Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C=NC1CCCCC1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)NC1CCCCC1
Yield: 48 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with cyclohexyl isocyanate (780 mg, 5.51 mmol) to provide 1.02 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-cyclohexylurea as a solid, m.p. 179-180° C. Analysis: Calculated for C23H32N6O2.0.75 H2O: % C, 63.06; % H, 7.71; % N, 19.18. Found: % C, 62.74; % H, 7.57; % N, 19.16.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:19](=[O:21])[CH3:20])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Phenylpiperidine (87 mmol) and pyridine (96 mmol) are dissolved in dry CH2Cl2 (100 ml) and acetylchloride (96 mmol) in CH2Cl2 (40 ml) is added dropwise to the stirred solution at 10° C. The reaction is stirred for 1 hour at rt. The mixture is extracted three times with water and the water phase is extracted again with CH2Cl2. The combined organic phases are dried over sodium sulfate and evaporated. A pale brown oil with Rf=0.13 (ethyl acetate/hexane=1:1) is obtained.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=O)[CH2:2]1>C(OC(=O)C)(=O)C>[CH:1]12[CH2:2][CH:3]([CH2:4][CH2:5][CH2:6]1)[C:7](=[O:9])[O:12][C:10]2=[O:11]
Reactant: O=C(O)C1CCCC(C(=O)O)C1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2CCCC1C2
Temperature: 140 °C
Yield: 86 %

Procedure:
A suspension of 1,3-cyclohexanedicarboxylic acid (490 g, 2.88 mol) in acetic anhydride (1500 ml) was heated to 140° C., refluxing for 2 hours. Acetic anhydride was then removed with distillation (oil bath 180° C). To the residue was added acetic anhydride (1000 ml) and refluxed at 140° C. for 1 hour. The acetic anhydride was removed again with distillation (under house vacuum, about 50° C.). After crystals appeared, the mixture was cooled to room temperature and MTBE (400 ml) was added. The mixture was then cooled to 0-5° C. The crystals were filtered, washed with MTBE (250 ml), and dried under house vacuum to give the title compound (382 g). The filtrate was concentrated to a residue and suspended in MTBE (100 ml) to give the second crop of the title compound (14.0 g). The total yield was 396 g (90.5%). Mp 138-140° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+].CN(C)C=O.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>O>[N:1]1([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cccn2)cc1
Temperature: 80 °C
Yield: 61.5 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1H-pyrazole (422 mg, 6.21 mmol, 1.50 equiv), sodium hydroxide (248 mg, 6.20 mmol, 1.50 equiv), and N,N-dimethylformamide (20 mL). The mixture was stirred and heated to 80° C. for 30 min, then to this was added 4-fluorobenzonitrile (500 mg, 4.13 mmol, 1.00 equiv). The resulting solution was stirred for 3 h at 110° C. in an oil bath. The resulting solution was diluted with 50 mL of H2O. The solids were collected by filtration and dried in an oven. The product was obtained as 0.43 g (62%) of a white solid.
Reaction SMILES: [CH2:1]([C:4]([NH2:10])([CH2:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH2:2][CH3:3].Br[CH2:12][CH:13]=[O:14].[OH-].[Na+]>CO>[CH2:1]([C:4]([NH:10][CH2:12][CH:13]=[O:14])([CH2:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH2:2][CH3:3]
Reactant: O=CCBr
Reactant: C#CC(N)(CCC)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CC(CCC)(CCC)NCC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,1-Dipropylprop-2-ynylamine (1.6 mole), the diethyl acetal of 2-bromoacetaldehyde (1.0 mole) and methanol (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and sodium hydroxide (20 grams) is added. The reaction mixture is then stirred for an additional period of about 16 hours. The mixture is then filtered and the filtrate is distilled to yield the desired product the diethyl acetal of 2-(1,1-dipropylprop-2-ynylamino)acetaldehyde.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:9]=1[C:10](O)=[O:11].CN(C=O)C>C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OCc1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid in CH2Cl2 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice-bath and LiBH4 (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2SO4) and the solvent is evaporated under reduced pressure to give the crude product.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19](C5C=CC=CC=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:31](N=C=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:19]1[CH2:20][CH2:21][N:17]([CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([C:6]3[C:5]4[CH:29]=[CH:30][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH2:10][CH2:11]2)[C:18]1=[O:28])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Reactant: O=C=NCc1ccccc1
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1Cc1ccccc1

