Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([O:26]CC1C=CC=CC=1)=[O:25])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[NH:1]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
The substance [18] (81 g, 135.5 mM) was dissolved in ethanol (300 ml). 1 N NaOH (176.15 ml, 1.3 molar excess) was added dropwise at 0° C. during 30 minutes and the mixture was stirred at room temperature for three hours. The reaction mixture was neutralized by adding 1 N HCl at 0° C. and ethanol was distilled off in vacuo. Water (300 ml) was added to the aqueous layer, which was then washed twice with ether, and 1 N HCl (150 ml) was at 0° C. and the mixture was extracted with ethyl acetate (400 ml). The ethyl acetate layer was washed with water, dried with anhydrous magnesium sulfate and concentrated in vacuo. The thus-obtained oily material was dried in vacuo. The powder was reprecipitated with ether-hexane to obtain the substance [19] (65.0 g, yield: 94.5%).
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15](I)[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:15]2[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([C:1]34[CH2:8][CH:7]5[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]5)[CH2:10]3)[CH2:2]4)[CH:16]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(I)cc1C12CC3CC(CC(C3)C1)C2
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(Br)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 42.8 %

Procedure:
To a stirred solution of 2-(1-admantanyl)-4-iodo-1-methoxybenzene (0.19 g; 0.5 mmol) and 4-bromophenylboronic acid (0.1 g, 0.47 mmol) in 1,4-dioxane (10 ml) Pd(PPh3)4 (0.04 g) was added at 80° C., followed by the addition of the solution of NaHCO3 (0.2 g) in H2O (2 ml). The mixture was stirred at reflux for 2 h and the solvents were evaporated. The residue was diluted to 100 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4, filtered and the filtrate was evaporated to dryness to give The residue was purified by FCC (SiO2) to give the title product (0.08 g; 39%), as creamy gum. 1H-NMR (CDCl3) 1.77 (s, 6H); 2.07 (s, 3H); 2.12 (s, 6H); 3.86 (s, 3H); 6.92 (d, 1H, J=8.39 Hz); 7.34 (dd, 1H, J=2.42, 8.42 Hz), 7.38-7.42 (m, 3H); 7.50 (d, 2H, J=8.57 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH2:9](O)[CH2:10][OH:11].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1cncc(C2OCCO2)c1
Yield: 88.8 %

Procedure:
3-Pyridinecarboxaldehyde (3.00 mL, 31.8 mmol), ethylene glycol (2.66 mL, 47.7 mmol) and p-toluenesulfonic acid (302 mg, 1.59 mmol) were suspended in toluene (100 mL). The mixture was heated to reflux under a nitrogen atmosphere for 2 hours, during which produced water was removed by use of a Dean-Stark trap. Then, a saturated aqueous potassium carbonate solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate=1/1) to give 3-(1,3-dioxolan-2-yl)pyridine (4.27 g, yield: 89%).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[N:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=3[CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]2)[CH2:4][CH2:3][CH2:2]1.[ClH:36].O1CCOCC1>CO>[Cl:36][CH2:4][CH2:3][CH2:2][NH:1][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=2)[N:9]=[C:8]1[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=2[CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C(C)C)CC3)n2)ccc1F
Reactant: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(-c2cn(CCNCCCCl)c(C3CCN(c4ncnc(N)c4C(C)C)CC3)n2)ccc1F
Temperature: 40 °C
Reaction time: 72 h

Procedure:
To a solution of 6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropyl-pyrimidin-4-ylamine (70.0 mg; 0.15 mmol; 1.0 eq.) in methanol (0.5 ml), was added 4.0M HCl in dioxane (0.37 ml; 1.47 mmol; 10.0 eq.). The reaction mixture was stirred at 40° C. for 72 hr. After removal of the solvents, the crude was purified by prep HPLC to afford the title compound. LC-MS (M+H=515, obsd=515).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25](O)=[O:26])[N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([N:30](CC)CC)C.C(Cl)(=O)C(C)(C)C.CN>CN(C)C=O.O.O1CCCC1>[CH3:28][NH:30][C:25](=[O:26])[CH2:24][C@@H:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:14]2[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]12
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Agent: CN
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2c(sc(C)c2C)-n2c(C)nnc21
Temperature: -5 °C
Reaction time: 2 h

