Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.FC(F)(F)C(O)=O.CO[CH2:24][N:25]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][Si](C)(C)C.[OH-].[Na+]>ClCCl.O>[CH2:31]([N:25]1[CH2:26][C:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[C:5]([C:4]([OH:3])=[O:14])[CH2:24]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)C#Cc1ccc(Cl)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 78.8 %

Procedure:
To a solution of (4-chloro-phenyl)-propynoic acid ethyl ester (92.65 g, 444.1 mmol) in dichloromethane (425 mL) was added trifluoroacetic acid (3.4, 44.4 mmol). The reaction mixture was cooled with a water bath and a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (164.7 g, 666.1 mmol) in dichloromethane (325 mL) was added dropwise over a period of 1.5 h. It was stirred for 22 h at ambient temperature. Further N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (27.5 g, 111.0 mmol) in dichloromethane (50 mL) was added and stirring was continued for 2 h at ambient temperature. The solvent was distilled off and the residue was taken up in dioxane (950 mL). After addition of water (475 mL) and sodium hydroxide (32%, 114.3 mL, 1.23 mol), it was stirred for 67 h at ambient temperature. After concentration the residue was diluted with water (400 mL) and extracted with tert-butylmethylether (400 mL). The organic layers were washed with water (400 mL). The aqueous layers were combined, cooled to 5° C. and set to pH=1.5 with aqueous HCl (25%, 172). After stirring for 1 h at 5° C., the solid was filtered off and was washed with water (1400 mL) and ethanol (400 mL). Drying (50° C., 25 mbar) afforded the title compound (109.85 g, 79%) as an off-white solid. MS m/e: 312.2/314.1 [M−H]−.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:14](=[O:29])[CH:15](Br)[C:16]1[C:17]([CH:22](Br)[C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:19]=[CH:20][CH:21]=1>C1C=CC=CC=1>[CH3:26][O:25][C:23]([CH:22]1[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]2[C:14](=[O:29])[N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][CH2:10][N:11]12)=[O:24]
Reactant: NCCNCc1ccccc1
Reactant: COC(=O)C(Br)c1ccccc1C(Br)C(=O)OC
Solvent: c1ccccc1
Product: COC(=O)C1c2ccccc2C2C(=O)N(Cc3ccccc3)CCN12

Procedure:
N-(Phenylmethyl)ethylene diamine (10.38 g) is added dropwise to a solution of α,α'-dibromo-1,2-benzenediacetic acid dimethyl ester [24 g, described by G. Cignarella and A. Vigevani, Gazz. Chim. Ital., 98, 1474 (1968)] in benzene (600 ml). The mixture is refluxed for 6 hr, cooled and filtered. The filtrate is evaporated and the residue is chromatographed on silica gel using diethyl ether-methanol (9:1). The appropriate fractions are evaporated to give isomer A (5.7 g) of the title compound, nmr (CDCl3) δ3.3(m), 3.8(s), 4.6(d), 4.92(d), 5.30(d) and 7.3-7.8(m). The eluant for the above chromatography is changed to methanol-diethyl ether (3:7) and the appropriate eluate fractions are evaporated to give isomer B (4.1 g) of the title compound, nmr (CDCl3) δ3.3(m), 3.8(s), 4.6(d), 4.92(d), 5.30(d) and 7.3-7.8(m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([CH2:21][CH2:22][NH:23]C(OCC[Si](C)(C)C)=O)[N:18]=[CH:17]1)=[O:12].CCOC(C)=O.CO.[NH4+].[OH-].[ClH:43]>C(#N)C>[ClH:43].[ClH:43].[ClH:43].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([CH2:21][CH2:22][NH2:23])[N:18]=[CH:17]1)=[O:12]
Reactant: C[Si](C)(C)CCOC(=O)NCCc1cn(CCNC(=O)CCSSc2ccccn2)cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NCCc1cn(CCNC(=O)CCSSc2ccccn2)cn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
13 mg (0.026 mmol) of IV is dissolved in 1 ml of acetonitrile containing 0.15 ml of conc. HCl. The reaction mixture is stirred at room temperature for 2.5 hours. TLC on silica gel with EtOAc--MeOH--NH4OH (80:20:1) as the mobile phase shows that the trimethylsilylethyloxycarbonyl protective group has been completely removed after 2.5 hours. The reaction solution is evaporated, whereupon an NMR analysis is run in D2O+ deuterated acetonitrile. ##STR4## 1-CH2 -imidazole 4.18 t, --CH2NHCO 3.52 t, H3N+CH2 -- 3.18 t, 4-CH2 -imidazole about 3.0 t, --CH2S-- 3.0 t, --COCH2 -- 2.57 t.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>ClCCl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3ccccc3C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2CN1C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.58 mmol) in dichloromethane (15 mL) was added trifluoro-acetic acid (3.0 mL) and the reaction mixture stirred at ambient temperature during 4 h. The solvent was removed under reduced pressure and the crude product (0.710 g) used in the consecutive step without further purification assuming quantitative deprotection and formation of the trifluoroacetate salt. MS (ISP): 217.4 [M+H]+.