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by benzyl isocyanate in Step 1 of the synthesis. The expected product melts at 126°-130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14](OC(=O)C)(=O)[CH3:15]>>[CH3:14][C:15]1[O:5][C:4](=[O:6])[C:3]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Temperature: 200 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of 2-amino-6-nitro-benzoic acid (1.5 g, 8.2 mmol) in acetic anhydride (15 mL) was heated at 200° C. for 30 minutes in a microwave oven. The mixture was filtered and washed with ethyl acetate (20 mL). The filtrate was concentrated in vacuo. The solid was stirred in ether (20 mL) for 2 hrs. The suspension was filtered and washed with ether (20 mL) to give 2-methyl-5-nitro-benzo[d][1,3]oxazin-4-one as a light brown solid (1.4 g, 85% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, CH3CN/0.1% H3PO4, 5% grad 95% in 5 min, 5.36 min (92%); 1H NMR (DMSO-d6) δ 2.42 (s, 3H, CH3), 7.79 (dd, J=1, 8 Hz, 1H, Ar), 7.93 (dd, J=1, 8 Hz, 1H, Ar), 8.06 (t, J=8 Hz, 1H, Ar); 13C NMR (DMSO-d6) δ 20.87, 107.79, 121.54, 128.87, 137.19, 147.12, 148.46, 155.18, 161.78; LCMS: MH=207.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[C@@H:10]([CH2:21][CH3:22])[CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:23][CH3:24])[CH:4]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[N:31]#CBr>C(Cl)(Cl)Cl>[C:19]([N:18]1[CH2:17][CH2:16][C@:14]23[C:15]4[C:2]5[O:1][C@H:13]2[C:12](=[O:20])[CH2:11][C@H:10]([CH2:21][CH3:22])[C@H:9]3[C@H:8]1[CH2:7][C:6]=4[CH:5]=[CH:4][C:3]=5[O:23][CH3:24])#[N:31]
Reactant: CC[C@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN(C)[C@H](C4)[C@H]13
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC[C@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN(C#N)[C@H](C4)[C@H]13
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
4,5α-Epoxy-8β-ethyl-3-methoxy-17-methylmorphinan-6one (5.00 g, 13.7 mmole; prepared in Part A) was dissolved in 50 ml chloroform. After the addition of K2CO3 (2.84 g, 20.6 mmole), the stirred suspension was treated dropwise with a solution of cyanogen bromide (1.95 g, 18.4 mmole) in 40 ml chloroform. The mixture was stirred at room temperature for 30 minutes and heated for 1.5 hours at reflux temperature. After cooling, the insoluble material was removed from the mixture by filtration and the filtrate was evaporated to a crystalline residue which was boiled with ethanol (30 ml). After chilling, the crystals were collected to give 4.30 g (92%) of white needles, mp sinters 194° C., melts 197°-198.5° C.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[C:21]([NH:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26])(=[O:23])[CH3:22]>ClCCl.N1C=CC=CC=1>[C:21]([NH:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([S:25]([NH:24][C:21](=[O:23])[CH3:22])(=[O:27])=[O:26])=[CH:29][CH:30]=2)=[O:13])=[CH:30][CH:29]=1)(=[O:27])=[O:26])(=[O:23])[CH3:22]
Reactant: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(S(=O)(=O)NC(C)=O)cc2)cc1
Yield: 8.9 %

