Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH:10]1([NH2:13])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH:10]1([NH:13][C:2]2[C:3]([C:8]#[N:9])=[CH:4][N:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11]1
Reactant: N#Cc1cnccc1Cl
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: N#Cc1cnccc1NC1CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 79.2 %

Procedure:
A mixture of 4-chloro-3-cyanopyridine (5.0 g, 36.1 mmol), cyclopropylamine (5.0 mL, 72.2 mmol, 2.0 eq), and potassium carbonate (5.2 g, 37.9 mmol, 1.05 eq) in isopropyl alcohol (130 mL) was stirred at 60° C. under N2 for 20 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was absorbed onto silica and purified by flash column chromatography (silica, ISCO, 45 mL/min, 10-100% ethyl acetate in hexane). Trituration from hexane afforded the title compound as an off-white solid (4.55 g, 79.3%). 1H-NMR (400 MHz; DMSO-d6) δ ppm 8.43 (d, J=0.55 Hz, 1H), 8.29 (dd, J=6.10 Hz, 1H), 7.55 (s, 1H), 7.00-6.88 (m, 1H), 2.54 to 2.40 (m, 1H), 0.89-0.69 (m, 2H), 0.68-0.48 (m, 2H); LC-MS (method C): [M+H]+=160.2, RT=0.28 min.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:11]3[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:31]1([NH:36][C:37]([NH2:39])=[NH:38])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:31]1([NH:36][C:37]2[N:39]3[N:13]=[C:14]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[C:15]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[N:12]=4)=[C:16]3[CH:17]=[CH:18][N:38]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: N=C(N)NC1CCCC1
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)nccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3c(NC4CCCC4)nccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 140 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of 1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-one (160 mg, 0.41 mmol) in N,N-dimethylformamide (10 mL) was added N-cyclopentylguanidine hydrochloride (130 mg, 0.82 mmol). Freshly ground anhydrous potassium carbonate (56 mg, 0.41 mmol) was added and the reaction heated to 140° C. for 4 hours. Additional freshly ground anhydrous potassium carbonate (120 mg, 0.87 mmol) and N-cyclopentylguanidine hydrochloride (75 mg, 0.46 mmol) were added and the reaction heated for additional 3 hours. The reaction was allowed to cool and was stirred at room temperature for 16 hours. The mixture was quenched with water, extracted with ethyl acetate (2×), washed with brine, concentrated, and the residue purified by silica chromatography eluting with 5% acetone in dichloromethane to yield 140 mg (75%) of N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine. 1H NMR (CDCl3): δ 8.09 (d, 1H), 7.80 (d, 1H), 7.66 (dd, 2H), 7.54 (d, 1H), 7.19 (t, 2H), 6.42 (d, 1H), 6.30 (d, 1H), 5.14 (d, 1H), 4.57 (m, 1H), 4.34 (m, 1H), 2.22 (m, 2H), 2.09 (m, 2H), 1.52–1.89 (m, 12H).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:11]=[C:12]([CH:22]=O)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:7]=[CH:6][C:5]=12.[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[CH2:33][N:34]([CH3:36])[CH3:35])[C:28]#[N:29].CC(O)=O.[BH4-].[Na+].Cl>ClCCCl>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:11]=[C:12]([CH2:22][NH:24][C:25]4[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=4[CH2:33][N:34]([CH3:36])[CH3:35])[C:28]#[N:29])[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:7]=[CH:6][C:5]=12
Reactant: Cc1cccc(-c2[nH]c(C=O)nc2-c2ccc3ncnn3c2)n1
Reactant: CN(C)Cc1ccc(C#N)cc1N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cccc(-c2[nH]c(CNc3cc(C#N)ccc3CN(C)C)nc2-c2ccc3ncnn3c2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
