Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N(C(C)(C)C#N)=N[C:11](C)(C)[C:12]#N.[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:22]([C:23]1[CH:28]=[CH:27][C:26]([CH:11]=[CH2:12])=[CH:25][CH:24]=1)=[CH2:21]
Reactant: CCCCCCCC
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C=Cc1ccccc1
Solvent: O
Product: C=Cc1ccc(C=C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 g of the amphiphilic macromolecule reversible addition-fragmentation chain transfer agent and 80 g of deionized water were formulated into an aqueous solution as an aqueous phase, which was added and uniformly mixed with an oil phase consisting of 6 g of styrene, 12 g of p-vinyl benzene, 0.1 g of azobisisobutyronitrile and 9 g of n-octane, and prepared by an ultrasonic crasher into a miniemulsion under the effect of a high shear field. The miniemulsion was transferred to a reactor and subjected to the reaction at a temperature of 80° C. which stopped after 4 hours, and then cooled to the room temperature and discharged to yield polymeric nanocapsules with highly crosslinked shells which were formed by the polymerization of styrene and p-divinyl benzene, wherein the polymeric nanocapsules have an average diameter of 90 nm.
Reaction SMILES: Cl.[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH:15]N)[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH:17]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]>>[CH2:2]([C:6]1[C:10]2=[C:11]3[C:12](=[CH:13][CH:14]=[C:9]2[S:8][CH:7]=1)[NH:15][C:23]1[CH2:24][CH2:25][N:20]([CH:17]([CH3:19])[CH3:18])[CH2:21][C:22]3=1)[CH2:3][CH2:4][CH3:5]
Reactant: CC(C)N1CCC(=O)CC1
Reactant: CCCCc1csc2ccc(NN)cc12
Agent: Cl
Product: CCCCc1csc2ccc3[nH]c4c(c3c12)CN(C(C)C)CC4

Procedure:
The compound is formed analogously to that described in Example 15, from 25.6 g of 3-butyl-5-hydrazinobenzothiophene hydrochloride and 17 g of 1-isopropyl-4-piperidone. Melting point: 157°-158° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:29](I)=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[N+:31]([O-:33])=[O:32])[CH:21]=3)[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:37][C:38]1[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][C:41](B(O)O)=[C:40]([O:50][CH3:51])[CH:39]=1.O>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:29]([C:41]4[CH:42]=[C:43]([CH:44]([CH3:46])[CH3:45])[C:38]([F:37])=[CH:39][C:40]=4[O:50][CH3:51])=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[N+:31]([O-:33])=[O:32])[CH:21]=3)[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2cccc([N+](=O)[O-])c2cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1cc2c([N+](=O)[O-])cccc2cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 85 °C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-iodo-5-nitro-2-naphthyl)methyl]-4-methyl-1,3-oxazolidin-2-one (34.0 mg, 0.0545 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (23.1 mg, 0.0109 mmol), and 1,1′-bis(di-t-butylphosphinoferrocene)palladium dichloride (3.5 mg, 0.00545 mmol) in 1N aqueous potassium carbonate (2 mL) and THF (2 mL) was heated at 85° C. in a sealed tube for 2 h. The reaction mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-30% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-5-nitro-2-naphthyl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.23 (20% EtOAc/hexanes). LCMS calc.=665.2; found=664.9 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 8.46 (s, 1H); 8.26 (d, J=7.5 Hz, 1H); 8.17 (t, J=9.0 Hz, 1H); 8.07 (s, 0.5H); 7.95 (s, 0.5H); 7.85 (s, 1H); 7.69 (s, 2H); 7.58 (t, J=7.9 Hz, 1H); 7.14 (d, J=8.4 Hz, 0.5H); 7.10 (d, J=8.4 Hz, 0.5H); 6.72 (d, J=12.0 Hz, 0.5H); 6.71 (d, J=12.0 Hz, 0.5H); 5.57 (d, J=8.1 Hz, 0.5H); 5.44 (d, J=8.0 Hz, 0.5H); 4.97 (d, J=15.9 Hz, 0.5H); 4.93 (d, J=15.9 Hz, 0.5H); 4.29 (d, J=15.9 Hz, 0.5H); 4.03 (d, J=15.8 Hz, 0.5H); 3.91-3.83 (m, 0.5H); 3.77 (m, 3.5H); 3.26-3.18 (m, 1H); 1.28-1.24 (m, 4.5H); 1.20 (d, J=6.9 Hz, 1.5H); 0.58 (d, J=6.5 Hz, 1.5H); 0.40 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: [C:1](#[N:4])[CH2:2][OH:3].[N+:5]([C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]>>[N+:5]([C:8]1[CH:9]=[C:10]([S:14]([O:3][CH2:2][C:1]#[N:4])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: N#CCO
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: N#CCOS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Preparation: The technique of Example 2 is used to react glycolonitrile with m-nitrobenzenesulfonyl chloride. The product is recovered from the reaction mixture by filtration and recrystallized from ethanol. The dried product (45% conversion) is an amber solid, m.p. 66°-69° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:33]([CH2:32][CH:29]2[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]2)=[O:34])[CH:7]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (400 mg) was dissolved in dimethylformamide (4.0 ml) under nitrogen atmosphere. To the solution were added 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]acetic acid (487 mg), triethylamine (0.335 ml) and BOP reagent (1.06 g) at room temperature, followed by stirring at 60° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by silica gel column chromatography (eluent; ethyl acetate:heptane=1:2 to 1:1) to provide the titled compound (328 mg, 43%) as pale yellow powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[C:26](Cl)([CH3:28])=[O:27].C([O-])(O)=O.[Na+]>C1COCC1>[C:26]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1)(=[O:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A solution of tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (219 mg, 0.62 mmol) in THF (10 ml) was treated with AcCl (53 μl, 0.75 mmol) and stirred at room temperature for 1 hour. More AcCl (200 μl) was added and stirred for a further hour. Sat. NaHCO3 solution was added and the layers separated. The organic extract was washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (247 mg, 100%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>N1C=CC=CC=1>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21]([NH:13][C:10]2[N:9]=[CH:8][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:12][CH:11]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccc(N2CCCCC2)cn1
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(N2CCCCC2)cn1
Temperature: 50 °C
Yield: 25.6 %