Procedure:
The compound was prepared according to the general method of Preparation 9 using 2,2'-dithiobisbenzoyl chloride (3.0 g, 8.0 mmol) in 30 mL of dichloromethane and 4-[(acetylamino)sulfonyl]aniline (5.6 g, 26.0 mmol) in 100 mL of pyridine. The crude product was purified on a silica gel column using chloroform/methanol (1:1 v/v) as the mobile phase. The pure fractions were pooled, concentrated in vacuo, and the solid was crystallized from ethanol/water (1:1 v/v) to yield 0.5 g of the title compound, mp 180°-182° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.C(=O)(O)[O-].[Na+].[F:22][C:23]([F:37])([F:36])[C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[C:6]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:31][CH2:32]2)[N:7]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(Cl)n2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Combine 2,4-dichloro-6-(3-chloro-4-fluoro-phenyl)-pyrimidine (1.6 g, 5.75 mmol), sodium bicarbonate (1.28 g, 15 mmol), MeOH (100 mL) and cool over ice. Drip in a mixture of 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (1.33 g, 5.75 mmol) in MeOH (50 mL), and let the reaction stir for 16 hours at room temperature. Evaporate the mixture and purify directly using 10:1 hexanes/EtOAc, obtaining 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine as a white solid.
Reaction SMILES: [CH:1]1[C:6]([C@H:7]2[O:16][C:15]3[CH:14]=[C:13]([OH:17])[CH:12]=[C:11]([OH:18])[C:10]=3[CH2:9][C@H:8]2[OH:19])=[CH:5][C:4]([OH:20])=[C:3]([OH:21])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[OH:21][C:3]1[CH:2]=[CH:1][C:6]([C@@H:7]2[C@H:8]([OH:19])[CH2:9][C:10]3[C:15](=[CH:14][C:13]([OH:17])=[CH:12][C:11]=3[OH:18])[O:16]2)=[CH:5][C:4]=1[O:20][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: Oc1cc(O)c2c(c1)O[C@H](c1ccc(O)c(O)c1)[C@H](O)C2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc([C@H]2Oc3cc(O)cc(O)c3C[C@H]2O)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (−)-epicatechin (1.16 g, 4 mmol) and potassium carbonate (1.1 g, 8 mmol) in DMF (10 mL) at −20° C. was added ethyl bromoacetate (490 mL, 4.4 mmol). The reaction was stirred at the same temperature for 2 hr, allowed to warm to RT, and stirred for 2 hr. The reaction was diluted with ethyl acetate, washed with citric acid then brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative reverse phase HPLC using a gradient of 10% to 80% acetonitrile/(0.2% formic acid/water) over 20 min, analyzing at 280 nm. The appropriate fractions were frozen and lyophilized to give as white powders:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>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.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: C#CCNC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, N-methyl propargyl amine (23.3 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (15.6 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 8 h to give (Z)-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 17 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7](=[O:21])[CH:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:7](=[O:21])[CH:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1NC(CCc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)NC(=O)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
7-Chloro-3-(2-chlorophenethyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1.0 g, 1 eq), 1-(chloromethyl)-4-methoxybenzene (448 mg, 1 eq), and potassium carbonate (1.19 g, 3 eq) were suspended in DMF (11.5 mL), and the mixture was stirred at room temperature overnight. Water was then added and the mixture was stirred for 30 minutes. The solid was collected by filtration, and the solid was returned to a flask and concentrated from toluene to remove water. The crude material was purified by chromatography (gradient: 9:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) yielding a white solid (970 mg, 72% yield). 1H-NMR (300 MHz, DMSO-d6) δ 8.90 (d, 1H), 7.60-7.50 (m, 3H), 7.38-7.17 (m, 4H), 6.97 (d, 2H), 6.78 (d, 2H), 5.32 (d, 1H), 4.81 (d, 1H), 3.80 (m, 1H), 3.65 (s, 3H), 2.74 (t, 2H), 2.10 (m, 1H), 1.90 (m, 1H). MS (ES+) m/z 490.9 (M+Na).
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][C:9]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)([CH2:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:10]([C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)([OH:12])[OH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:42]([C@H:45]1[CH2:50][CH2:49][C@H:48]([C:51]2[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=2)[CH2:47][CH2:46]1)[CH2:43][CH3:44]>>[N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][C:9]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)([CH2:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:57][C:54]2[CH:55]=[CH:56][C:51]([C@H:48]3[CH2:49][CH2:50][C@H:45]([CH2:42][CH2:43][CH3:44])[CH2:46][CH2:47]3)=[CH:52][CH:53]=2)[C:10]([C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:57][C:54]2[CH:55]=[CH:56][C:51]([C@H:48]3[CH2:47][CH2:46][C@H:45]([CH2:42][CH2:43][CH3:44])[CH2:50][CH2:49]3)=[CH:52][CH:53]=2)([OH:12])[OH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reactant: O=C(CCCCCBr)CC(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(O)(O)C(=O)CCCCCBr
Product: CCC[C@H]1CC[C@H](c2ccc(OCCCCCC(=O)CC(Cc3ccc([N+](=O)[O-])cc3)(Cc3ccc([N+](=O)[O-])cc3)C(O)(O)C(=O)CCCCCOc3ccc([C@H]4CC[C@H](CCC)CC4)cc3)cc2)CC1