Reaction SMILES: BrC1C=CC(O)=CC=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-])=O)[CH:11]=1.CC(C)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH:11]=1)[NH2:17]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=S([O-])S(=O)[O-]
Agent: Oc1ccc(Br)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
A portion of 4-bromophenol is converted to 4-bromo-2-nitrophenol by the method described in Rec. Trav. Chim. 29, 187(1910). A 28 g. portion of 4-bromo-2-nitrophenol is dissolved in 280 ml. of acetone. A 280 ml. portion of water and 112 g. of Na2S2O4 are added with stirring. The mixture is refluxed for 2 hours, cooled to room temperature and extracted six times with ether. The ether extracts are washed twice with brine, dried over magnesium sulfate and recrystallized from a mixture of charcoal and 400 ml. of water giving an oil. This oil is redissolved in 600 ml. of water, cooled to 0° C. and filtered giving 5-bromo-2-hydroxyaniline as tan crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([OH:18])=O)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][N:19]=3)=[CH:30][N:29]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1
Reactant: O=C(O)Cc1ccc(-c2ccnc(F)c2)c(F)c1
Reactant: Nc1ccc(-c2cnccn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccnc(F)c2)c(F)c1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 207-6 (50 mg, 0.20 mmol), was dissolved in DMF (2 mL), 5-(pyrazin-2-yl)pyridin-2-amine (41 mg, 0.24 mmol) and DIEA (174 uL, 1.0 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (114 mg, 0.30 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 212. MS m/z 404.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.10 (s, 1H), 9.31 (d, 1H), 9.11 (dd, 1H), 8.73-8.71 (m, 1H), 8.63 (d, 1H), 8.52 (dd, 1H), 8.34 (d, 1H), 8.21 (d, 1H), 7.70-7.52 (m, 2H), 7.43-7.34 (m, 3H), 3.89 (s, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[CH2:34]([O:41][C:42]1[N:43]=[N:44][C:45]([C:56]#[CH:57])=[CH:46][C:47]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>[Cu]I.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.O1CCCC1>[CH2:34]([O:41][C:42]1[N:43]=[N:44][C:45]([C:56]#[C:57][C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[CH:46][C:47]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: FC(F)(F)c1ccc(I)cn1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cn1
Temperature: 80 °C
Yield: 10 %

Procedure:
A microwave vial was charged with 5-iodo-2-(trifluoromethyl)pyridine (617 mg, 2.260 mmol), copper(I) iodide (39.1 mg, 0.205 mmol), bis(triphenylphosphine)palladium(II) chloride (72.1 mg, 0.103 mmol), 1,8-diazabicycloundec-7-ene (DBU; 1858 μl, 12.33 mmol) and tetrahydrofuran (6849 μl). The reaction mixture was then purged and evacuated with nitrogen and to this was then added 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5: 650 mg, 2.1 mmol). The reaction was heated to 80° C. whilst being subjected to microwave radiation for 1 hour. Upon cooling the reaction mixture was partitioned between ethyl acetate and water, at which point a solid formed which was filtered and discarded. The organics were then washed with water and brine, dried (MgSO4), filtered and concentrated to afford a brown oil. This was purified by silica chromatography (eluting with 0-100% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-{[6-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine as a yellow amorphous solid (yield=10%)
