Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([CH2:25][NH2:26])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][S:28]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([CH2:25][NH:26][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:32]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:33][CH:34]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CN)cc1OC
Product: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CNC(=O)c2ccc(NS(C)(=O)=O)cc2)cc1OC

Procedure:
In a manner similar to Preparation 3, react 4-(3-chlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-2-piperazinemethanamine(3.0 g, 7.9 mmol) with 4-[(methylsulfonyl)amino]benzoyl chloride (2.4 g, 10mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5](OC2C=CC=CC=2)=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[NH2:25][CH2:26][CH2:27][NH2:28]>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]([NH:25][CH2:26][CH2:27][NH2:28])=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NCCN
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccccc2)cc1Oc1ccccc1
Solvent: C1COCCO1
Product: Cl
Product: NCCNc1cc(Oc2ccccc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
6.83 gm of 6-chloro-4-nitro-1,3-diphenoxy-benzene were dissolved in 15 ml of dioxane, an excess of 1,2-diamino-ethane was added to the solution, and the mixture was heated for 12 hours at 70° C. Thereafter, the reaction mixture was worked up as in Example 3, and the reaction product was purified by recrystallization from ethanol. 6.1 gm (88% of theory) of the white crystalline compound of the formula ##STR10## having a melting point of 255° C. (decomp.) were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([O:18]CC)=[O:17])[O:13]2)=[CH:8][CH:7]=1.[CH2:23]([C:26]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]=1[OH:40])[CH2:24][CH3:25]>>[CH2:23]([C:26]1[CH:31]=[C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]=1[O:40][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([OH:18])=[O:17])[O:13]2)=[CH:8][CH:7]=1)[CH2:24][CH3:25]
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1O
Reactant: CCOC(=O)C1(CC)CCc2ccc(OCCCBr)cc2O1
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1OCCCOc1ccc2c(c1)OC(CC)(C(=O)O)CC2

Procedure:
The title compound was prepared from ethyl 7-(3-bromopropoxy)-2-ethylchromane-2-carboxylate and 2-propyl-4-(4-chlorophenoxy)phenol (U.S. Pat. No. 6,008,237) following the procedures described in Example 1, Steps B-C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26]>ClCCl.O>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cccnc2c1NCCCO
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of 4-chloro-3-nitro[1,5]naphthyridine (18.0 g, 85.9 mmol) in dichloromethane (220 mL) at room temperature was added triethylamine (15.6 mL, 112 mmol) and 3-amino-1-propanol (7.20 ML, 94.5 mmol). The solution was stirred for 4 hours, then was concentrated under reduced pressure to yield an orange solid. The solid was slurried in water (250 mL) for 30 minutes, isolated by filtration, washed with water (3×30 mL), and dried at 70° C. in a vacuum oven to afford 20.9 g of 3-[(3-nitro[1,5]naphthyridin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1Cl.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][C:47]([NH2:50])=[N:48][CH:49]=2)O1>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=3[C:44]3[CH:45]=[N:46][C:47]([NH2:50])=[N:48][CH:49]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3cc(C(F)(F)F)ccc3-c3cnc(N)nc3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 838 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromo-1-chloro-4-(trifluoromethyl)benzene in Step A and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine in Step B. MS (ESI): mass calcd. for C21H14F4N6, 426.12; m/z found, 427.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.36 (dd, J=2.1, 1.5, 1H), 8.10 (s, 2H), 8.05 (d, J=1.5, 1H), 7.90-7.85 (m, 1H), 7.81-7.77 (m, 1H), 7.74 (d, J=1.8, 1H), 7.66 (d, J=8.0, 1H), 7.13 (dd, J=2.6, 1.7, 1H), 7.11 (dd, J=6.5, 1.6, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:3]1.[CH:18](Br)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:18]([N:16]1[NH:15][N:14]=[C:13]([C:4]2[C:5](=[O:12])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:2]([CH3:1])[CH:3]=2)[NH:17]1)([CH3:20])[CH3:19]
Reactant: Cn1cc(-c2nnn[nH]2)c(=O)c2ccccc21
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)N1NN=C(c2cn(C)c3ccccc3c2=O)N1
Reaction time: 7 h

