Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[OH:3].Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[C:17]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:2]([CH3:1])[O:3][C:25]2=[O:27])[CH2:16][CH2:15]1)([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1OC(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl-(2-(1-Boc-4-piperidinylamino)phenyl) carbinol from Step 2 above (1.9 g, 5.9 mmol) was stirred in dry THF in an ice bath under nitrogen, and triphosgene (0.59 g, 1.98 mmol) was added followed by triethylamine (2.5 ml, 1.8 g, 17.8 mmol). The ice bath was removed and the mixture was stirred at ambient temperature for 18 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined ethyl acetate fractions were washed with 1N HCl followed by saturated sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 1-(1-Boc-4-piperidyl)-4-methyl-3,1-benzoxazin-2-one.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([C:27](O)=O)[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([CH2:27][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:2]([O-:1])=[N:3]2)[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCCOCc1cccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCOCc1cccc(Cn2n[n+]([O-])c3ccccc32)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.1 %

Procedure:
To a suspension of 1-Hydroxybenzotriazole (0.283 g) and 6-octyloxymethylpicolinic acid (0.505 g) in dichloromethane (15 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.473 g), and stirred for 3 hours at ambient temperature. The reaction mixture was poured into water. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-(6-Octyloxymethylpicolinyl)benzotriazole 3-oxide (737 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[N:18]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:17]3[N:18]=[C:14]([CH3:13])[S:15][CH:16]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc(C(=O)O)cs1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cs1
Yield: 68 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-methylthiazole-4-carboxylic acid (311 mg, 2.17 mmol), and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP—Cl (203 mg, 2.17 mmol). After 1 hour the solid formed was filtered and washed with CH2Cl2 (3×4 mL) to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide (210 mg, 68% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.14 (s, 1H), 9.83 (s, 1H), 8.38 (d, 1H), 8.26 (s, 1H), 7.74 (d, 1H), 2.77 (s, 3H); LCMS (APCI+) m/z 354.9, 356.9 (M+H)+, Retention time=3.39 minutes (Method 2).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:9]2)(=[O:4])=[O:3].[Cl:19][C:20]1[CH:21]=[N+:22]([O-:45])[CH:23]=[C:24]([Cl:44])[C:25]=1[CH2:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[N+:22]([O-:45])[CH:23]=[C:24]([Cl:44])[C:25]=1[CH2:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[O:17][C:16](=[O:18])[CH2:15][N:11]1[C:12]2[C:8](=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCN2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 25.4 %

Procedure:
A mixture of 2-(5-(methylsulfonamido)indolin-1-yl)acetic acid (0.154 g, 0.571 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol), EDC (0.128 g, 0.666 mmol) and DMAP (0.116 g, 0.952 mmol) in dry DCM (10 ml) was stirred at room temperature for 2.5 hours. Additional 2-(5-(methylsulfonamido)indolin-1-yl)acetic acid (0.072 g, 0.267 mmol) was added, and the mixture was stirred overnight at room temperature. The solvent was removed and the crude was purified by flash chromatography on silica gel column (DCM:MeOH=98:2). A further purification by preparative HPLC (Method 1) under neutral conditions was required to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(methylsulfonamido)indolin-1-yl)acetoxy)ethyl)-pyridine 1-oxide (0.0817 g, 0.121 mmol, 26% yield). MS/ESI+ 672.05 [MH]+; [αD]=+10.81, c=0.518; DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.84 (br. s., 1H), 8.55 (s, 2H), 7.17 (d, 1H), 7.08 (d, 1H), 6.94 (dd, 1H), 6.92 (d, 1H), 7.06 (t, 1H), 6.81 (dd, 1H), 6.22 (d, 1H), 6.03 (dd, 1H), 4.10 (d, 1H), 3.90 (d, 2H), 3.92 (d, 1H), 3.43 (dd, 1H), 3.32-3.39 (m, 2H), 3.22 (dd, 1H), 2.89 (t, 2H), 2.83 (s, 3H), 1.08-1.31 (m, 1H), 0.49-0.68 (m, 2H), 0.18-0.46 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]O)=[CH:37][CH:36]=1>>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][O:23][C:22]([C:21]2[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]3[C:19]([C:20]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=3)=[O:24])=[CH:37][CH:36]=1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: OCc1ccc(F)cc1