To a stirred solution of 4-((1,2,4)triazolo(1,5-a)pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazole-2-carbaldehyde (0.50 g, 1.64 mmol) in 1,2-dichloroethane (30 mL) were added 3-amino-4-((dimethylamino)methyl)benzonitrile (0.43 g, 2.46 mmol) and AcOH (0.20 g, 3.29 mmol), and the mixture was heated at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in anhydrous MeOH (30 mL). To a methanolic solution at 0° C. was added NaBH4 (0.25 g, 6.57 mmol), and then the mixture was allowed to warm to room temperature and stirred for an additional 3 h. The pH of the reaction mixture was adjusted to 7-8 at 0° C. with 1 N HCl, and then MeOH was removed under reduced pressure. The aqueous mixture was extracted with CH2Cl2 (2×50 mL), and the CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 (1:19 (v/v)) as eluent to give the titled compound (0.60 g, 79%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 8.36 (s, 1H), 7.86 (dd, 1H, J=9.2, 1.6 Hz), 7.78 (dd, 1H, J=9.2, 0.8 Hz), 7.47 (t, 1H, J=7.6 Hz), 7.23 (br d, 1H, J=7.6 Hz), 7.09 (d, 1H, J=7.6 Hz), 7.01 (d, 1H, J=7.6 Hz), 6.98 (dd, 1H, J=7.6, 1.6 Hz), 6.93 (br s, 1H), 4.59 (s, 2H), 3.63 (s, 2H), 2.53 (s, 3H), 2.33 (s, 6H); MS (ESI) m/z 464.23 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)(C(F)(F)F)=O.[N+:30]([O-])([OH:32])=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N+:30]([O-:32])=[O:31])=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCC2CCN(C)CC2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A solution of ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, 89 mmol) in methylene chloride (75 ml) was cooled to 0-5° C. TFA (37.5 ml) was added followed by the dropwise addition over 15 minutes of a solution of fuming 24N nitric acid (7.42 ml, 178 mmol) in methylene chloride (15 ml). After completion of the addition, the solution was allowed to warm up and stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was dissolved in methylene chloride (50 ml). The solution was cooled to 0-5° C. and ether was added. The precipitate was collected by filtration, and dried under vacuum at 50° C. The solid was dissolved in methylene chloride (500 ml) and 3M hydrogen chloride in ether (30 ml) was added followed by ether (500 ml). The solid was collected by filtration and dried under vacuum at 50° C. to give ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (28.4 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[Cl:8].[NH3:16]>>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[NH2:16].[NH2:16][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Product: Nc1c(Cl)cnn(-c2ccccc2)c1=O
Product: Nc1cnn(-c2ccccc2)c(=O)c1Cl

Procedure:
4-Chloro-5-amino-2-phenyl-3(2H)-pyridazinone is prepared from 4,5-dichloro-2-phenyl-3(2H)-pyridazinone and ammonia in high yield and substantially free from 4-amino-5-chloro-2-phenyl-3(2 H)-pyridazinone in a method comprising reacting 4,5-dichloro-2-phenyl-3(2H)-pyridazinone with aqueous ammonia in the presence of a catalyst which is capable of selectively exchanging the 5-chlorine atom in 4,5-dichloro-2-phenyl-3(2H)-pyridazinone with a leaving group of such a nature that the resulting intermediate compound is capable of alkylating ammonia to 4-chloro-5-amino-2-phenyl-3(2H)-pyridazinone in high yield in the reaction medium, thereby regenerating the catalyst. The end product is isolated by filtration after the reaction and washed with water, and the mother liquor plus the wash water are used as reaction medium for the next batch.
