Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.[CH3:29]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>C1COCC1.CN(C=O)C>[OH:2][C:3]1[CH:20]=[C:19]([C:21]([N:64]2[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]2)=[O:23])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:29])[C@H:14]([CH2:15][S:16]2(=[O:24])=[O:25])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)cc2c1[C@@H]1CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Reactant: CN1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN1CCN(C(=O)c2cc(O)c3c(c2)S(=O)(=O)C[C@@H]2[C@@]4(C)CCCC(C)(C)[C@@H]4CC[C@@]32C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
A mixture of (1R,10S,11S,16S)-3-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (61) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methylmorpholine (0.10 mL, 1.5 mmol) and 1-methylpiperazine (0.15 mL, 1.5 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1) to give (1R,10R,11S,16S)-3-hydroxy-1,11,15,15-tetramethyl-5-[(4-methyl piperazin-1-yl)-carbonyl]-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (89) (0.13 g, 54%) as a white solid. 1H NMR (CDCl3): δ 9.55 (s, 1H), 7.23 (d, 1H), 7.07 (d, 1H), 3.84 (m, 2H), 3.49 (m, 2H), 3.18 (m, 3H), 2.52 (m, 2H), 2.38 (m, 2H), 2.33 (s, 3H), 2.15 (d, 1H), 1.78-1.32 (m, 6H), 1.28 (s, 3H), 1.24-1.05 (m, 2H), 0.98 (m, 1H), 0.90 (s, 6H), 0.86 (m, 1H), 0.82 (s, 3H). MS m/z 489 (C27H40N2O4S+H+).
Reaction SMILES: [C:1](OC1C2C(=CC=C(C)C=2)N(CC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:28](=[O:37])[C:27]2=[O:38]>>[C:1]([O:38][CH:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=2)[N:29]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:28]1=[O:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: CC(C)CN1C(=O)C(=O)c2cc(Cl)ccc21
Product: CC(C)CN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 5-chloro-1-isobutylindoline-2,3-dione. 1H NMR δ 8.11 (d, 2H), 7.60 (dd, 1H), 7.52-7.32 (m, 4H), 6.80 (d, 1H), 6.10 (s, 1H), 3.75 (m, 2H), 1.72-1.57 (m, 1H), 1.01 (dd, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH2:20][CH2:21][N:22]([CH2:27][C:28]([OH:30])=[O:29])[CH2:23][C:24]([OH:26])=[O:25])[CH2:9][N:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=[O:13].C(OC([NH:42][CH2:43][CH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][NH-:51])[CH2:46][CH2:45]1)=O)(C)(C)C>C(OCC)C>[CH2:20]([N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH2:8][CH2:9][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:15][C:16]([OH:18])=[O:17])[CH2:21][N:22]([CH2:27][C:28]([OH:30])=[O:29])[CH2:23][C:24]([OH:26])=[O:25].[NH2:42][CH2:43][CH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][NH-:51])[CH2:46][CH2:45]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(C[NH-])CC1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: [NH-]CC1CCC(CN)CC1
Reaction time: 3 h

Procedure:
Subsequently, 95 ml of trifluoroacetic acid (produced by Wako Pure Chemical Industries, Ltd.) was added to 9.22 g of the DTPA-mono-(4-(N-tert-butoxycarbonylaminomethyl)cyclohexyl)methylamide obtained above, and, after stirring the mixture for 3 hours, the reaction mixture was added dropwise to diethyl ether to precipitate the reaction product. The reaction product precipitated was collected by suction filtration, and was dried under a reduced pressure, to obtain 11.0 g of DTPA-mono-(4-(aminomethyl)cyclohexyl)methylamide as the objective compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=3[F:30])[CH:14]=2)=[N:11][CH:12]=1.CC[N:33]([CH:37](C)C)[CH:34]([CH3:36])[CH3:35].ClC(Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:29]=[CH:28][C:26]([NH:27][C:37]([NH:33][CH:34]4[CH2:35][CH2:36]4)=[O:43])=[CH:25][C:24]=3[F:30])[CH:14]=2)=[N:11][CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: NC1CC1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 230.8 %

Procedure:
A 100 mL round bottom flask was charged with 319 (0.55 g, 1.3 mmol) and DIPEA (0.91 mL, 5.2 mmol) in dry tetrahydrofuran (55 mL) to give a colorless solution. The reaction mixture was cooled to 0° C. then triphosgene (0.154 g, 0.520 mmol) was added. The reaction mixture was stirred for 1 h at 0° C. then cyclopropylamine (1.8 mL, 26 mmol) was added. Finally the reaction mixture was stirred at r.t. for 3 h then concentrated. The residue was partitioned between water and ethyl acetate, resulting in the formation a thick white solid. This was isolated by suction filtration, rinsed with water and ethyl acetate, and dried in vacuo to give crude 320 (0.65 g, 1.2 mmol, 99% yield) which was used without further purification. MS: 507.2 (M+H).
