Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH2:8]([O:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH3:9].C([N-]C(C)C)(C)C.[Li+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:8]([O:10][C:11](=[O:15])[C:12]([CH3:14])([CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7])[CH3:9]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)(C)CCCCCBr
Yield: 31 %

Procedure:
Using the method described in Example 5(i). 1,5-dibromopentane (23 g, 0.1 mol) and ethylisobutyrate (10.4 g, 0.09 mol) were reacted in the presence of lithium diisopropylamide (0.1 mol) and hexamethylphosphoramide (22 g) to give the title compound as an oil (7.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.[N+:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([O-:21])=[O:20].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[CH:22]([N+:19]([O-:21])=[O:20])[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:27]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(C(c1ccc(OC)cc1)c1ccc(OC)cc1)[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a stirred (0° C.) solution of bis-(4-methoxyphenyl)methanol (2.5 g, 10.2 mmol) and ethyl nitroacetate (2.26 ml, 20.4 mmol) in CH2Cl2 (50 ml) under argon was added AlCl3 (1.36 g, 10.2 mmol) in one portion. After 1 h, the reaction mixture was allowed to warm to approximately 10° C. and poured into a mixture of ice and 2M HCl. The resulting mixture was stirred for 45 min, and the aqueous layer extracted with CH2Cl2. The combined organic layers were washed with 10% Na2CO3, dried over MgSO4, treated with activated carbon, and concentrated to give a reddish oil that was chromatographed (CHCl3 elution) to afford the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25](Cl)=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:28]([NH2:31])([CH3:30])[CH3:29].N1C=CC=CC=1>ClCCl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)Cl)nn1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1cc(C(=O)NC(C)C)nn1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 5-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]pyrazole-3-carbonyl chloride (550 mg) in dichloromethane (5 ml) were added isopropylamine (0.2 ml) and pyridine (0.2 ml), and the mixture was stirred at room temperature for 0.5 hours. The mixture was then evaporated to dryness under reduced pressure, and the residue was shaken with a mixture of 0.1 N hydrochloric acid (50 ml), dichloromethane (15 ml), and ether (60 ml). The mixture was allowed to separate into layers. The organic layer was washed with an aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate, followed by evaporation of the solvent to give a light yellow syrup (550 mg, 98%).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:22]=[C:21]([C:23]2[C:32]3[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[S:35][C:31]=3[C:30]([Br:40])=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[CH:28]3)[CH:20]=[C:19]([Br:41])[C:5]=1[O:6][C@H:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10]C)=[O:9].CO>C1COCC1>[Br:3][C:4]1[CH:22]=[C:21]([C:23]2[C:32]3[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[S:35][C:31]=3[C:30]([Br:40])=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[CH:28]3)[CH:20]=[C:19]([Br:41])[C:5]=1[O:6][C@H:7]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Yield: 67 %

Procedure:
Aqueous potassium hydroxide (1 N, 6.37 mL, 6.37 mmol) was added to a stirred solution of (R)-2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11 -yl)-phenoxy]-3-phenyl-propionic acid, methyl ester (2.31 g, 3.19 mmol) in THF (22 mL)/methanol (15 mL). After 2 h the solution was concentrated, diluted with water (100 mL) and acidified with 10% aqueous HCl. The solid was filtered, washed with water and triturated with petroleum ether. It was then recrystalyzed from methanol to provide the title compound as a white solid (1.52 g, 67%): mp 140-142° C.: [a]D25=+25.66 (10.52 mg/mL CHCl3); NMR (DMSO-d6);δ13.26 (broad s, 1 H), 8.29 (d, J=8 Hz, 1 H), 8.07 (d, J=8 Hz, 1 H), 7.80 (m, 1 H), 7.79 (dd, J=7, 3 Hz, 2 H), 7.63 (ddd, J=8, 7, 1 Hz, 1 H), 7.55 (d, J=8 Hz, 1 H), 7.51 (ddd, J=8, 7, 1 Hz, 1 H), 7.41 (d, J=7 Hz, 2 H), 7.38-7.32 (m, 3 H), 7.31-7.22 (m, 3 H), 6.64 (d, J=8 Hz, 1 H), 5.32 (t, J =7 Hz, 1 H), 3.41 (d, J=7 Hz, 2 H); MS (EI): [M+], 3 bromine isotope pattern, 708 (35%), 710 (90%) 712 (100%) 714 (40%); Anal. Calc. for C31H19Br3O3S: C, 52.35, H, 2.69, N, 0.00. Found: C, 52.46, H, 2.59, N, 0.10. Chiral analytical HPLC determined that this compound had approx. 100% EE [column:Chirobiotic V, 5 micron (4.6 ×250 mm); isocratic, 1:1 ethanol:hexane; flow rate =0.80 mL/min; injection volume =0.3 μL; sample conc. =0.25 mg/mL; retention time, R-enantiomer =21 min; retention time, S-enantiomer =16 min⟧
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)[N:3]=1.Br[CH2:17][CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:21][O:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17][N:12]1[CH:13]=[C:8]([C:4]2[N:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: O=c1[nH]cc(-c2cccnn2)c(=O)[nH]1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(CCn1cc(-c2cccnn2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.7 %

