Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:23][S:24][C:25]1[S:29][C:28]([C:30]([OH:32])=O)=[C:27]2[CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:26]=12.C(N(C(C)C)CC)(C)C.[C:47]([O:51][C:52]([N:54]([CH2:62][C:63]1[CH:64]=[C:65]([CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[CH:66]=[CH:67][CH:68]=1)[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[O:53])([CH3:50])([CH3:49])[CH3:48]>CN(C)C=O>[C:58]([O:57][C:55]([N:54]([CH2:62][C:63]1[CH:64]=[C:65]([CH:69]2[CH2:70][CH2:71][N:72]([C:30]([C:28]3[S:29][C:25]([S:24][CH3:23])=[C:26]4[C:36](=[O:37])[CH2:35][CH2:34][CH2:33][C:27]=34)=[O:32])[CH2:73][CH2:74]2)[CH:66]=[CH:67][CH:68]=1)[C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:53])=[O:56])([CH3:59])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCNCC2)c1)C(=O)OC(C)(C)C
Reactant: CSc1sc(C(=O)O)c2c1C(=O)CCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1sc(C(=O)N2CCC(c3cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)CC2)c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (120 mg, 0.38 mmol) was added to a room temperature solution of 3-methylsulfanyl-4-oxo-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (88 mg, 0.36 mmol) and diisopropylethylamine (140 mg, 1.08 mmol) in dimethylformamide (2 mL), under nitrogen. The reaction mixture was stirred for 10 minutes at room temperature before adding a solution of 4-[3-(N,N-di-tert-butoxycarbonylaminomethyl)phenyl]piperidine (140 mg, 0.36 mmol) and diisopropylethylamine (140 mg, 1.08 mmol) in dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 16 hours, concentrated to dryness in vacuo, and subjected to dry flash column chromatography on silica with 50:50, dichloromethane:ethyl acetate. 1-{1-[4-(3-(N,N-di-tert -butoxycarbonylaminomethyl)phenyl)-piperidin-1-yl]-methanoyl}-3-methylsulfanyl-6,7-dihydro-5H-benzo[c]thiophen-4-one was isolated as a colorless oil (177 mg). The intermediate was dissolved in dichloromethane (20 mL), cooled at 0° C., and treated with trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 hours, and concentrated to dryness in vacuo. The residue was dissolved in 20% acetonitrile/water [containing 0.1% trifluoroacetic acid] (9 mL) and purified by preparative reverse-phase HPLC (C-18, 10 micron reverse-phase column), eluting with 10% to 100% acetonitrile/water (containing 0.1% trifluoroacetic acid). The product fractions were combined and the acetonitrile removed in vacuo. The aqueous residue was frozen and lyophilized to give the title compound as an amorphous white solid (122 mg, 64%). 1H NMR [(CD3)2SO]: δ 8.16 (br s, 3H, NH3+); 7.41-7.24 (m, 4H); 4.21 (br d, 2H); 4.03 (q, 2H); 3.18-3.02 (m, 2H); 2.91-2.72 (m, 3H); 2.59 (s, 3H); 2.53-2.41 (m, 2H); 1.98-1.90 (m, 2H); 1.90-1.79 (m, 2H); 1.68-1.50 (m, 2H). MS(Ion spray): 415 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][OH:8])=[NH:6].[CH:12]1([N:15]2[C:19]([CH2:20][CH:21]([CH3:25])[C:22](O)=O)=[CH:18][N:17]=[C:16]2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13]1.CCN=C=NCCCN(C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O>O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:22]([CH:21]([CH3:25])[CH2:20][C:19]3[N:15]([CH:12]4[CH2:14][CH2:13]4)[C:16]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)=[N:17][CH:18]=3)[O:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: N=C(NO)c1cccc(Cl)c1
Reactant: CC(Cc1cnc(-c2ccncc2)n1C1CC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(Cc1cnc(-c2ccncc2)n1C1CC1)c1nc(-c2cccc(Cl)c2)no1
Temperature: 120 °C
Yield: 38.4 %

Procedure:
3-chloro-N-hydroxy-benzamidine (486 mg, 2.85 mmol), 3-(3-cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propionic acid (702 mg, 2.59 mmol), EDCl (546 mg, 2.85 mmol) and HOBt hydrate (385 mg, 2.85 mmol) were mixed with DMF (20 ml) and stirred o.n. at r.t. The reaction was diluted with water and extracted with EA. The combined organic phase was successively washed with sat. aq. sodium bicarbonate, brine, dried (Na2SO4), filtered and concentrated in-vacuo. The residue was heated in DMF (10 ml) at 120° C. for 2 h. The reaction mixture was cooled to r.t., diluted with EA (50 ml), successively washed with water and brine, dried (Na2SO4), filtered and concentrated in-vacuo. The crude was purified via column chromatography using 2% MeOH in DCM to isolate the title compound (404 mg). 1H-NMR: 8.69 (dd, 2H), 8.09 (m, 1H), 7.96 (d, 1H), 7.67 (dd, 2H), 7.46 (m, 2H), 6.94 (s, 1H), 3.66 (m, 1H), 3.48 (m, 1H), 3.31 (m, 1H), 3.16 (m, 1H), 1.59 (d, 3H), 1.19 (m, 2H), 0.72 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: CC(C)(C)N