Procedure:
A mixture of 1-methyl-3-(1H-tetrazol-5-yl)-4-quinolone (0.74 g), isopropyl bromide (0.31 ml), anhydrous potassium carbonate (0.45 g) and butanone (30 ml) was boiled under reflux for 16 hours. More isopropyl bromide (0.5 ml) was added and boiling under reflux was continued for 7 hours. More isopropyl bromide (0.5 ml) was added and boiling under reflux was continued for a further 24 hours. The mixture was evaporated to dryness and the residue treated with water (30 ml). The solid product was collected by filtration and partially purified by high pressure liquid chromatography over silica gel using dichloromethane:methanol 95:5 as the eluent. The solid product was recrystallised from ethyl acetate:diethyl ether 3:2 to give the novel compound 3-(2-isopropyl-1H-tetrazol-5-yl)-1-methyl-4-quinolone, m.p. 134°-137°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][N:11]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[C:12]2=[O:17])=[O:6].[C:26](O)(=[O:48])[CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[O:25]=[C:19]1[CH:18]([N:11]2[CH2:10][C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][C:26](=[O:48])[CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH3:47])[C:12]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Reactant: NCCC(=O)Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCC(=O)Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The HCl salt of 3-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propanamide (0.1 mmol) is taken up in 5 mL of DMF along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 0.1 mmol), HATU (0.11 mmol) and DIEA (0.3 mmol). The resulting reaction mixture is stirred at room temperature for 4 h and then diluted with EtOAc (20 mL). The organic layer is washed with water (3×5 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by silica gel chromatography (95% CH2Cl2, 5% MeOH) affords (4Z,7Z,10Z,13Z,16Z,19Z)-N-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-oxopropyl)docosa-4,7,10,13,16,19-hexaenamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:15][CH2:14]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+:25].[ClH:26]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][CH2:18]3)=[N:10][N:9]=2)=[CH:6][CH:7]=1.[Na+:25].[Cl-:26]
Reactant: COC(=O)CN1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1
Product: [Cl-]
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetate (97.8 mg, 0.306 mmol) in ethanol (1 mL) was added 2 N NaOH (1 mL). The cloudy reaction suspension was stirred for 4 h until LCMS confirmed the reaction was complete. The mixture was treated with 0.7 mL 1 N HCl dropwise until pH 7. The solvent was evaporated and the residue triturated with ether. The precipitate was filtered, washed with ether and dried under high vacuum, yielding the title compound as a white solid as a NaCl salt (130 mg) which was used without further purification. 1H NMR (400 MHz, chloroform-d) δ ppm 8.10 (dd, J=9.03, 5.02 Hz, 2H) 7.33 (t, J=8.78 Hz, 2H) 3.47 (br. s., 4H) 3.30 (s, 2H) 3.43-3.55 (br. s., 2H) 2.28-2.45 (m, 2H) 2.07-2.28 (m, 2H). MS (m/z, MH+): 306.3
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH3:59][O:60][C:61]1[CH:69]=[C:68]([O:70][CH3:71])[CH:67]=[CH:66][C:62]=1[C:63](Cl)=[O:64]>>[CH3:59][O:60][C:61]1[CH:69]=[C:68]([O:70][CH3:71])[CH:67]=[CH:66][C:62]=1[C:63]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:64]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC)cc4OC)cc3)cc2C1=O
Yield: 73 %

Procedure:
The compound of example 155 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2,4-dimethoxy benzoyl chloride.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[NH:23]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]1.C(N(CC)CC)C>C(#N)C>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:9][CH:6]([N:23]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]3)[CH2:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OC1CCNC1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OC1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C1
Yield: 92.6 %