Procedure:
(S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (7.0 g) and triethylamine (2.73 ml) are added to a mixed solvent of dimethylformamide (70 ml) and tetrahydrofuran (30 ml). The mixture is cooled to -5° C., and pivaloyl chloride (2.38 ml) is dropwise added at said temperature. Ten minutes later, a solution of methylamine (0.69 g) in dimethylformamide (5 ml) is dropwise added at said temperature, and the mixture is stirred at room temperature for 2 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled away, and the residue is recrystallized from water/methanol to give 2.29 g of (S)-N-methyl-4-(4-chloro-phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a]-[1,4]diazepine-6-acetamide 1/4 hydrate, melting point 143°-145° C.
Reaction SMILES: Cl.[O:2]1[C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4][CH2:3]1.[F:20][C:21]([F:31])([F:30])[C:22]1[S:23][CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59]>CN(C=O)C.ClCCl.C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59].[O:2]1[C:7]2([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH2:6][N:5]([C:27]([C:25]2[N:26]=[C:22]([C:21]([F:31])([F:20])[F:30])[S:23][CH:24]=2)=[O:28])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: O=C(O)c1csc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1csc(C(F)(F)F)n1)N1CCOC2(CCNCC2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.594 g) and 2-(trifluoromethyl)thiazole-4-carboxylic acid (0.4 g) in DMF (10 mL) was treated with triethylamine (0.848 mL) and cooled to 0° C. HATU (1.003 g) was added and the mixture stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 40% ethyl acetate in isohexane to yield the product as the free base. This was dissolved in dichloromethane (40 mL) and treated with trifluoroacetic acid (10 mL) and then the mixture was allowed to stand at 20° C. for 1 hour. Toluene (60 mL) was added and the solvent removed under reduced pressure to afford the subtitled compound. Yield 0.740 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:4][CH:3]=1.Cl.[CH3:29][NH:30][CH3:31].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C(O)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:30]([CH3:31])[CH3:29])=[CH:3][CH:4]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(Br)cc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CN(C)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Yield: 52.9 %

Procedure:
A suspension of (S)-2-(4-bromophenyl)-1,4-di(t-butoxycarbonyl) piperazine (1.14 g, 2.59 mmol), N,N-dimethylamine hydrochloride (422 mg, 5.17 mmol), palladium acetate (23 mg, 0.10 mmol), 2-(di-t-butylphosphino)biphenyl(62 mg, 0.21 mmol), and sodium t-butoxide (845 mg, 8.80 mmol) in t-butanol (15 mL) was heated at 90° C. for 3 h. After dilution with ethyl acetate, the resulting solution was passed through a Celite column. The filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting 10-20% ethyl acetate-hexane to afford (S)-1,4-di(t-butoxycarbonyl)-2-(4-(N,N-dimethylamino) phenyl)piperazine (556 mg, 53%) as white crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[CH3:21][S-:22].O>CN(C=O)C>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])[C:6]1([CH:9]1[CH:10]([O:18][CH3:19])[CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][S:22][CH3:21])[OH:16])[CH3:8]
Reactant: C[S-]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC1C(O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
Fumagillol (3.00 g) was dissolved in DMF (6 ml), to which was added thiomethoxide (2.23 g). The mixture was stirred for 30 minutes, to which was added water to suspend the reaction. The product was extracted with isopropylether. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by means of a silica gel column chromatography (carrier 150 g, developing solvent : ethyl acetate - hexane=1:2), followed by recrystallization from hexane to afford 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (2.43 g:yield 69%) as colorless powder, m.p. 52° to 53° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12](C)[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[NH:12][C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3ncc4[nH]c(=O)n(-c5cn(C)nc5C)c4c3c2)cn1
Temperature: 105 °C
Reaction time: 1.5 h