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCc2ccc(F)cc2)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and 4-fluorobenzyl alcohol. A colorless powder (145 mg). HPLC analysis (Agilent 1100 system): purity 98% (retention time: 4.33 min). MS (ESI+): 571 (M+H), 573.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:45]=[CH:46][CH:47]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:50])=[O:51])[CH:45]=[CH:46][CH:47]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 90.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.19 mmol) was coupled with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methane sulfonamide (intermediate 3) (84.8 mg, 0.285 mmol) in sodium carbonate (60.5 mg, 0.57 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (13.3 mg, 0.019 mmol) and toluene/ethanol/water (12/6/2 ml) to afford 106 mg of the crude product which was taken as such for next step. MS: m/z=615.7 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C:10]([CH3:12])=[CH:11][C@@H:6]2[C@H:5]([C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=[O:19].[O:25]=[O:26]>ClCCl.C1C=CC(C2C3NC(C(C4C=CC=CC=4)=C4C=CC(=C(C5C=CC=CC=5)C5C=CC(=C(C6C=CC=CC=6)C6C=CC=2N=6)N=5)N4)=CC=3)=CC=1>[CH3:1][C@H:2]1[C@@H:7]2[CH2:8][CH2:9][C@:10]3([CH3:12])[O:25][O:26][C@:6]42[C@H:5]([C@@H:13]([CH3:14])[C:15]([O:17][C@@H:11]4[O:19]3)=[O:16])[CH2:4][CH2:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=O
Reactant: CC1=C[C@H]2[C@@H](CC1)[C@H](C)CC[C@H]2[C@@H](C)C(=O)O
Agent: C1=Cc2nc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Solvent: ClCCl
Product: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of dihydroartemisinic acid (4) (1.18 g, 5.0 mmol) and tetraphenylporphyrin (12 mg, 20 μmol) in dichloromethane (total volume of the solution: 10.0 mL, volumetric flask) was prepared. The lamp was turned on 30 min prior to the beginning of the experiment. The reactor was flushed with pure dichloromethane (2.5 mL/min) and oxygen (5 mL/min, 11.5 bar) for 5 min. The reagents were then injected at a flow rate of 2.5 mL/min and the flow of oxygen was readjusted to 5 mL/min (11.5 bar). After the injection of the entire solution of (4), the reactor was flushed with pure dichloromethane (2.5 mL/min) to recover all material. The reaction mixture was collected in a round bottom flask and was cooled down to 0° C. Oxygen was bubbled into the reaction mixture at atmospheric pressure. After 2 min of bubbling, TFA (0.19 mL, 2.5 mmol, 0.5 eq.) was added drop wise. The resulting mixture was stirred at 0° C. for 2 h, while maintaining the oxygen bubbling. Then, the reaction was quenched with a saturated aqueous solution of NaHCO3. The resulting biphasic mixture was stirred at room temperature until disappearance of the green colour. The phases were separated and the aqueous phase was extracted with dichloromethane (3 times). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification over silica gel (5%-20% EtOAc in cyclohexane) afforded artemisinin (0.707 g, 50%) as a yellow solid.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.Cl.CNC.C1COCC1.[I:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>O>[I:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:3]([CH3:4])[CH3:2])=[O:26]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(I)c1
Reaction time: 18 h

Procedure:
EDCl (1.3 g, 6.6 mmol) was added to a solution of dimethylamine in THF (2 M, 6 mL, 10 mmol) and 3-iodobenzoic acid (1.5 g, 6 mmol). After 18 h stirring the reaction was transferred into water, and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The solvent was evaporated to afford the product as a viscous, clear oil. The product was used in the next reaction step without further purification. MS m/z: 276 [M+H].