Procedure:
A mixture of 5-pyridazin-3-yl-1H-pyrimidine-2,4-dione hydrochloride (Prep121, 656 mg, 2.89 mmol), 3-bromo-1,1dimethoxy-propane (609 mg, 3.33 mmol) and K2CO3 (400 mg, 2.89 mmol) in DMSO (10 ml) was stirred for 24 hours at room temperature. 3-Bromo-1, 1dimethoxy-propane (100 mg, 0.55 mmol) was then added and the reaction was left for 11 days at room temperature. 3-Bromo-1,1dimethoxy-propane (100 mg, 0.55 mmol) was further added and stirring continued for additional 6 days. The mixture was lyophilized and the residue washed with diethyl ether and filtrate. The solid washed with ethyl acetate. After evaporation of the organic phase, 200 mg of the title compound as a light brown powder was obtained (24% yield).
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:2].[CH:19](=O)[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>>[O:24]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:19]1[O:12][C:3]([C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:1][O:2]1
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Reactant: O=Cc1ccco1
Product: O=C(c1ccccc1)C1(c2ccccc2)COC(c2ccco2)O1
Yield: 78 %

Procedure:
The procedure of Example 1 was repeated except that the starting materials were α-methylolbenzoin and furfural. The product, 2-furyl-4-benzoyl-4-phenyl-1, 3-dioxolane, was obtained in a yield of 78% and analyzed as follows:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>>[C:2]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:20])[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
Compound 1c was prepared from N-Boc-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and 4-amino-1-benzylpiperidine, using the method described in Example 1.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl:24][C:25]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:26]=1[C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[C:26]2[CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=[CH:37][C:25]=2[Cl:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)CNC(=O)c1cc(C(F)(F)F)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(C(F)(F)F)ccc2Cl)C1