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][NH:20][C:21]([NH2:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[N:19][NH:20][C:21]([NH2:23])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(N)=O
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=O)NN=C(c1ccccc1)c1cc2ccncc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (108 mg, 0.49 mmol), semicarbazide hydrochloride (57 mg, 0.51 mmol) and potassium carbonate (58 mg, 0.42 mmol) in ethanol (3.0 mL) was refluxed under a nitrogen atmosphere overnight (14 h). The reaction mixture was cooled to room temperature, water was added, and the reaction mixture was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4. After filtration and concentration, the crude material was purified by Biotage chromatography to afford phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone semicarbazone as two isomers, Example 62 (5.3 mg, 4%) and Example 63 (5.9 mg, 4%), as a yellow solid:
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.Cl.Cl.C(NN=C(NCCCN(CCCN[C:75]([NH:77][C:78]1[CH:83]=[C:82]([C:84](=[O:86])[CH3:85])[CH:81]=[C:80]([C:87](=[O:89])[CH3:88])[CH:79]=1)=[O:76])CCCNC(=NNC(=N)N)NC1C=C(C(=NNC(=N)N)C)C=C(C(=NNC(=N)N)C)C=1)NC1C=C(C(=NNC(=N)N)C)C=C(C(=NNC(=N)N)C)C=1)(=N)N.[C:90]([C:93]1[CH:94]=[C:95]([N:102]=[C:103]=[O:104])[CH:96]=[C:97]([C:99](=[O:101])[CH3:100])[CH:98]=1)(=[O:92])[CH3:91].[NH2:105][CH2:106][CH2:107][CH2:108][N:109]([CH2:114][CH2:115][CH2:116][NH2:117])[CH2:110][CH2:111][CH2:112][NH2:113]>O1CCCC1>[C:99]([C:97]1[CH:96]=[C:95]([NH:102][C:103]([NH:105][CH2:106][CH2:107][CH2:108][N:109]([CH2:114][CH2:115][CH2:116][NH:117][C:75]([NH:77][C:78]2[CH:79]=[C:80]([C:87](=[O:89])[CH3:88])[CH:81]=[C:82]([C:84](=[O:86])[CH3:85])[CH:83]=2)=[O:76])[CH2:110][CH2:111][CH2:112][NH:113][C:75]([NH:77][C:78]2[CH:83]=[C:82]([C:84](=[O:86])[CH3:85])[CH:81]=[C:80]([C:87](=[O:89])[CH3:88])[CH:79]=2)=[O:76])=[O:104])[CH:94]=[C:93]([C:90](=[O:92])[CH3:91])[CH:98]=1)(=[O:101])[CH3:100]
Reactant: NCCCN(CCCN)CCCN
Reactant: CC(=O)c1cc(NC(=O)NCCCN(CCCNC(=NNC(=N)N)Nc2cc(C(C)=NNC(=N)N)cc(C(C)=NNC(=N)N)c2)CCCNC(=NNC(=N)N)Nc2cc(C(C)=NNC(=N)N)cc(C(C)=NNC(=N)N)c2)cc(C(C)=O)c1
Reactant: CC(=O)c1cc(N=C=O)cc(C(C)=O)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(NC(=O)NCCCN(CCCNC(=O)Nc2cc(C(C)=O)cc(C(C)=O)c2)CCCNC(=O)Nc2cc(C(C)=O)cc(C(C)=O)c2)cc(C(C)=O)c1

Procedure:
Compound 36, FIG. 7H.36: 3,5-Diacetylphenyl isocyanate (0.4 g) and tris(3-aminopropyl)amine (0.12 g) in tetrahydrofuran (5 mL) were stirred at r.t. for 30 min. Filtration gave 0.32 g of tris(3-[([(3,5-diacetylphenyl)amino]carbonyl)amino]propyl)amine, mp 147°-8 C. This hexa-ketone (0.4 g) and aminoguanidine dihydrochloride (0.49 g) were heated in methanol (3 mL) for 4 hours. Addition of ethanol and filtration gave 0.58 g of tris(3-[([(3,5-diacetylphenyl)amino]carbonyl)amino]propyl)amine hexakis(amidinohydrazone) heptahydrochloride (Compound 36) as the dihydrate hemi-ethanolate, mp 250°-1° C. (dec).