Procedure:
3,4,5,6-Tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine (0.19 g) and 3-chloro-2-methylbenzenesulfonyl chloride (0.24 g) were dissolved in pyridine (4 mL) and heated at 50° C. over night. The mixture was concentrated in vacuo, taken up in ethyl acetate and extracted with 1M Cu(II)SO4 solution. The organic layer was washed once again with Cu(II)SO4 solution, dried over Na2SO4 and evaporated in vacuo. The product was purified by flash chromatography on silica gel (gradient of ethyl acetate in heptane) to give 3-chloro-2-methyl-N-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-benzenesulfonamide (0.1 g) as a light brown foam. MS (ESI−): 364.0 ([M−H]−).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[CH:4]=1.BrCC1CCCCO1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[N:7]1[O:8][N:9]=[C:5]2[CH:4]=[C:3]([CH2:2][N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]4([C:40]5[C:31](=[CH:32][C:33]6[O:38][CH2:37][CH2:36][O:35][C:34]=6[CH:39]=5)[O:30][CH2:29]4)[C:21]3=[O:41])[CH:11]=[CH:10][C:6]=12
Reactant: BrCc1ccc2nonc2c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc3nonc3c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-(bromomethyl)-2,1,3-benzooxadiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(2,1,3-benzoxadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (44%) as a colorless solid: mp 164-166° C.; 1H NMR (300 MHz, CDCl3) δ7.86 (d, J=9.3 Hz, 1H), 7.75 (s, 1H), 7.43-7.37 (m, 1H), 7.25-7.19 (m, 2H), 7.08 (dd, J=7.5, 7.5 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.23 (s, 1H), 5.13 (d, J=16.2 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.94 (d, J=16.2 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.24-4.10 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.7, 155.3, 149.0, 148.7, 144.8, 141.4, 139.7, 138.4, 132.0, 131.4, 129.0, 124.3, 124.0, 120.6, 117.8, 113.9, 111.4, 108.8, 99.6, 80.1, 64.5, 63.9, 58.0, 44.0; MS (ES+) m/z 427.9 (M+1).
Reaction SMILES: CS([O-])(=O)=O.[F:6][C:7]([F:33])([C:18]1N2N=C(C3C=NN(C)C=3)C=CC2=[N:20][N:19]=1)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2.C(=O)([O-])[O-:35].[Na+].[Na+]>C(OCC)(=O)C.O>[F:6][C:7]([F:33])([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:18]([NH:19][NH2:20])=[O:35]
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1