Procedure:
The preparation was carried out analogously to Synthesis Example 4 using 3.14 g (4.48 mmol) 2,2-bis(4-nitrobenzyl)-1,3 di(6-bromohexanoyl)propanediol and 1.96 g (8.98 mmol 4-(trans-4-propylcyclohexyl)phenol yield 2,2-bis(4 -nitrobenzyl)-1,3-di{6-[4-(trans-4-propylcyclohexyl)phenoxy]hexanoyl}propanediol.
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([C:1](=[O:14])[C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C1C(=O)N2CCCc3cccc1c32
Product: O=C1C(=O)N2CCCc3cc([N+](=O)[O-])cc1c32
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred fuming nitric acid (20 ml) at 0° C. was added 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (5 g) portionwise. The reaction mixture was stirred for additional one hour, poured into ice water and the resultant precipitate was collected by filtration. This precipitate was washed with water and dried to yield the title compound. The compound was recrystallized from ethanol-hexane to give 3.8 g (61%) as yellow needles, mp 198°-199° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[CH3:25][C:26]1([NH:30][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])[CH:16]=2)=[O:23])[CH2:29][O:28][CH2:27]1
Reactant: CC1(N)COC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2(C)COC2)n(C)n1
Yield: 95 %

Procedure:
As described for example 3, 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (85 mg, 0.26 mmol), was converted, using 3-methyl-3-oxetanamine instead of 4-aminotetrahydropyran, to the title compound (98 mg, 95%) which was obtained as a white solid. MS: m/e=401.3 [M+H]+.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:4]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([NH:20][CH2:19][CH2:17][OH:18])[CH:4]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCNc1cc(Nc2ccc(Cl)cc2)ncn1
Temperature: 200 °C
Yield: 67 %

Procedure:
75 mg of 6-chloro-N-(4-chlorophenyl)pyrimidin-4-amine hydrochloride, 18 mg of ethanolamine and 87 mg of DIPEA were dissolved in n-BuOH (1 mL) and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH 10:1. 2-(6-(4-Chlorophenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:15]=[CH:16]/[C:17]2[N:21]([C:22]3[N:27]=[N:26][C:25]([C:28]([NH2:30])=O)=[CH:24][CH:23]=3)[C:20]3[CH:31]=[CH:32][CH:33]=[CH:34][C:19]=3[N:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:15]=[CH:16]/[C:17]2[N:21]([C:22]3[N:27]=[N:26][C:25]([C:28]#[N:30])=[CH:24][CH:23]=3)[C:20]3[CH:31]=[CH:32][CH:33]=[CH:34][C:19]=3[N:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cccc(/C=C/c2nc3ccccc3n2-c2ccc(C(N)=O)nn2)c1OC1CCCC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3ccccc3n2-c2ccc(C#N)nn2)c1OC1CCCC1
Reaction time: 1 h

Procedure:
The final compound was prepared by adding triethylamne (80.0 mg, 0.78 mmol) to a stirred solution of Step 2 product (121 mg, 0.263 mmol) dissolved in dry DCM (5 ml) follwed by addition of triflouroacetic anhydride (84 mg, 0.395 mmol) at 0° C., under nitrogen atmosphere and the reaction mixture stirred for 1 h. The reaction mixture was then extracted with CHCl3 and the combined organic layers washed with water, brine, dried (Na2SO4), filtered and concentrated under vaccum. The crude product was purified by silica gel column chromatography using 2% acetone in chloroform to give 79 mg of the product of off-white solid; IR (KBr) 2959, 2243, 1573, 1455, 1263, 743 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 1.62-1.68 (m, 4H), 1.78-1.89 (m, 4H), 3.86 (s, 3H), 4.89 (br s, 1H), 6.90 (d, J=7.8 Hz, 1H), 7.03 (t, J=7.8 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.23-7.28 (m, 1H), 7.35-7.44 (m, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.87 (d, J=9.3 Hz, 2H), 8.06 (d, J=9.0 Hz, 1H), 8.19 (d, J=15.9 Hz,1H); APCI-MS (m/z) 438.21 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[N+:10]([O-:12])=[O:11].CCN(CC)CC.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=CC=1>CCO>[OH:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([C:23]2[S:26][CH:20]=[CH:25][CH:24]=2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Sc1ccccc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(O)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(-c2cccs2)c([N+](=O)[O-])c(O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-chloro-2-hydroxy-6-methyl-3-nitropyridine (188 mg, 1.0 mmol) in 2 mL of EtOH and 0.2 mL (1.4 mmol) of Et3N was added 0.11 mL (1.0 mmol) of PhSH. Precipitation occurred immediately and the solution was allowed to stir at room temperature for 16 h. The solid was filtered and washed with EtOH to afford II-2.