Procedure:
1-(Diphenylmethyl)azetidin-3-yl methanesulfonate (see J. Org. Chem.; 56; 1991; 6729; 310 mg, 0.98 mmol) was dissolved in acetonitrile (3.5 mL). Pyrrolidin-3-ol (104 mg, 1.2 mmol) and triethylamine (124 mg, 1.2 mmol) were added and the mixture was subjected to microwave single node heating for 10 minutes. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. The solution was washed with water, dried over MgSO4 and then the solvent was evaporated. There was obtained 280 mg (93%) of 1-[1-(diphenylmethyl)azetidin-3-yl]pyrrolidin-3-ol as an oil. 1H NMR (300 MHz, CDCl3): 1.6-1.8 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.6 (m, 2H), 2.6-2.8 (m, 1H), 2.9-3.0 (m, 2H), 3.1-3.2 (m, 1H), 3.3-3.4 (m, 2H), 4.3 (m, 1H), 4.4 (s, 1H), 7.1-7.5 (m, 10H); LCMS: m/z 309 (M+1)+.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[O:31]1[CH2:36]COCC1.C(N(CC)CC)C.C(Cl)(Cl)=O.[C:48]([CH2:50][CH2:51][NH2:52])#[N:49]>C1(C)C=CC=CC=1>[C:48]([CH2:50][CH2:51][NH:52][C:36]([NH:18][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:8]([N:7]3[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]3[CH3:1])[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=2)=[CH:20][CH:19]=1)=[O:31])#[N:49]
Reactant: C1COCCO1
Reactant: N#CCCN
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ccncn1)C2
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCC#N)cc2)nc2c1CCN(c1ccncn1)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline (0.0700 g, 0.000173 mol) in dry 1,4-Dioxane (1.50 mL, 0.0192 mol) was added Triethylamine (0.0266 mL, 0.000191 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.100 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added β-Cyanoethylamine (0.0764 mL, 0.00104 mol). The reaction mixture was stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.56 (s, 1H), 8.22 (d, J=8.8, 2H), 8.17 (s, 1H), 7.52 (d, J=8.8, 2H), 6.96 (d, J=5.5, 1H), 6.58 (t, J=5.9, 1H), 4.76 (d, J=18.3, 1H), 4.65 (d, J=18.0, 1H), 4.13 (d, J=6.6, 1H), 3.99 (s, 1H), 3.88 (d, J=11.3, 1H), 3.81-3.55 (m, 7H), 3.46-3.32 (m, 1H), 2.74 (d, J=10.3, 2H), 2.70 (t, J=6.4, 2H), 1.26 (d, J=6.6, 3H). LC/MS-m/z+500.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1.[CH:12]([O:15][CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH3:14])[CH3:13]>ClCCl.C(=O)([O-])O.[Na+]>[C:8]([O-:10])(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]/[CH:3]=[CH:2]\[CH2:7][CH2:6][CH2:27][CH2:28][CH2:23][CH2:22][CH2:16][CH3:17].[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:15][CH:12]([CH3:14])[CH3:13])[CH2:22][C:23]1[CH:24]=[CH:25][NH+:26]=[CH:27][CH:28]=1)[CH3:21]
Reactant: CCOC(=O)C(Cc1ccncc1)OC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Product: CCOC(=O)C(Cc1cc[nH+]cc1)OC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 119.8 %