Product: CCOC(=O)c1cnc(Cl)cc1NC(C)(C)C
Yield: 60 %

Procedure:
A solution of ethyl 4,6-dichloronicotinate (10 g, 45.7 mmol) in tert-butylamine (100 mL) was stirred at 50° C. for 10 h. The solvent was removed under reduced pressure and the residue was suspended in H2O and extracted with EtOAc (3×100 mL). The organics were washed with brine, dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to provide ethyl 4-(tert-butylamino)-6-chloronicotinate (7 g, 60% yield). 1HNMR (400 MHz, DMSO-d6): δ 8.53 (s, 1 H), 8.39 (s, 1 H), 6.80 (s, 1 H), 4.25 (d, J=7.2 Hz, 2H), 1.37 (s, 9 H), 1.27 (t, J=7.2 Hz, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[CH3:11][O:12][C:13]1[C:18](B(O)O)=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.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>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:18]1[C:13]([O:12][CH3:11])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: COc1ncccc1B(O)O
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncccc1-c1cc(C=O)ccc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol), (2-methoxypyridin-3-yl)boronic acid (1.2 g, 7 mmol) and sodium hydrogen carbonate (1.5 g, 15 mmol) was stirred in dioxane (20 mL) and water (8 mL). The mixture was degassed for 10 minutes, then tetrakis(triphenylphosphine)palladium (0) (0.130 g, 0.1 mol) was added. The reaction mixture was stirred at 100° C. for 1 hour then cooled and concentrated in vacuo. The resulting residue was partitioned between EtOAc (60 mL) and water (15 mL), dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography eluting with 20% EtOAc in heptane to afford the title compound as a white solid (0.85 g).
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:9][CH2:8][CH2:7]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][CH2:5][C@@H:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:9][CH2:8][CH2:7]1
Reactant: CC(=O)OC[C@@H]1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CO)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
A mixture of (5R)-5-acetyloxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.49 g), potassium carbonate (1.11 g) and methanol (15 ml) is stirred at room temperature for 20 minutes. The reaction solution is poured into water, and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate, and concentrated under reduced pressure to give (5S)-5-hydroxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.33 g).
Reaction SMILES: CC1NC([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=C(C)N=1.I[C:20]1[NH:24][C:23]([C:25]2([CH3:29])[CH2:28][O:27][CH2:26]2)=[N:22][C:21]=1[CH3:30].IC1NC(C)=NC=1C>>[CH3:18][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:20]1[NH:24][C:23]([C:25]2([CH3:29])[CH2:28][O:27][CH2:26]2)=[N:22][C:21]=1[CH3:30]
Reactant: Cc1nc(C2(C)COC2)[nH]c1I
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C3(C)COC3)nc2C)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except 5-iodo-4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 301 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:27][O:28][CH2:29][CH2:30][OH:31]>C(Cl)Cl.C(O)(=O)C>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C:11]3([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH2:13][CH2:12]3)=[N:15][N:16]=2)[N:19]=1)\[CH3:24]
Reactant: NOCCO
Reactant: CC(=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: C/C(=N\OCCO)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1

Procedure:
A solution of 1-(3-(1-(quinolin-6-yl)cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (30 mg, 0.09 mmol) (59.4) and 2-aminooxy-ethanol hydrochloride (intermediate S) (14 mg, 0.18 mmol) in 4 mL of DCM and 0.5 mL of acetic acid was stirred at 40° C. overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with a EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.84 (t, 1H), 8.30 (d, 1H), 8.25 (d, 1H), 7.93-7.91 (m, 2H), 7.71-7.68 (m, 2H), 7.51 (dd, 1H), 4.73 (t, 1H), 4.23 (t, 2H), 3.65 (q, 2H), 2.02 (s, 3H), 1.78-1.75 (m, 2H), 1.68-1.64 (m, 2H). LCMS (method A): [MH]+=389, tR=4.55 min.