Reaction SMILES: I[CH2:2][C:3]1[CH:8]=[CH:7][C:6](C)=[CH:5][C:4]=1[O:10][S:11]([CH3:14])(=[O:13])=[O:12].[CH3:15]C1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:37]([O:44][C:45]1[CH:50]=[C:49](I)[CH:48]=[C:47]([F:52])[C:46]=1[N:53]1[S:57](=[O:59])(=[O:58])[N:56]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:55](=[O:69])[CH2:54]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:37]([O:44][C:45]1[CH:50]=[C:49]([CH:48]=[C:47]([F:52])[C:46]=1[N:53]1[CH2:54][C:55](=[O:69])[N:56]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[S:57]1(=[O:59])=[O:58])[CH2:2][C:3]1[CH:8]=[C:7]([CH3:15])[CH:6]=[CH:5][C:4]=1[O:10][S:11]([CH3:14])(=[O:12])=[O:13])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C1CN(c2c(F)cc(I)cc2OCc2ccccc2)S(=O)(=O)N1COCc1ccccc1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: Cc1ccc(CI)c(OS(C)(=O)=O)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Zn]
Solvent: CN(C)C=O
Product: Cc1ccc(OS(C)(=O)=O)c(Cc2cc(F)c(N3CC(=O)N(COCc4ccccc4)S3(=O)=O)c(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Zinc dust (200 mg, 3.08 mmol) is added to a flask and heated with a heat gun under high vacuum to remove moisture. DMF (1.0 mL, freshly distilled) is added under argon. 1,2-Dibromoethane (0.02 mL) is added and heated with heat gun until bubbling is observed. After it is cooled to RT, TMSCl (0.02 mL) is added and the mixture is stirred at RT for 20 min. Then a solution of methanesulfonic acid 2-iodomethyl-5-methylphenyl ester (224 mg, 0.688 mmol) in DMF (0.6 mL, freshly distilled) is added and the mixture is heated at 40° C. for 45 min. Then it is cooled to RT. Pd2(dba)3 (20 mg, 0.02 mmol), P(o-tolyl)3 (28.4 mg, 0.10 mmol) is added followed by a solution of 5-(2-benzyloxy-6-fluoro-4-iodophenyl)-2-benzyloxymethyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one (200 mg, 0.344 mmol) in DMF (1.4 mL, freshly distilled). The mixture is stirred at RT for 2 h. ETOAc is added and it is filtered through Celite. The filtrate is then washed with 1N HCl solution, water and brine. It is then dried and concentrated. The residue is purified to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][CH:10]=[C:11]3[CH2:15][CH2:14][O:13][C:12]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl.CO>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:8]=[CH:9][CH:10]=[C:11]4[CH2:15][CH2:14][O:13][C:12]=34)[CH2:6][CH2:5]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1cc2c(c(N3CCNCC3)n1)OCC2
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-(piperazin-1-yl)-2,3-dihydro-furo[2,3-c]pyridine (0.96 g, 4.68 mmol) in dichloromethane (30 ml) and MeOH (0.8 ml) was added at room temperature commercially available trans-tert-butyl-4-(2-oxoethyl)-cyclohexylcarbamate (1.71 mg, 6.02 mmol) and triethylamine (1.02 g, 1.4 ml, 10 mmol) and the solution was allowed to stir for 30 min. Sodium triacetoxyboron hydride (1.91 g, 9.03 mmol) was added step wise and the mixture was allowed to stir for 4 h at room temperature. The solution was added to ice/2N sodium carbonate solution (50 ml), extracted with dichloromethane (2×30 ml). The combined organic layers were dried (MgSO4) and evaporated. The crude material (2.53 g) was purified by flash chromatography on silica gel (20% to 100% dichloromethane/dichloromethane-MeOH 9:1) to yield trans-(4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester as off-white solid (1.3 g, 65%), MS (ISP) m/z=431.5 [(M+H)+], mp 141° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1C(O)=O)=[O:7])(C)(C)C.C([N:45](CC)CC)C>C1C=CC=CC=1.O1CCOCC1>[NH2:45][CH:19]1[CH:18]([C:11]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=2[O:9][CH2:8][C:6]([OH:5])=[O:7])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]1[C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OC(C)(C)C)C(C(=O)O)C2c1ccc2c(c1)OCO2
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(N)C2c1ccc2c(c1)OCO2
Temperature: 75 °C
Yield: 45.2 %

Procedure:
(1RS,2SR,3RS)-3-(2-tert-butoxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (100 mg, 0.18 mmol), triphenylphosphonyl azide (0.03 ml, 0.18 mmol), and triethylamine (73 mg, 0.72 mmol) were dissolved in dry benzene (4 ml) and heated at 40° C. for 2 h and at 75° C. for 2 h. The reaction mixture was then partitioned between 1 N HCl and ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4 anhyd.), filtered and evaporated to give the corresponding isocianate as a colorless oil. After purification by column chromatography (silica gel, ethyl acetate/hexane 30:70), the isocianate (100 mg) thus obtained was dissolved in 1 M HC1 in dioxane (3 mL) and the mixture was heated at 80° C. overnight. The solvent was removed in vacuo, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and concentrated to give a colorless oil that was purified by HPLC (1:1 CNCH3 :H2O (containig 0.1% TFA)) to produce the desired product (40 mg, 42%) as an off-white solid, m.p. 181-182° C. (dec).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][N:17]([C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:16][CH2:15]3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=S(=O)(c1cccc2cnccc12)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 3 h
Yield: 70.9 %

Procedure:
In 50 ml of chloroform were added 2.77 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound 35 and 1.54 g of anhydrous potassium carbonate, and to the mixture was added dropwise 1.70 g of benzoyl chloride under cooling with ice, and the mixture was stirred at a temperature of 15° C. to 20° C. for three hours. The reaction solution was washed with a 1N aqueous sodium hydroxide solution, then with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom, the residue thus obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 2.7 g of 1-(5-isoquinolinesulfonyl)-4-benzoylpiperazine, i.e., Compound (58) in a yield of 71%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[O:40][CH3:41])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:17]3)[C:11]=2[Br:13])[C:6]([CH3:52])=[CH:5]1.C(N(CC)CC)C.[CH3:60][N:61](C)[CH:62]=[O:63]>>[Br:13][C:11]1[C:10]([CH2:14][O:15][CH:16]2[CH:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[CH2:17]2)=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][CH2:2][NH:1][C:62]([NH:61][CH3:60])=[O:63])[CH:5]=[C:6]2[CH3:52]
Reactant: CN(C)C=O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCN)c3c2Br)cc1
Solvent: CCN(CC)CC
Product: CNC(=O)NCCn1cc(C)c2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)c(Br)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 0.270 g of benzyl 3-[1-(2-aminoethyl)-7-bromo-3-methyl-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 76b) in 1.5 ml of N,N-dimethylformamide is cooled to 0° C. and admixed successively with 0.066 g of N-succinimidyl N-methyl carbamate and 0.043 ml of triethylamine. The reaction mixture is stirred at room temperature over 2 hours, subsequently poured onto water (40 ml) and extracted with dichloromethane (2×40 ml). The organic phases are washed successively with water (40 ml), 1M sodium hydrogencarbonate solution (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (2:1 EtOAc-heptane); Rt=5.76.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[N:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[S:55][CH2:56][CH2:57]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][CH2:57][CH2:56][S:55][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][N:49]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCCCSc1ccccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCSc4ccccn4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 4.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (73 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (110 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-pyridylsulfanyl)-1-propanol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (5 mg, yield 4%). Mass spectrometry value (ESI-MS, m/z): 494 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(Cl)c(Cl)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3,4-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.16 (d, J 8.4, 1H), 7.31 (s, 1H), 7.52 (d, J 8.4, 1H), 7.77 (t, J 7.8, 1H), 7.89 (d, J 6.5, 1H), 8.16 (d, J 8.1, 1H), 8.22 (d, J 6.4, 1H), 8.59 (d, J 6.2, 1H), 8.64 (t, J 5.8, 1H), 9.49 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].C([O-])(O)=O.[Na+].[Cl:50][C:51]1[C:56]([CH3:57])=[C:55](I)[CH:54]=[CH:53][N:52]=1>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C:26]([C:55]3[CH:54]=[CH:53][N:52]=[C:51]([Cl:50])[C:56]=3[CH3:57])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)ccnc1Cl