Procedure:
The title compounds were prepared as white solids from EDCI coupling between 3-amino-azetidine-1-carboxylic acid tert-butyl ester and (2-chloro-5-trifluoromethyl-benzoylamino)-acetic acid (prepared by the method similar to Ingersoll, A. W. et. al., Organic Syntheses 1932, XII, 40-2) using the procedure described in Step C of Example 1.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH:11]([NH:13][NH2:14])=[O:12].[C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:26][C:27]([CH3:45])([C:29]2[N:33]([CH3:34])[C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:43])[F:42])=[N:31][N:30]=2)[CH3:28])=[C:21]([CH:25]=1)[C:22](O)=O)#[N:16].O>CN(C=O)C>[CH3:45][C:27]([C:29]1[N:33]([CH3:34])[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:43])([F:44])[F:42])=[N:31][N:30]=1)([O:26][C:20]1[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:25][C:21]=1[C:22]1[O:12][CH:11]=[N:13][N:14]=1)[CH3:28]
Reactant: NNC=O
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C#N)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C#N)cc1-c1nnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
WSC•monohydrochloride (81 mg), HOBt (57 mg) and formic hydrazide (30 mg) were sequentially added to a solution of 5-cyano-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (140 mg) in DMF (2 ml), followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid (130 mg) was dissolved in dichloromethane (2 ml) and pyridine (0.090 ml) was added thereto, followed by cooling to −78° C. Trifluoromethanesulfonic acid (0.090 ml) was added to the reaction solution and was elevated to room temperature, followed by stirring for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1). The resulting solid was washed with diisopropylether to obtain, as a white solid, 4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)-3-(1,3,4-oxadiazol-2-yl)benzonitrile (65 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=O)=[CH:4][C:3]=1[CH2:12][O:13]C.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([C:22](=[N:24]O)[NH2:23])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:24]=[C:12]([C:3]3[CH:2]=[CH:11][C:10]([C:2]4[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=4[CH3:12])=[C:5]([CH2:6][O:8][CH3:9])[CH:4]=3)[O:13][N:23]=2)=[CH:20][N:21]=1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: NC(=NO)c1ccc(Cl)nc1
Product: COCc1cc(-c2nc(-c3ccc(Cl)nc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in Method B starting from Intermediate A1 and 6-chloro-N′-hydroxypyridine-3-carboximidamide (J. Med. Chem., 2005, 5215-5223). After purification by flash chromatography (silica, EtOAc/cHex), the title compound was obtained as a colorless oil (661 mg, 70%). HPLC (Method A), Rt: 5.8 min (purity: 99%). UPLC/MS, M+(ESI): 392.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[C:7]([CH2:29]O)=[N:8][CH:9]=[CH:10][C:11]=1[S:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=2)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:3][CH2:29][C:7]1[C:6]([CH3:5])=[C:11]([S:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=3)[N:22]=2)[CH:10]=[CH:9][N:8]=1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Temperature: 0 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A solution of 3.6 ml (49.8 mmol) of thionyl chloride in 30 ml of dichloromethane is added dropwise at room temperature to a solution of 15.0 g (38.3 mmol) of {3-methyl-4-[3-(3-nitroimidazo[1,2-b]pyridazin-6-yl-sulfanyl)propylsulfanyl]pyridin-2-yl}methanol in 400 ml of anhydrous dichloromethane and the mixture is then stirred for a further 18 h. It is then cooled to 0° C. and aqueous sodium carbonate solution (100 ml) is cautiously added dropwise. The dichloromethane is distilled off. The suspension is then treated with 400 ml of water and stirred at 0° C. for 30 min. The precipitate is filtered off, washed with water, dried at 40° C. in vacuo and then suspended in 300 ml of acetone. After filtration and drying, 15.3 g (97%) of the title compound are isolated as a beige powder. M.p.: 155-156° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:20]([C:40]2[CH:45]=[C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:43]([O:50][Si](C)(C)C)=[C:42]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH:41]=2)[C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([O:31][Si](C)(C)C)=[C:23]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:22]=2)[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[O:11][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].O>CO>[C:27]([C:25]1[CH:26]=[C:21]([P:20]([C:7]2[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[C:40]2[CH:45]=[C:44]([C:46]([CH3:47])([CH3:48])[CH3:49])[C:43]([OH:50])=[C:42]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH:41]=2)[CH:22]=[C:23]([C:36]([CH3:39])([CH3:37])[CH3:38])[C:24]=1[OH:31])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1cc(P(c2cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O[Si](C)(C)C
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(P(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
A solution of 5.0 g (5.8 mmol) of tris(3,5-di-tert-butyl-4-trimethylsilyloxyphenyl)phosphine and 4.0 ml of water in 100 ml of methanol is heated at reflux temperature for 48 hours. The solvent is removed in vacuo from the reaction mixture and the residue is recrystallized from nitromethane. The mass spectrum shows a molecular ion at m/z=646.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:23]
Reactant: C=COCCON
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
To a solution of 5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2.10 g, 5.29 mmol) and O-(2-vinyloxyethyl)-hydroxylamine (0.87 g, 8.46 mmol) in DMF (30 mL) was added EDCI hydrochloride (1.31 g, 6.90 mmol), HOBt (0.93 g, 6.90 mmol) and DIPEA (1.17 mL, 6.90 mmol). The reaction mixture was stirred at room temperature for 5 hours before being concentrated in vacuo. The resultant residue was dissolved in 1:1 tert-butylmethylether: ethyl acetate (20 mL) and aqueous saturated sodium hydrogen carbonate solution (20 mL) was added. The resultant mixture was sonicated until a precipitate formed, the precipitate was collected by filtration and dried in vacuo at 45° C. to yield the title compound as a tan solid (1.55 g, 60%). LCMS (Method B): RT=2.80 min, M+H+=483.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH2:63][CH2:62][N:61]([NH2:64])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:61]5[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-methylpiperazin-1-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.64 (m, 4 H) 1.67-1.75 (m, 2 H) 1.89-1.97 (m, 2 H) 2.79 (d, J=4.6 Hz, 3 H) 3.11-3.30 (m, 6 H) 3.32 (s, 3 H) 3.44 (d, J=12.6 Hz, 2 H) 3.93 (s, 3 H) 4.09 (t, J=13.9 Hz, 2 H) 4.76-4.81 (m, 1 H) 7.46 (d, J=8.3 Hz, 1 H) 7.48 (s, 3 H) 8.24 (d, J=8.34 Hz, 1 H) 8.27 (s, 1 H) 9.79 (s, 1 H). Melting point: 168-174° C. [M+H] calc'd for C26H34F2N8O3, 545; found 545.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:19])=O>>[Cl:19][C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(N2C(=O)C=CC2=O)cc1
Product: O=C(Cl)c1ccc(N2C(=O)C=CC2=O)cc1