Procedure:
A mixture of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage A.1, 49 mg, 0.137 mmol), 2-methoxypyridine-5-boronic acid (Sigma-Aldrich, Buchs, Switzerland, 26 mg, 0.170 mmol), and PdCl2(PPh3)2 (6 mg, 0.0085 mmol) in DMF (1.2 ml) and 1 M aqueous K2CO3 (0.343 ml) was stirred under argon at 105° C. for 1.5 h. The RM was cooled toll. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.46 min (Method A); M+H=387 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 11.66 (s, br, 1H), 8.72 (s, 1H), 8.33-8.26 (m, 1H), 8.16-8.10 (m, 1H), 8.09-8.01 (m, 1H), 7.91-7.84 (m, 1H), 7.81-7.74 (m, 1H), 7.51-7.43 (m, 1H), 6.98-6.91 (m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:37](Cl)(=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41]>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: CCCCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.025 ml pentanoyl chloride (0.2 mmol). After 2 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 89 mg yellow solid (93%). MS (ISP) 585.3 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[C:15]([C:22]([O:24]C)=[O:23])=[CH:14]2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].Cl>O1CCCC1>[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[C:15]([C:22]([OH:24])=[O:23])=[CH:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:6]
Reactant: COC(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2cc(C(=O)O)c3cccnc32)cc1

Procedure:
1.6 cm3 of a 10N sodium hydroxide solution were added to methyl 1-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate in 15 cm3 of tetrahydrofuran. After stirring at reflux of the solvent for 48 h, the reaction mixture was acidified with 2 cm3 of 10N hydrochloric acid and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, characterized by LC/MS (m/z 317 [MH]+), which was used directly in the following stage.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[N+:10]([C:13]1[CH:29]=[CH:28][C:16]([CH2:17][O:18][C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH:26]=[O:27])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:29]=[CH:28][C:16]([CH2:17][O:18][C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH:26]([OH:27])[C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=C[C@@H]1CCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: Ic1ncn2ccsc12
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC[C@H]1C(O)c1ncn2ccsc12
Yield: 65.9 %

Procedure:
7-[[(2S)-1-(4-Nitrobenzyloxycarbonyl)pyrrolidin-2-yl]hydroxymethyl]imidazo[5,1-b]thiazole (2.21 g) was prepared in the same manner as in step a) of Synthesis Example 1, except that 2.50 g of 7-iodoimidazo[5,1-b]thiazole and 2.32 g of (2S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine-2-aldehyde were used as the starting compounds.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][CH2:17][C:18]([N:20]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:19].[CH:57]1[CH:62]=[CH:61][C:60]([CH2:63][O:64][C:65]([NH:67][CH2:68][C:69](O)=[O:70])=[O:66])=[CH:59][CH:58]=1>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:21]([N:20]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:18](=[O:19])[CH2:17][O:16][C:69](=[O:70])[CH2:68][NH:67][C:65]([O:64][CH2:63][C:60]1[CH:59]=[CH:58][CH:57]=[CH:62][CH:61]=1)=[O:66])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CO
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COC(=O)CNC(=O)OCc1ccccc1
Yield: 84.9 %

