[N:28]=[N:29][N:30]=4)=[CH:16][CH:15]=3)[C:6]=2[N:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(C)c2c(n1)N(Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(=O)CC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: Cc1nc(C)c2c(n1)N(Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(=O)CC2
Reaction time: 60 h
Yield: 83.1 %

Procedure:
To a solution of 2,4-dimethyl-8-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (2.00 g, 4.86 mmol) (prepared according to J. W. Ellingboe, et al. U.S. Pat. No. 5,149,699) in CHCl3 (50 mL) was added triethylamine (0.49 g, 4.86 mmol) and triphenylmethyl chloride (1.36 g, 4.86 mmol). After 2.5 days, the mixture was washed with 0.1N NaOH, brine, dried MgSO4), and concentrated to give a white foam. Trituration with hexane gave 2.64 g (85%) of product as a white solid, mp 160°-161° C.
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:4]=1.[NH2:32][C:33]1[C:34]([O:47][CH3:48])=[CH:35][C:36]([CH3:46])=[C:37]([NH:39][C:40](=[O:45])[CH2:41][N:42]([CH3:44])[CH3:43])[CH:38]=1.[OH-].[NH4+:50]>FC(F)(F)CO.C1COCC1.CCOC(C)=O>[CH3:43][N:42]([CH3:44])[CH2:41][C:40]([NH:39][C:37]1[C:36]([CH3:46])=[CH:35][C:34]([O:47][CH3:48])=[C:33]([NH:32][C:3]2[NH:4][C:5]3=[N:21][CH:20]=[CH:19][C:6]3=[C:7]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=3[C:15]([NH2:50])=[O:17])[N:16]=2)[CH:38]=1)=[O:45]
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Reactant: COc1cc(C)c(NC(=O)CN(C)C)cc1N
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: OCC(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(C)c(NC(=O)CN(C)C)cc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccnc-2[nH]1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt (375 mg, 0.782 mmol) in 2,2,2-trifluoroethanol (10 mL) was added N1-[5-amino-2-methyl-4-(methyloxy)phenyl]-N2,N2-dimethylglycinamide (204 mg, 0.861 mmol). The resulting mixture was let stir at 60° C. for 45 min. Solvents were removed under reduced pressure to afford a green residue. Half of this material was dissolved in THF (10 mL) and aqueous ammonium hydroxide (27%) (30 mL, excess) was added. After stirring at rt for ˜36 h, the reaction was diluted with EtOAc and the organic layer was washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure. The residue was dissolved in dioxane (6 mL) in a microwave safe vessel and 2N NaOH (4 mL) was added. The reaction was then heated in a microwave at 120° C. for 15 min and then diluted with EtOAc. The organic layer was washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2-[(2-{[5-[(N,N-dimethylglycyl)amino]-4-methyl-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide (52 mg, 0.103 mmol) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.17 (s, 3 H) 2.32 (s, 6 H) 3.03 (s, 2 H) 3.84 (s, 3H) 6.25 (dd, J=3.30, 1.65 Hz, 1 H) 6.86-6.97 (m, 2 H) 6.97-7.03 (m, 1 H) 7.40-7.49 (m, 1 H) 7.52 (s, 1 H) 8.04 (br. s., 1 H) 8.11 (s, 1 H) 8.16 (s, 1 H) 8.47 (d, J=8.42 Hz, 1 H) 9.19 (s, 1 H) 10.53 (s, 1 H) 11.37 (br. s., 1 H). ESIMS (M+H)+=507.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1.Cl.[C:26]1([C@H:32]2[CH2:34][C@@H:33]2[N:35]2[C:43](=[O:44])[C@@H:38]3[CH2:39][NH:40][CH2:41][CH2:42][N:37]3[C:36]2=[O:45])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC#N>[O:44]=[C:43]1[C@@H:38]2[CH2:39][N:40]([C:18]([NH:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[CH:9][CH:10]=3)=[O:19])[CH2:41][CH2:42][N:37]2[C:36](=[O:45])[N:35]1[C@H:33]1[CH2:34][C@@H:32]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccnn1-c1ccccc1
Reactant: O=C1[C@@H]2CNCCN2C(=O)N1[C@H]1C[C@@H]1c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CC#N
Product: O=C(Nc1ccnn1-c1ccccc1)N1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
F1 (1.0 eq.) was dissolved in MeCN (0.1M) and CDI (1.0 eq.) was added. The reaction was stirred at 80° C. for 5 h. After cooling at RT a solution of (D2) (0.5 eq.) and TEA (0.6 eq.) in MeCN (0.2M) was added dropwise. The mixture was stirred overnight. The solvents were removed under reduced pressure. Crude product was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound in 33% yield. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.91 (1H, s), 7.62 (1H, d, J=1.7 Hz), 7.54-7.47 (4H, m), 7.37 (1H, m), 7.30 (2H, m), 7.22-7.20 (3H, m), 6.31 (1H, d, J=1.7 Hz), 4.24 (1H, m), 4.02-3.96 (2H, m), 3.87 (1H, m), 2.97 (1H, m), 2.84 (2H, m), 2.67 (1H, m), 2.38 (1H, m), 1.52-1.48 (1H, m), 1.40 (1H, m). MS (ES+) C25H24N6O3 requires 456, found: 457 (M+H+).