Procedure:
A mixture of one molar equivalent of N-(4-carboxyphenyl)maleimide is reacted with excess thionyl chloride at 50° C. for three hours. The excess thionyl chloride is distilled off, and the residual product recrystallized from benzene to obtain pure N-(4-(chlorocarbonyl)phenyl)maleimide.
Reaction SMILES: [CH2:1]([C:13]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:1]([C:13]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:22][C:36]2[CH:37]=[CH:38][C:33]([O:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:34][CH:35]=2)=[O:21])=[CH:18][CH:17]=1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
{circle around (3)}: A mixture comprising 2.14 g of 4-n-dodecylcarbonyloxybenzoic acid, 1.40 g of 4-benzyloxyphenol, 1.44 g of DCC and 20 g of dichloromethane was stirred at room temperature for 30 minutes. Then, a catalytic amount of 4-N,N-dimethylaminopyridine was added to the mixture, and the mixture was further stirred at room temperature for 12 hours. After finishing the reaction, insoluble substances were filtered off, and dichloromethane was distilled off from the filtrate under reduced pressure. The resultant residue was purified by means of silica gel column chromatography, whereby 3.3 g of 4-(4′-n-dodecylcarbonyloxyphenylcarbonyloxy)-1-benzyloxybenzene was obtained in the form of a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][CH:8]=[N:7][C:6]2=O.P(Cl)(Cl)([Cl:17])=O.O.C(=O)([O-])O.[Na+]>C(N(CC)C(C)C)(C)C>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:12]([CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(=O)nc[nH]c2cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Cl)ncnc2cc1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
6-Methoxy-7-methyl-1H-quinazolin-4-one (275 mg) was suspended in N,N-diisopropylethylamine (3.78 ml), phosphorus oxychloride (0.3 ml) was added to the suspension, and the mixture was stirred at 100° C. for 6 hr. The reaction solution was added in small portions to water of 0° C., an aqueous sodium hydrogencarbonate solution was further added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 4-chloro-6-methoxy-7-methyl-quinazoline (199 mg, yield 66%).
Reaction SMILES: Cl[CH2:2][S:3]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]=[O:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4].[Cl:14][C:15]1[CH:22]=[C:19]([CH:20]=O)[C:18]([OH:23])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][C:2]([S:3]([N:6]3[CH2:11][CH2:10][N:9]([CH:12]=[O:13])[CH2:8][CH2:7]3)(=[O:5])=[O:4])=[CH:20][C:19]=2[CH:22]=1
Reactant: O=CN1CCN(S(=O)(=O)CCl)CC1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CN1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 12.4 %

Procedure:
A mixture of 1-(chloromethanesulfonyl)-4-formylpiperazine (2.26 g), 5-chlorosalicylaldehyde (1.56 g) and potassium carbonate (1.38 g) in DMF (30 ml) was stirred at 100° C. for 48 hours. The reaction solution was concentrated, and to the residue was added ethyl acetate. The organic layer was washed with water and brine, dried, concentrated and purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of 1-(5-chlorobenzofurane-2-sulfonyl)-4-formylpiperazine (406 mg).