Reaction SMILES: CO.[CH3:3][NH:4][NH2:5].CN([CH:9]=[C:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=O)C>C(OCC)(=O)C>[CH3:3][N:4]1[CH:11]2[CH:10]([C:15](=[O:16])[CH2:14][CH2:13][CH2:12]2)[CH:9]=[N:5]1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: CNN
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1N=CC2C(=O)CCCC21
Temperature: 50 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A MeOH solution of methylhydrazine 0.046 g (0.01 mol) and 2-dimethylaminomethylene-cyclohexane-1,3-dione 1.67 g (0.01 mol) was stirred at room temperature for 1 h, and then was stirred at 50° C. for 1 h. NMR of crude material indicated the reaction was completed. Work up: The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried with MgSO4, and the solvent was rotary evaporated. The crude product was filtered through silica gel, and 1.03 g pure product was obtained, the yield is 69%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
5-chloro-2-methylbenzoic acid (4.0 g, 23 mmol) was added portionwise to cooled conc. H2SO4 (27 mL) at −10° C. After 10 minutes a nitrating mixture {prepared by mixing conc. HNO3 (3.3 g, 52.68 mmol) with conc. H2SO4 (4.4 mL)} was added dropwise at −10° C. The resulting reaction mass was stirred at −10° C. for 30 minutes. On completion, the reaction mixture was poured on ice cold water, the solid precipitate was filtered, washed with water and dried under vacuum giving the title compound (4.95 g, 99%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[C:17]([C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([C:28]([O:30]C)=[O:29])[CH:26]=5)[NH:21][N:20]=4)[N:16]=[N:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>C1COCC1.O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[C:17]([C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=5)[NH:21][N:20]=4)[N:16]=[N:15]3)=[CH:10][CH:9]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2[nH]nc(-c3cn(-c4ccc(CN5CCOCC5)cc4)nn3)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]nc(-c3cn(-c4ccc(CN5CCOCC5)cc4)nn3)c2c1
Yield: 107.7 %

Procedure:
A solution of methyl 3-{1-[4-(morpholin-4-ylmethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole-5-carboxylate (351 mg; 0.84 mmol; 1.0 eq.) and lithium hydroxide (201 mg; 8.4 mmol; 10 eq.) in THF (3.5 mL) and water (3.5 mL) was stirred O/N at 40° C. A 5N solution of HCl was then added and the precipitate was filtered, rinsed with water and dried under reduced pressure at 40° C. O/N to give the title compound as a white powder (366 mg, 100%). UPLC/MS: (MS+) 405.1, (MS−) 403.1.
Reaction SMILES: [CH3:1][CH:2]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[NH:4][CH2:3]1.CC1N([C:26]([CH2:28][C:29]#[N:30])=[O:27])N=C(C)C=1.O1CCOCC1.C(=O)(O)[O-].[Na+]>O>[CH3:1][CH:2]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[N:4]([C:26](=[O:27])[CH2:28][C:29]#[N:30])[CH2:3]1
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Reactant: CC1CNC12CCCN(c1ncnc3[nH]ccc13)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1CN(C(=O)CC#N)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 21.3 %

Procedure:
An optically-active compound of 4-(3-methyl-1,6-diazaspiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (25 mg) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (32 mg) and 1,4-dioxane (750 μl), and the mixture was stirred at 100° C. for 3.5 hours. The mixture was cooled to room temperature. Thereto were added water and saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted with ethyl acetate five times, and the combined organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica-gel thin layer chromatography (eluent: chloroform/methanol=9/1). The resulting residue was purified by silica-gel thin layer chromatography (eluent: ethyl acetate/methanol=93/7) again. The resulting solid (8.0 mg) was slurry-washed with n-hexane/ethyl acetate solution to give the titled compound (6.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:35][NH:36][C:37](=O)[CH2:38][N:39]([CH3:41])[CH3:40])=[N:10][N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:37]([CH2:38][N:39]([CH3:41])[CH3:40])=[N:36][N:35]=3)[N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)CN(C)C)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc(CN(C)C)n21