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=O)(C)(C)C.[Si]([N:19]=C=O)(C)(C)C.[ClH:22].O1CCOCC1>C(Cl)Cl>[ClH:22].[C@H:9]12[CH2:14][C@H:12]([NH:11][CH2:10]1)[CH2:13][N:8]2[C:6]([NH2:19])=[O:5]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.00 g, 5.04 mmol) in DCM (15 mL) is added TMS-isocyanate (2.68 mL, 20.2 mmol) and the reaction stirred at about 25° C. for 72 hours. The reaction is concentrated, and the residue dissolved in DCM (15 mL) and treated with 4M HCl in 1,4-dioxane (5.04 mL, 20.2 mmol). The reaction is stirred overnight, and the solid filtered to afford the title compound (P).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)Nc1ccnc(Cl)n1
Yield: 19 %

Procedure:
Prepared in analogy to example 98a), using 2,4-dichloro-pyrimidine and 2-amino-2-methylpropan-1-ol. The title compound was isolated as a yellowish solid in a yield of 19%. MS ISP (m/e): 200.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.84 (d, 1H), 7.49 (s, 1H), 6.50 (d, 1H), 4.85 (s, 1H), 3.53 (d, 2H), 1.29 (s, 6H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-].[Na+].[C:27](#[N:30])[CH:28]=[CH2:29]>O>[C:1]([CH2:4][N:5]1[CH2:16][CH2:15][N:14]([CH2:29][CH2:28][C:27]#[N:30])[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: C=CC#N
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCCN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50 ml round bottom flask was placed 5.22 g (0.0151 mol) of 1,4,7,-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (DO3A) and dissolved in 21 ml of water. The pH of the solution was raised to 8.28 with 6N NaOH. Then 1.35 ml (1.09 g, 0.0205 mol) of acrylonitrile was added and the reaction allowed to stir overnight at room temperature. The reaction is then concentrate in vacuo, and then re-dissolved in methanol and concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH:31]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(-c2ccccn2)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(-c3ccccn3)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-pyridin-2-ylphenol (Chem. Pharm. Bull. 1985, 33, 1009): 1H-NMR (CDCl3) δ 8.71–8.68 (1H, m), 8.56 (1H, d, J=2.8 Hz), 8.22 (1H, d, J=7.4 Hz), 8.13 (1H, d, J=2.8 Hz), 8.02–7.99 (2H, m), 7.92–7.81 (2H, m), 7.79–7.76 (2H, m), 7.57 (1H, t, J=7.9 Hz), 7.44 (2H, d, J=8.2 Hz), 7.30–7.20 (2H, m), 5.43–5.33 (1H, m), 3.89 (3H, s), 1.60 (3H, d, J=6.9 Hz); MS (ESI) m/z 488 (M+H)+, 486 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[C:5]=2[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2].CC[N:31]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:31])=[O:25])[C:5]=2[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2]
Reactant: COc1ncc(C#N)c2c1c(Nc1cccc(C(=O)O)c1)cn2C1CCCC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(C#N)c2c1c(Nc1cccc(C(N)=O)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of 3-((7-cyano-1-cyclopentyl-4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)benzoic acid (80 mg) and HOBt ammonium salt (52 mg) in DMF (2 mL) was added EDCI hydrochloride (65 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (65 mg).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:8]2[C:13](=O)[C@@H:12]3[CH2:15][CH2:16][N:9]2[C@H:10]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36].C1COCC1.B1C2CCCC1CCC2>C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[C:25]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:8]2[C@H:13]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=3[O:32][CH3:31])[C@@H:12]3[CH2:15][CH2:16][N:9]2[C@H:10]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11]3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1[C@@H]2CCN([C@H](CCc3ccccc3)C2)[C@@H]1C(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1CN
Agent: B1C2CCCC1CCC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccccc1CN[C@@H]1[C@@H]2CCN([C@H](CCc3ccccc3)C2)[C@@H]1C(c1ccccc1)c1ccccc1
Yield: 23.3 %

Procedure:
Compound 7 (357 mg, 0.904 mmol), 2-methoxybenzylamine (189 mg, 1.38 mmol) and camphorsulfonic acid (2.0 mg) were dissolved in toluene (30 ml), and the resultant mixture was heated at reflux for 3 days under a dehydrating condition with MS 4A. After replacement of the solvent with THF a solution of 9-BBN (0.5M in THF, 5.4 ml) was added, and the resultant mixture was stirred for 4 days at room temperature. After evaporation of the solvent the residue was basified at pH=13, extracted with CH2Cl2, dried over Na2SO4, and concentrated down. The crude material was purified by combination of column chromatography (silica-gel, MeOH/CH2Cl2), preparative TLC (silica-gel, 10% MeOH/CH2 Cl2) and crystallization from MeOH to provide pure compound 8 (109 mg, 23%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:9]([O-])=O.[Na+].[CH2:13]1[C:18](=[O:19])[O:17][CH2:16][C:14]1=[O:15].O.O.O.C([O-])(=O)C.[Na+]>O>[C:3]1([N:2]=[N:9][C:13]2[C:18](=[O:19])[O:17][CH2:16][C:14]=2[OH:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: O=N[O-]
Reactant: O=C1COC(=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1OCC(O)=C1N=Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
300 ml of 6N hydrochloric acid solution was placed in a 1.5-liter flask equipped with a 250-ml dropping funnel, a mechanical stirrer and a thermometer. 57.6 g (0.61 mol) of distilled aniline was added with ice cooling. A solution of 43.92 g (0.64 mol) of sodium nitrite in 90 ml of ice water was added dropwise to the resulting suspension and stirred for 40 min. The resultant diazonium salt solution was added dropwise to a solution of 60 g (0.6 mol) of tetronic acid and 120 g (0.88 mol) of sodium acetate trihydrate in 900 ml of water for 30 min. After this addition a yellow solid immediately precipitated. The reaction mixture was stirred at 10° C. for 1.5 hours, and filtered off; and the product was washed with 500 ml of cold methanol. It was dried at 35° C. in a vacuum. Concerning the product:
Reaction SMILES: CS[C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][O:13][CH3:14])=[CH:4][N+:5]([O-:7])=[O:6].[CH:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:24])[CH2:22][NH2:23])=[CH:17][CH:16]=1>C(O)C>[OH:24][CH:21]([C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)[CH2:22][NH:23][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][O:13][CH3:14])=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: COCSCCNC(=C[N+](=O)[O-])SC
Reactant: NCC(O)c1ccccc1
Solvent: CCO
Product: COCSCCNC(=C[N+](=O)[O-])NCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
With 15 ml of ethanol were mixed 7.5 g of the 1-methylthio-1-[2-(methoxymethylthio)ethylamino]-2-nitroethene and 5.6 g of DL-β-hydroxyphenethylamine, and the resulting mixture was stirred at room temperature for 8 hours, and then allowed to stand overnight at room temperature. The solvent was removed by distillation under reduced pressure, and the crystals thus obtained were washed with 15 ml of isopropanol and then dried to obtain 7.3 g (yield 71%) of N-(β-hydroxyphenethyl)-N'-[2-(methoxymethylthio)ethyl]-2-nitro-1,1-ethenediamine having a melting point of 107°-109.5° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[N:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2=[N:22][N:23]=[C:24]([C:25]3[CH:29]=[C:28]([CH3:30])[O:27][N:26]=3)[N:14]2[N:13]=1>>[CH3:30][C:28]1[O:27][N:26]=[C:25]([C:24]2[N:14]3[N:13]=[C:12]([O:1][CH2:2][C:3]4[N:8]=[N:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=4)[C:21]4[C:16]([C:15]3=[N:22][N:23]=2)=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:29]=1
Reactant: OCc1ccc(CO)nn1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CO)nn4)nn23)no1
Yield: 12.7 %

Procedure:
(6-Hydroxymethylpyridazin-3-yl)methanol (J. Het. Chem., 1996, 33 (6), 2059-2061) (0.10 g, 0.71 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (0.22 g, 0.77 mmol) were coupled together and purified as in Example 1, step 4 to give {6-[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yloxymethyl]pyridazin-3-yl}methanol as a white solid (35 mg). 1H NMR (400 MHz, d6-DMSO) δ 2.58 (3H, s), 4.80 (2H, s), 5.65-5.75 (1H, br s), 5.92 (2H, s), 6.99 (1H, s), 7.81 (1H, d, J 8), 7.98 (1H, t, J 8), 8.07-8.15 (2H, m), 8.32 (1H, d, J 8), 8.58 (1H, d, J 8). m/z (ES+) 390 (M+H+).