Procedure:
A solution of DCC (2.1 g; 10.3 mmol) in CHCl3 (50 mL) was added dropwise to a solution of 2-hydroxy-N,N-dioctadecylacetamide (5 g; 8.6 mmol) and Z-glycine (2 g; 9.5 mmol) in CHCl3 (250 mL). DMAP (0.1 g; 0.9 mmol) was added to the resulting solution. After 1 h the reaction mixture was filtered and the solvent was evaporated. The crude was purified by flash chromatography (n-Hexane/EtOAc=7/3 (v/v)) to give the desired compound (5.6 g; 7.3 mmol). Yield 84%. HPLC: 99% (area %). K.F.: <0.1%. The 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([NH:12][C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[CH2:14]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28]>CN(C=O)C>[Cl:3][C:4]1[CH:11]=[C:10]([N:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[CH2:14]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Clc1ccccc1CBr
Reactant: CN1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C[C@@H](N(Cc2ccccc2Cl)c2ccc(C#N)c(Cl)c2)CC1=O
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
NaH (60% in mineral oil, 0.010 g, 0.26 mmol) was added to a solution of 2-chloro-4-{[(3S)-1-methyl-5-oxo-3-pyrrolidinyl]amino}benzonitrile (0.06 g, 0.24 mmol) in DMF (2 mL) at 0° C. under a N2 atmosphere. After stirring for 10 min, 1-(bromomethyl)-2-chlorobenzene (0.054 g, 0.26 mmol) was added and the reaction mixture was stirred at 0° C. for 15 min. The reaction was quenched with H2O and then partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified via column chromatography with 5% EtOAc in hexane grading to 100% EtOAc in hexane to yield the titled compound (0.03 g, 37%) as a clear oil. 1H-NMR (CDCl3) δ: 2.486 (1H, m), 2.797 (1H, m), 2.866 (3H, s), 3.383 (1H, m), 3.785 (1H, m), 4.563 (2H, m), 4.281 (1H, m), 6.519 (1H, dd, J=8.8 Hz, 2.8 Hz), 6.717 (1H, d, J=2.8 Hz), 6.757 (1H, dd, J=7.6 Hz, 1.2 Hz), 7.264 (2H, m), 7.420 (2H, m). LC-MS (ES) m/e 374.2 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:44][CH2:43]3)(=[O:41])=[O:40])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:55]([O:57][CH:58]1[CH2:62][CH2:61][O:60][CH2:59]1)=[O:56]>C(Cl)Cl>[O:60]1[CH2:61][CH2:62][CH:58]([O:57][C:55](=[O:56])[NH:3][CH:4]2[C:22](=[O:23])[N:21]3[CH:17]([CH2:18][CH:19]([O:24][C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][N:26]=4)[CH2:20]3)[C:16](=[O:35])[NH:15][C:14]3([C:36]([NH:38][S:39]([CH:42]4[CH2:43][CH2:44]4)(=[O:40])=[O:41])=[O:37])[CH:12]([CH2:13]3)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:59]1
Reactant: NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Reactant: O=C(Cl)OC1CCOC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O)OC1CCOC1
Yield: 52.6 %

Procedure:
Prepared from cyclopropanesulfonic acid [14-amino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carbonyl]-amide bis hydrochloride (50 mg, 0.075 mmol), 44 μL (0.25 mmol) of DIPEA and 0.10 mL (0.1 mmol) of tetrahydro-furan-3-yl chloroformate (prepared by treating tetrahydrofuran-3-ol with phosgene) in DCM as described in the procedure above to give 28 mg (52%) of a white solid. Preparative HPLC condition: YMC ODS-A, S5, 30×50 mm, gradient: 50% B to 85% B, 8 min, hold 2 min, flow rate 45 ml/min. LC-MS (Method A, retention time: 3.05 min), MS m/z 710 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH:9](C(OCC)=O)[C:10]([O:12]CC)=[O:11]>C(O)C.[OH-].[Na+]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(CCc1ccccn1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCc1ccccn1
Yield: 77.3 %

Procedure:
A solution of diethyl β-(2-pyridyl)-ethylmalonate (25 g, 94 mmol) in ethanol (100 mL) and NaOH (1M, 200 mL) was refluxed for 2 hours. The ethanol was removed by distillation, and the solution was acidified with concentrated H2SO4. The resulting solution was refluxed for 30 minutes, and then the pH was adjusted to 4. The solvent was removed and the residue was dried under vacuum. The residue was suspended in ethanol and filtered. The ethanol was removed to yield 4-(2-pyridyl)butanoic acid (46) (12 g).
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].N1C=CC=CC=1>O>[NH2:16][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:2]=1[I:1])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(c1ccccc1)c1ccc(I)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Nc1cc(C(=O)c2ccccc2)ccc1I
Temperature: 40 °C

Procedure:
A mixture of 5.0 g (14 mmol) of 4-iodo-3-nitro-benzophenone, 7.5 g (42 mmol) of sodium dithionite, 40 ml of pyridine and 15 ml of water is heated to 40° C. for 2 hours. Then the mixture is concentrated in vacuo, combined with ice water and extracted with ethyl acetate. The organic phase is dried with sodium sulphate and the solvent is distilled off in vacuo.