Procedure:
Methanesulphonate (mesylate) salt of the compound of formula (I) (8.7 g) is dissolved in ethyl acetate/water mixture (50/50 vol/vol; 400 mL). Addition of sodium carbonate (2.5 g) liberates the free base form of the compound of formula (I) which crystallises from the solvent mixture. The solids are filtered, washed and dried at 50° C. to provide 6.53 g of Form III.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].Cl.[CH3:29][S:30]([OH:33])(=[O:32])=[O:31].C1C=CC=CC=1>C(O)C>[CH3:29][S:30]([OH:33])(=[O:32])=[O:31].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[C:11]=2[C:10](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:9]1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2Cl)Cc2nncc(C(F)(F)F)c21
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2nncc(C(F)(F)F)c21

Procedure:
To a solution of 7-(2-chlorophenyl)-4-trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.335 g) and aminoguanidine hydrochloride (165 mg) in ethanol (10 ml) were added methanesulfonic acid (0.3 ml) and benzene (10 ml), and the mixture was refluxed for 80 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in acetone, and to the solution was added methanesulfonic acid (0.15 ml). Precipitated crystals were filtered, washed with acetone and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-trifluoromethyl-5,6,7,8-tetrahydrocinnoline methanesulfonate (Compound 136) (0.240 g) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][C:4]([NH:6][NH:7][C:8]([O:10][CH3:11])=[O:9])=[S:5].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][S:5]/[C:4](=[N:6]\[NH:7][C:8]([O:10][CH3:11])=[O:9])/[CH2:3][C:2]([CH3:13])([CH3:12])[CH3:1]
Reactant: C=CC(=O)OC
Reactant: COC(=O)NNC(=S)CC(C)(C)C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)CCS/C(CC(C)(C)C)=N\NC(=O)OC
Yield: 92.7 %

Procedure:
A mixture of 20.5 g of 2-(3,3-dimethyl-1-thioxobutyl)hydrazinecarboxylic acid, methyl ester, 12.92 g of methyl acrylate, 1 ml of triethylamine and 300 ml of dry benzene was heated at reflux for 8 hours, then cooled and concentrated in vacuo. The residual oil was chromatographed through a bed of hydrous magnesium silicate, eluting with dichloromethane and evaporated, giving 27 g of (Z)-[1-[(3-methoxy-3-oxopropyl)thio]-3,3-dimethylbutylidene]hydrazinecarboxylic acid, methyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].C(OCC)(=O)C>C(O)C>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: NCCCCN
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCCCCNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,4-diaminobutane (8.8 g) in ethanol (100 ml) at room temperature was added a solution of 4-chloro-3-nitropyridine in ethanol (50 ml). The mixture was stirred at room temperature for 30 minutes, poured into ethyl acetate (400 ml), and then washed with water (3×150 ml). The aqueous phases were back-extracted with methylene chloride (3×120 ml) and all the organic phases were combined, dried over Na2SO4, filtered and evaporated under vacuum. The residue was chromatographed on silica eluting with a mixture of methylene chloride and methanol containing 1% ammonium hydroxide. The fractions containing the product were combined and evaporated under vacuum to give the title compound, (4.2 g), which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[N:10]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[C:18](=O)([O-])[O-].[Cs+].[Cs+].ClCI>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[O:8][CH2:18][N:13]3[C:12]4[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=4[N:10]=[C:9]3[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ncc(Br)cc1-c1nc2c([nH]1)CCCC2
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cnc2c(c1)-c1nc3c(n1CO2)CCCC3
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of 5-bromo-3-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)pyridin-2-ol (0.3 g, 1.02 mmol) and Cesium carbonate (0.663 g, 2.04 mmol) in DMF (10 mL), was heated to 100° C. Then chloroiodomethane (215 mg, 1.22 mmol) was added by dropwise, the react mixture was stirred at 100° C. for 30 minutes. The solvent was removed off and the resulting residue was purified using flash column (petroleum ether:EtOAc 3:1) to provide 2-bromo-8,9,10,11-tetrahydro-6H-benzo[4,5]imidazo[1,2-c]pyrido[3,2-e][1,3]oxazine (50 mg, yield 16%) as a solid. 1HNMR (400 MHz, CDCl3): δ=8.30 (d, J=2.4 Hz, 1H), 8.20 (d, J=2.4 Hz, 1H), 5.87 (s, 2H), 2.66˜2.68 (m, 2H), 2.58˜2.61 (m, 2H), 1.87˜1.88 (m, 4H). MS (M+H)+: 306/308.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:28]=[O:29].[Se](=O)=[O:31]>C(OCC)(=O)C.CCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:31])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:28]=[O:29]
Reactant: O=[Se]=O
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCCBr)c(OC)cc23)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCBr)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 6-(3-bromo-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (70 mg, 0.15 mmol) was added selenium dioxide (132 mg, 1.20 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL), saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-(3-bromo-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (62 mg, 88% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Cl.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][N:13]1[CH2:18][CH2:17][N:16]([CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:15][CH2:14]1
Reactant: COc1ccc(CCl)cc1OC
Reactant: C1CNCCN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2CCN(Cc3ccc(OC)c(OC)c3)CC2)cc1OC
Temperature: 97.5 °C
Reaction time: 8 h