Procedure:
6.0 g of m-chloroperbenzoic acid was added to a solution of 4.88 g ethyl 2-isopropoxy-3-(4-pyridyl)propanoate in dichloromethane (50 mL), followed by stirring at room temperature for 1.5 hours. After the reaction solution was diluted with saturated aqueous sodium hydrogencarbonate solution, the aqueous layer was extracted with dichloromethane for 3 times. The combined organic layer was dried over anhydrous sodium sulfate and then concentrated, to give 6.40 g crude 4-(3-ethoxy-2-isopropoxy-3-oxopropyl)-1-pyridinium oleate as a yellow oil.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[S:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:21][N:22]=1>>[C:23]([C:20]1[S:19][C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[N:22][N:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Product: CC(C)(C)c1nnc(N=C2SC[C@@H]3Cc4ccccc4CN23)s1
Yield: 40.6 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g) and 2-amino-5-tert.-butyl-1,3,4-thiadiazole (15.7 g) as the starting materials, (S)-3-[(5-tert.-butyl-1,3,4-thiadiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (7.0 g) is obtained in the form of white crystals, m.p.=137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:17]([NH:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.C(OCC)(=O)C>[S:8]1[C:4]2[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([NH:25][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:27]=3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: Nc1ccc2ncsc2c1
Reactant: O=C(Cl)c1cccc(NC(=O)c2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(=O)Nc2ccc3ncsc3c2)c1)c1ccccc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of 0.1 g of 6-aminobenzothiazole and 0.1 g of pyridine added to 5 ml of tetrahydrofuran and stirred at room temperature was introduced dropwise 0.2 g of 3-(benzoylamino)benzoyl chloride dissolved in 1 ml of tetrahydrofuran. The resulting solution was stirred at room temperature for 1 hour, and then ethyl acetate and 1N hydrochloric acid were added thereto for separating the organic phase. The organic phase was washed with saturated sodium hydrogen carbonate solution one time, and then dried over anhydrous magnesium sulfate. The solution was filtered off, the filtrate was collected, and the solvent was removed under a reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain 0.15 g of the desired product (Yield: 52%) as a white solid.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:13][C:14]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=[CH:16][C:15]=1[N:29]1[CH2:41][CH2:40][C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:31]=2[C:30]1=[O:50].Cl[C:52]1[CH:53]=[C:54]([NH:67][C:68]2[CH:77]=[C:71]3[CH2:72][N:73]([CH3:76])[CH2:74][CH2:75][N:70]3[N:69]=2)[C:55](=[O:66])[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[N:57]=1>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.O>[CH3:13][C:14]1[C:19]([C:52]2[CH:53]=[C:54]([NH:67][C:68]3[CH:77]=[C:71]4[CH2:72][N:73]([CH3:76])[CH2:74][CH2:75][N:70]4[N:69]=3)[C:55](=[O:66])[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:63])([CH3:65])[CH3:64])[N:57]=2)=[CH:18][CH:17]=[CH:16][C:15]=1[N:29]1[CH2:41][CH2:40][C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:31]=2[C:30]1=[O:50]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(n(COCC[Si](C)(C)C)c3ccccc23)C1=O
Reactant: CN1CCn2nc(Nc3cc(Cl)nn(COCC[Si](C)(C)C)c3=O)cc2C1
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: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(COCC[Si](C)(C)C)n2)cccc1N1CCc2c(n(COCC[Si](C)(C)C)c3ccccc23)C1=O
Temperature: 100 °C
Yield: 89.4 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (5 mL), water (1 mL) and sodium carbonate (143 mg, 1.35 mmol). After bubbling nitrogen through the resulting mixture for 30 min, 117c (240 mg, 0.451 mmol), 117e (185 mg, 0.451 mmol) and tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) were added, and the reaction mixture was heated at 100° C. for 3 h. After this time, the reaction was cooled to room temperature and partitioned between water (25 mL) and methylene chloride (50 mL). The organic layer was separated, washed with brine (75 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to a dark oil, which was purified by flash chromatography to afford an 89% yield (315 mg) of 117f as a yellow oil: 1H NMR (500 MHz, CDCl3) d 7.88 (s, 1H), 7.66 (d, 1H, J=8.0 Hz), 7.45 (m, 3H), 7.39 (t, 1H, J=8.0 Hz), 7.34 (d, 1H, J=8.0 Hz), 7.24 (t, 2H, J=8.0 Hz), 6.12 (d, 1H, J=10.5 Hz), 6.05 (d, 1H, J=10.5 Hz), 5.69 (s, 1H), 5.63 (d, 1H, J=10.5 Hz), 5.52 (d, 1H, J=10.5 Hz), 4.09 (m, 2H), 3.88 (m, 2H), 3.75 (m, 2H), 3.68 (s, 3H), 3.59 (m, 2H), 3.26-3.17 (m, 4H), 2.61 (m, 2H), 2.29 (s, 3H), 0.98 (t, 2H, J=8.0 Hz), 0.85 (t, 2H, J=8.0 Hz), −0.01 (s, 9H), −0.07 (s, 9H); MS (ESI+) m/z 781.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:45])[CH2:19][CH2:20][C:21]([NH:23][CH2:24][C:25]2[C:26]([NH:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:27]3[CH:35]=[N:34][N:33]([CH2:36][CH3:37])[C:28]3=[N:29][C:30]=2[CH2:31][CH3:32])=[O:22])=[CH:4][CH:3]=1.C[C@H:47]1[CH2:52][NH:51][CH2:50][CH2:49][N:48]1C(OC(C)(C)C)=O.C(O)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:48]3[CH2:49][CH2:50][NH:51][CH2:52][CH2:47]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:45])[CH2:19][CH2:20][C:21]([NH:23][CH2:24][C:25]2[C:26]([NH:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:27]3[CH:35]=[N:34][N:33]([CH2:36][CH3:37])[C:28]3=[N:29][C:30]=2[CH2:31][CH3:32])=[O:22])=[CH:4][CH:3]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(Cl)c(-c2cccc(C=O)c2)c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(Cl)c(-c2cccc(CN3CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.4 %

Procedure:
N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (37.8 mg. 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.18 mmol), acetic acid (3.6 mg, 0.6 mmol) and fitted with a magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered and purification was completed via reversed phase HPLC using the Gilson (acidic conditions with 0.1% TFA in the solvents). The product after HPLC purification was dissolved in 3 mL of MeOH and passed through a 0.5 g amine column (washed with 8 mL of MeOH) to afford 6.92 mg of the title compound (16.4%). LC-MS m/z 701 (M+H)+, 1.19 min (ret time).