Reaction SMILES: C(C1C=CC(C2/C(=C/C=C3/N(CCCS([O-])(=O)=O)C4C(C/3(C)C)=CC(S([O-])(=O)=O)=CC=4)/CCCC=2C=CC2C(C)(C)C3C(N=2)=[N+](CCCS([O-])(=O)=O)C=CC=3)=CC=1)(O)=O.[Na+:60].[Na+].Cl/[C:63](/[CH:90]=[CH:91]/[CH:92]=[C:93]1\[C:94]([CH3:112])([CH3:111])[C:95]2[C:96](=[N:110]\1)[N:97]([CH2:102][CH2:103][CH2:104][CH2:105][S:106]([O-:109])(=[O:108])=[O:107])[CH:98]=[C:99]([Cl:101])[CH:100]=2)=[CH:64]\[CH:65]=[CH:66]\[C:67]1[C:75]([CH3:77])([CH3:76])[C:74]2[C:69](=[CH:70][CH:71]=[C:72]([S:78]([O-:81])(=[O:80])=[O:79])[CH:73]=2)[N+:68]=1[CH2:82][CH2:83][CH2:84][CH2:85][S:86]([O-:89])(=[O:88])=[O:87].[Na+].[Na+].[C:115]([C:118]1[CH:119]=[C:120](B(O)O)[CH:121]=[CH:122][CH:123]=1)([OH:117])=[O:116]>>[C:115]([C:118]1[CH:119]=[C:120](/[C:63](/[CH:90]=[CH:91]/[CH:92]=[C:93]2\[C:94]([CH3:112])([CH3:111])[C:95]3[C:96](=[N:110]\2)[N:97]([CH2:102][CH2:103][CH2:104][CH2:105][S:106]([O-:109])(=[O:108])=[O:107])[CH:98]=[C:99]([Cl:101])[CH:100]=3)=[CH:64]\[CH:65]=[CH:66]\[C:67]2[C:75]([CH3:77])([CH3:76])[C:74]3[C:69](=[CH:70][CH:71]=[C:72]([S:78]([O-:81])(=[O:79])=[O:80])[CH:73]=3)[N+:68]=2[CH2:82][CH2:83][CH2:84][CH2:85][S:86]([O-:89])(=[O:87])=[O:88])[CH:121]=[CH:122][CH:123]=1)([OH:117])=[O:116].[Na+:60].[Na+:60]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C/C(Cl)=C/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: CC1(C)C(/C=C/C2=C(c3ccc(C(=O)O)cc3)/C(=C/C=C3/N(CCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=Nc2c1ccc[n+]2CCCS(=O)(=O)[O-]
Agent: CC1(C)C(C=CC2=C(c3ccc(C(=O)O)cc3)/C(=C/C=C3/N(CCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=Nc2c1ccc[n+]2CCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C/C(=C/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C)c1cccc(C(=O)O)c1

Procedure:
Compound 43 is prepared analogously to compound 17 (Example 17), except with compound 42 and m-carboxyphenyl boronic acid as starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C:5](Cl)=[O:6])[CH3:2].[C:9]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:25]([CH3:29])=[CH:26][C:27]=2[Br:28])[NH2:24])=[C:14]([CH2:32][CH2:33][CH3:34])[C:13]=1[OH:35])(=[O:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:8])[C:5]([NH:24][C:23]1[C:25]([CH3:29])=[CH:26][C:27]([Br:28])=[C:21]([O:20][CH2:19][CH2:18][CH2:17][O:16][C:15]2[CH:30]=[CH:31][C:12]([C:9](=[O:11])[CH3:10])=[C:13]([OH:35])[C:14]=2[CH2:32][CH2:33][CH3:34])[CH:22]=1)=[O:6])[CH3:2]
Reactant: CCCc1c(OCCCOc2cc(N)c(C)cc2Br)ccc(C(C)=O)c1O
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCCCOc2cc(NC(=O)C(=O)OCC)c(C)cc2Br)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In the course of approximately 5 minutes a solution of 12.3 ml of chloro-oxalic acid ethyl ester in 30 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 43.6 g (100 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylaniline and 15.3 ml of triethylamine in 400 ml of methylene chloride and the whole is then stirred for a further 90 minutes at room temperature. The reaction mixture is poured onto ice-water and the organic phase is separated off, washed with water, dried over sodium sulphate and concentrated under reduced pressure. Crystallisation from ethyl acetate/ether/petroleum ether yields N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylphenyl}-oxamic acid ethyl ester having a melting point of 100°-102°.