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)OC(C)(C)C)ccnc1Cl
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
To a solution of EXAMPLE 30A (1.22 g) in dioxane (4 mL), and aqueous NaHCO3 (2 mL) was added 2-chloro-4-iodo-3-methylpyridine (505 mg), and tetrakis(triphenylphosphine)palladium(0) (115 mg). The mixture was stirred at 120° C. for 20 minutes in a Biotage Initiator microwave reactor. The mixture was diluted with ethyl acetate (300 mL) and washed with water (3 times) and brine, and dried over Na2SO4. Filtration and evaporation of the solvent gave crude product which was loaded on a silica gel column and eluted with 20% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [OH2:1].[CH3:2][N+:3]1([O-])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[N+:10]([C:13]1[CH:22]=[CH:21]C=C2[C:14]=1[CH:15]=[CH:16]C(C=C)=N2)([O-:12])=[O:11]>C(O)(C)C.CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:1][CH:8]([N:3]1[C:4]2[C:14](=[C:13]([N+:10]([O-:12])=[O:11])[CH:22]=[CH:21][CH:5]=2)[CH:15]=[CH:16][CH2:2]1)[CH2:7][OH:6]
Reactant: O
Reactant: C=Cc1ccc2c([N+](=O)[O-])cccc2n1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc2c1C=CCN2C(O)CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
336 mg (2.5 mmol) of N-methylmorpholine-N-oxide hydrate and 10.22 ml of osmium tetroxide solution in isopropanol are added at 0° C. to a solution that consists of 3.18 g (15.88 mmol) of 5-nitro-2-vinylquinoline in 140 ml of acetone and 21 ml of water, and the reaction mixture is stirred for 24 hours at room temperature. Then, the solvent is removed in a vacuum, and the residue is taken up in ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution. The aqueous phase is extracted repeatedly with dichloromethane, diethyl ether and ethyl acetate. The combined organic phases are dried on sodium sulfate. After removal of the solvent and purification of silica gel with hexane-ethyl acetate (0-100%) as well as with ethyl acetate-methanol (0-20%), 1.64 g (44% of theory) of the product is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[CH2:19]([NH:24][CH2:25][C:26]1[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])[CH2:20][CH2:21][CH2:22][CH3:23]>C(OCC)(=O)C>[CH2:19]([NH:24][CH2:25][C:26]1[CH:31]=[C:30]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCNCc1cc(Br)ccc1OC
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCCNCc1cc(-c2ncc[nH]2)ccc1OC
Reaction time: 7 h
Yield: 58.6 %

Procedure:
Imidazole (11.8 g, 0.173 mol), potassium carbonate (0.147 mol), cuprous chloride (1.4 g, 0.014 mol), and N-methylpyrrolidone (270 ml) were added to N-pentyl-(5-bromo-2-methoxyphenyl) methylamine (38.0 g, 0.133 mol), and then the mixture was heated with stirring at 178°-182° C. for 7 hours. The reaction mixture was cooled and added with ethyl acetate (200 ml), and then, inorganic salts and the like were removed by filtration and the solvent was evaporated. The residue was extracted with ethyl acetate, and the extract was washed with 10% aqueous ammonia and then with saturated brine. After dryness over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gell C-300: 360 g, eluent: methyl alcohol/ethyl acetate=1/10 to 1/3) to give N-pentyl-(5-imidazolyl-2-methoxyphenyl)methylamine (21.3 g) as oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[C:7]([C:23]([OH:25])=O)=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:10][N:11]=1>C(Cl)(Cl)Cl.CN(C=O)C>[NH2:5][C:6]1[C:7]([C:23]([Cl:3])=[O:25])=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:10][N:11]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)Cl)n2)CC1
Temperature: 25 °C

Procedure:
Thionyl chloride (1.887 g, 1.157 mL, 15.86 mmol) was added to a solution of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carboxylic acid (1.25 g, 3.964 mmol) in chloroform (50 mL) and DMF (1 mL) and the resulting dark solution heated under reflux for 1 hour. The reaction mixture was allowed to cool to RT, concentrated in vacuo and taken through crude to the next stage.