Procedure:
3,4-dimethoxybenzyl chloride (10 g, 53.6 mmol) was combined with piperazine (2.3 g, 26.8 mmol) in anhydrous DMF (30 ml) and heated with stirring under nitrogen for 8 hours at 95-100° C. The cooled reaction mixture was diluted with water (100 ml) and acidified to pH 1 with concentrated hydrochloric acid. The white precipitate was collected by filtration and washed with water (50 ml). The solid was re-suspended in water (50 ml) and the pH adjusted to >9 by the dropwise addition of sodium hydroxide solution (50% NaOH in water). The resultant white solid was collected by filtration and dried under vacuum at 50° C., yield 10 g.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[C:44]([O:52][C:53](=[O:55])[CH3:54])=[C:45]([CH:49]=[CH:50][CH:51]=2)[C:46](O)=[O:47])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[C:44]([O:52][C:53](=[O:55])[CH3:54])=[C:45]([CH:49]=[CH:50][CH:51]=2)[C:46]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([C:2]([F:13])([F:1])[F:14])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[O:47])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.9 %

Procedure:
4-(Trifluoromethylsulfonyl)aniline (0.361 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.084 g, 0.144 mmol, 27%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[N:19]3[CH:20]=[C:21]([O:24][C@H:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C@@H:28]([NH:35][C:36]([NH:38][C:39]5[N:40]([C:48]6[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=6)[N:41]=[C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:43]=5)=[O:37])[CH2:27][CH2:26]4)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:44]([C:42]1[CH:43]=[C:39]([NH:38][C:36]([NH:35][C@@H:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:25]([O:24][C:21]3[CH:22]=[CH:23][C:18]4[N:19]([C:15]([CH2:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[N:16][N:17]=4)[CH:20]=3)[CH2:26][CH2:27]2)=[O:37])[N:40]([C:48]2[CH:49]=[CH:50][C:51]([CH3:54])=[CH:52][CH:53]=2)[N:41]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CC5CCN(C(=O)OC(C)(C)C)CC5)n4c3)c3ccccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CC5CCNCC5)n4c3)c3ccccc32)cc1

Procedure:
An orange solution of Intermediate 22c (155 mg, 0.211 mmol) and TFA (0.157 mL, 2.11 mmol) in DCM (3 mL) was stirred at RT for 3 h. The solution was concentrated in vacuo, redissolved in MeOH (1 mL), applied to an SCX-2 cartridge (2 g) and washed with MeOH (15 mL). The product was eluted with 2M NH3 in MeOH (15 mL); concentration in vacuo left the title compound as a pale brown solid (116 mg, 87%). LCMS (Method 3): Rt 2.90 min, m/z 633 [MH+].
Reaction SMILES: C([O-])(=O)C.[NH4+].[N+:6]([CH3:9])([O-:8])=[O:7].[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:21]=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[CH2:10]([O:17][C:18]1[CH:19]=[C:20](/[CH:21]=[CH:9]/[N+:6]([O-:8])=[O:7])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCCCOc1ccc(C=O)cc1OCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COCCCOc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
Ammonium acetate (6.10 g, 79.1 mmol) and nitromethane (8.93 mL, 165 mmol) were added to a solution of 3-(benzyloxy)-4-(3-methoxypropoxy)benzaldehyde described in Production Example 32-2 (19.8 g, 65.9 mmol) in acetic acid (52.8 mL) under nitrogen atmosphere at room temperature. The liquid mixture was stirred under a thermal condition of 130° C. for 2 hours. The reaction liquid was allowed to stand to cool to room temperature, then the precipitate was collected by filteration and washed with ethanol to quantitatively obtain the title compound.