Reaction SMILES: C(Br)CCC.[Li].Br[C:8]1[C:9]2[C:14]([N:15]=[C:16]3[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]3)=[CH:13][CH:12]=[CH:11][CH:10]=2.I[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1>CCOCC.[Co](Cl)Cl>[CH:27]([C:26]1[CH:29]=[CH:30][C:23]([C:8]2[C:9]3[C:14]([N:15]=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:24][CH:25]=1)=[CH2:28]
Reactant: Brc1c2ccccc2nc2ccccc12
Reactant: C=Cc1ccc(I)cc1
Agent: Cl[Co]Cl
Agent: [Li]
Solvent: CCOCC
Solvent: CCCCBr
Product: C=Cc1ccc(-c2c3ccccc3nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
A solution of butyl lithium in ether was obtained by reacting a solution consisting of 137 g of butyl bromide and 200 ml of ether with a suspension consisting of 17 g of lithium and 400 ml of ether by the use of the same apparatus as that used in Referential Example 1. This solution was added dropwise to 300 ml of an ether solution containing 180 g of 9-bromoacridine at 0°-5° C., and the mixture was then warmed gradually to room temperature and stirred for further 3 hours. To the mixture was added dropwise 322 g of p-iodostyrene diluted with 300 ml of ether in the presence of cobalt chloride with stirring in a nitrogen gas stream, and the mixture was then refluxed for 5 hours. The reaction mixture was poured onto hydrochloric acid-ice and stirred. The organic layer was extracted with ether, and the extract was dried over anhydrous sodium sulfate. The solvent was then distilled off to obtain yellowish white crystals. The crystals were purified by alumina column chromatography to obtain 75.6 g of 9-(p-vinylphenyl)acridine, yield 38.4%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>C1COCC1>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][NH:37][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[N:3]=2)=[CH:40][CH:41]=1
Reactant: NCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a suspension of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (10 g, 24.71 mmol) and Hunig's Base (8.63 mL, 49.4 mmol) in THF (100 mL) was added 4-(aminomethyl)phenol (3.19 g, 25.9 mmol). The resulting mixture was refluxed for 1 hour. After cooling to rt, the solvent was removed and the crude product was purified by silica gel chromatography using 20-40-100% EtOAc/Hexanes to give tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (10.3 g, 85%) as white solid.