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
To a round bottom flask was added N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)-2-(dimethylamino)acetohydrazide (25 mg, 0.0446 mmol) and toluene (3 ml). The reaction was stirred at 120° C. for 15 min. Then POCl3 (0.3 ml) was added and the reaction was stirred at 120° C. for additional 40 min. After this time, the solution was cooled to rt and the reaction mixture was concentrated. The residue was partitioned between EtOAc (30 ml) and NaHCO3 (sat, 20 ml). The organic layer was separated and washed with water (10 ml) and saturated NaCl (10 ml). The organic layer was then dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (4 g silica gel) eluting with a gradient of 0-80% EtOAc/CH2Cl2 to give product 4-(8-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as an off white solid (10 mg, 39% yield).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:35][C@H:36]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])/[CH:37]=[CH:38]\[C@H:39]([CH3:62])[C@H:40]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[C@@H:41]([CH3:53])[CH2:42][CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C)C)[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CN=CC=1.F.CCOC(C)=O.CCCCCC>N1C=CC=CC=1>[Si:55]([O:54][C@@H:40]([C@@H:39]([CH3:62])/[CH:38]=[CH:37]\[C@@H:36]([O:63][Si:64]([C:67]([CH3:68])([CH3:69])[CH3:70])([CH3:65])[CH3:66])[CH2:35][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:41]([CH3:53])[CH2:42][CH2:43][CH2:44][OH:45])([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56]
Reactant: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C[C@@H](/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C[C@@H](/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 70964.2 %

Procedure:
The procedure for 36 was used with 67 (1.82 g, 1.77 μmol) and HF-pyridine in pyridine (100 mL) to yield 68 (1.15 g, 71%) by flash column chromatography (EtOAc/Hexane 1:9) as a colorless oil: IR (CHCl3) 3349, 2956, 2929, 2856, 1471, 1448, 1254, 1060, 836, 773, 705 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.58-7.55 (m, 6H), 7.39-7.27 (m, 9H), 5.81-5.65 (m, 2H), 5.56 (t, J=10.7 Hz, 1H), 5.41 (dd, J=11.0, 8.4 Hz, 1H), 4.67 (m, 1H), 4.05 (m, 1H), 3.69-3.63 (m, 4H), 3.53 (m, 1H), 2.73 (m, 1H), 2.52 (m, 1H), 1.64 (m, 3H), 1.58-1.48 (m, 2H), 1.30-1.20 (m, 2H), 1.11 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H), 1.03-0.92 (m, 30H), 0.23-0.14 (m, 18H); 13C NMR (75 MHz, CDCl3) δ 144.3, 134.3, 132.9, 132.0, 128.6, 127.7, 126.8, 86.7, 80.1, 72.3, 66.4, 65.0, 63.1, 42.4, 41.7, 38.2, 35.5, 31.2, 29.5, 26.2, 25.95, 25.89, 19.6, 18.4, 18.1, 18.0, 15.1, 13.3, −2.9, −3.7, −3.8, −4.17, −4.24, −4.3; LRMS (ESI) 937.6 [M+Na]+; HRMS (ESI) calcd for C55H90O5Si3Na 937.5994 [M+Na]+, found 937.6035; [α]20D−10.8 (c 0.84, CHCl3).
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][CH: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.[CH2:30]([N:32]([CH2:35]C)[CH2:33]C)[CH3:31].ClC(Cl)([O:40][C:41](=O)[O:42]C(Cl)(Cl)Cl)Cl.CN(C)CCO>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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:40])[O:42][CH2:31][CH2:30][N:32]([CH3:35])[CH3:33])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Agent: CN(C)CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCN(C)C)cc3)c2cc1OC
Temperature: 25 °C
Yield: 25 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (83 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (40 mg) in methylene chloride was then added to the solution and the mixture was heated under reflux for 15 min. Subsequently, 2-dimethylaminoethanol (40 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 (31 mg, yield 25%).