Reaction SMILES: [I:1]Cl.[N+:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)([O-:5])=[O:4].O>C(O)(=O)C>[I:1][C:11]1[CH:12]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: ClI
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1I
Yield: 107.6 %

Procedure:
A solution of iodine monochloride (23.54 g) in acetic acid (50 ml) is added dropwise over an hour to a stirred solution of p-nitroaniline (20 g). After stirring for another hour, the dark mixture is poured into water (1 liter), the precipitated yellow solid is collected and dried to afford 41.15 g title product, m.p. 90°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>CO.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: BrCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OCCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-4-hydroxyphenylacetate and 1,4-dibromobutane (0.021 g, 0.044 mmol) in 0.5 mL of methanol was added 5N NaOH soln (0.04 mL, 5 eq) at rt. The reaction mixture was heated initially with a heat gun to reflux in order to dissolve the starting material. After heating, the reaction mixture stirred at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc and 0.1N HCl (5 mL). The organic layer was separated from the aqueous portion, and washed with 0.1N HCl (5 mL) followed by 10 mL brine. The organic layer was dried (MgSO4), filtered, and evaporated in vacuo to afford the title compound. This compound was taken forward without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:23][CH:24]=1.O>CN(C)C=O>[C:25]1([C:22]2[O:23][CH:24]=[C:20]([CH2:19][O:1][C:2]3[CH:15]=[CH:14][C:5]([CH2:6][CH:7]4[S:11][C:10](=[O:12])[NH:9][C:8]4=[O:13])=[CH:4][CH:3]=3)[N:21]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: ClCc1coc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)S1
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 5-(4-hydroxybenzyl)-2,4-thiazolidinedione (9.4 g) in N,N-dimethylformamide (80 ml) was added 60% sodium hydride in oil (3.4 g), and the mixture was stirred for 30 minutes. Then, a solution of 4-chloromethyl-2-phenyloxazole (9.6 g) in N,N-dimethylformamide (20 ml) was added dropwise thereto at room temperature. After being stirred at 70° C. for 1 hour, the reaction solution was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to give 5-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-2,4-thiazolidinedione (9.1 g, 47.4%). Recrystallization from ethanol yielded colorless needles. m.p. 188°-189° C. Elemental analysis for C20H16N2O4S; Calcd.: C, 63.15; H, 4.24; N, 7.36. Found: C, 63.19; H, 4.16; N, 7.23.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5].CN(P(N(C)C)(N(C)C)=O)C.C([Li])CCC.CON(C)[C:38](=O)[C@@H:39]([NH:41]C(=O)OC(C)(C)C)[CH3:40]>C1COCC1>[NH2:41][C@H:39]([C:40]1[N:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:4](=[O:5])[C:3]2[C:14]([CH:18]=1)=[CH:15][CH:16]=[CH:17][C:2]=2[Cl:1])[CH3:38]
Reactant: Cc1cccc(Cl)c1C(=O)NCCN1CCCC1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1CCN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-chloro-6-methyl-N-(2-(pyrrolidin-1-yl)ethyl)benzamide I-31 (1.33 g, 5.0 mmol, 1.0 eq) and HMPA (0.87 mL, 5.0 mmol, 1.0 eq) in THF (12.5 mL) at −60° C. under argon, n-butyllithium solution (2.5 M in hexanes, 5.0 mL, 12.5 mmol, 2.5 eq) was added dropwise while keeping the temperature below −60° C. The resulting mixture was stirred between −70° C. and −60° C. for 30 min. To this mixture, (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.39 g, 6.0 mmol, 1.2 eq) was added quickly. The resulting mixture was allowed to slowly warm to RT (over 1 h) and then stirred at RT for an additional 2 h. The reaction mixture was cooled to 0° C., quenched with water (5.0 mL), and then acidified with aqueous HCl (5 M) to adjust the pH to 5-6. The mixture was concentrated in vacuo. The residue was suspended in a mixture of MeOH (20 mL) and H2O (5.0 mL), concentrated HCl (10.0 mL) was added and the resulting mixture was stirred at reflux for 2 h. The mixture was cooled to −5° C. and basified with saturated aqueous NH4OH to adjust the pH to 8-9. The precipitate was filtered off and the filtrate was extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product (S)-3-(1-aminoethyl)-8-chloro-2-(2-(pyrrolidin-1-yl)ethyl)isoquinolin-1(2H)-one I-32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:32])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23](OC(=O)C)[CH:24]=[CH2:25])=[C:17]([CH3:30])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:31]=1.[C:33]1([P:39]2(=[O:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:32])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]=[CH:24][CH2:25][N:42]4[CH2:41][CH2:40][P:39](=[O:45])([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:44][CH2:43]4)=[C:17]([CH3:30])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:31]=1
Reactant: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Reactant: O=P1(c2ccccc2)CCNCC1
Product: Cc1c(C=CCN2CCP(=O)(c3ccccc3)CC2)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12

Procedure:
2-(2,6-Dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ5-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one was prepared following the procedure of Example 1 form acetic acid 1-[2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester and 4-phenyl-[1,4]azaphosphinane 4-oxide. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.38 (br s, 1H), 10.71 (br s, 1H), 7.90-7.60 (m, 9H), 7.56 (t, 1H, J=7.8 Hz), 7.22 (br d, 1H, J=15.3 Hz), 7.70-6.40 (br m, 1H), 4.23 (s, 3H), 4.18 (br m, 2H), 4.00-4.15 (br m, 4H), 2.60-2.40 (br n, 4H), 2.39 (s, 1H); ESMS (m/z): found, 606 (M+1)+.