Reaction SMILES: [CH:1]1([C:6](=O)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:12][NH2:13]>C(O)C>[CH:1]1([C:6]2[CH:7]=[C:8]([NH2:9])[NH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CCCC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(C2CCCC2)n[nH]1
Temperature: 80 °C
Yield: 46.2 %

Procedure:
To a solution of 3-cyclopentyl-3-oxo-propionitrile (1.0 g, 7.3 mmol, 1 eq) in ethanol (10 mL) was added a 64 wt.-% solution of hydrazine hydrate (1.1 mL, 14.6 mmol, 2 eq). The mixture was heated at 80° C. for 16 h and was evaporated to dryness. The residue was purified by flash chromatography using dichloromethane and methanol (100/0 to 90/10) to afford 5-cyclopentyl-2H-pyrazol-3-ylamine as yellow oil (510 mg, 46% yield).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:23](=[O:53])[CH2:24][N:25]1[C:30](=[O:31])[C:29]2[CH:32]=[C:33]([CH2:35][CH3:36])[S:34][C:28]=2[N:27]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:26]1=[O:52]>C(Cl)(Cl)Cl>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:23](=[O:53])[CH2:24][N:25]1[C:30](=[O:31])[C:29]2[CH:32]=[C:33]([CH2:35][CH3:36])[S:34][C:28]=2[N:27]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[C:50]3[NH:3][C:4](=[O:7])[O:5][N:51]=3)=[CH:40][CH:39]=2)[C:26]1=[O:52]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogencarbonate (1.35 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[3-[2-(2,4-dimethoxyphenyl)-2-oxoethyl]-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.91 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (30 mL), N,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.35 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[CH:5]2.C([N:22]1[CH2:26][CH2:25][NH:24][C:23]1=O)(=O)C>P(Cl)(Cl)(Cl)=O>[ClH:1].[NH:24]1[CH2:25][CH2:26][N:22]=[C:23]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[CH3:18]
Reactant: Cc1cc2cc(Cl)ccc2n1Cc1ccccc1
Reactant: CC(=O)N1CCNC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C2=NCCN2)c2cc(Cl)ccc2n1Cc1ccccc1
Product: Cl
Yield: 36.1 %

Procedure:
2.56 g (10 mmol) 5-chloro-2-methyl-1-benzylindole was treated with 1.28 g (10 mmol) 1-acetyl-imidazolidin-2-one and 10 ml phosphorous oxychloride as described in Example 89, Step 1 to give 0.65 g (18%) 3-(4,5-dihydro-1H-imidazol-2-yl)-5-chloro-2-methyl-1-benzyl-1H-indole Hydrochloride, mp: 273-275°, MS (Ei 70 eV) m/Z M+323.
Reaction SMILES: CC([Si](C)(C)[O:6]C1CC(CCC2C3C(=CC(C)CC3O)C=CC2C)OC(=O)C1)(C)C.[Cl:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39])=[CH:34][CH:33]=1>N1C=CC=CC=1>[Cl:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][C:37]([CH3:42])([CH3:41])[C:38]([OH:6])=[O:39])=[CH:34][CH:33]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: CC1C=C2C=CC(C)C(CCC3CC(O[Si](C)(C)C(C)(C)C)CC(=O)O3)C2C(O)C1
Solvent: c1ccncc1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of (1S-(1α(4R*,6R*),2α,6β,8β,8aα]]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-[2-(1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthalenyl)ethyl]tetrahydro-2H-pyran-2-one in an amount of 1.00 g (2.29 mmol), 18.6 ml of dry pyridine, 1.40 g (1.15 mmol) 4-N,N-dimethylaminopyridine and 5.34 g (22.9 mmol) of 2-(4-chlorophenoxy)-2-methylpropionyl chloride was heated at 50° C. for 63/4 hour, then stirred overnight at room temperature. Ice chips were then added, and after 30 min the mixture was poured into ice water and extracted four times with diethylether. The combined ether layers were washed with water, then washed with 0.1M H2SO4 and then dried over a conventional drying agent, preferably anhydrous sodium sulfate. The mixture was filtered and volatiles removed under reduced pressure (i.e. below atmospheric pressure, preferably around 30 mm). The residue was dissolved in diethylether, washed with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. The mixture was filtered and volatiles removed under reduced pressure to leave 1.6 of 2-(4-chlorophenoxy)-2-methylpropionic acid-[1S-[1α,3α,7β,8β(2R*,4R*),8aβ]]-8-[2[tetrahydro-4 -[[(1,1-dimethylethyl)dimethylsilyl]oxy]6-oxo-2H-pyran-2-yl]ethyl]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-1-naphthalenyl ester as a brown oil which was used directly without further purification.
Reaction SMILES: [ClH:1].[O:2](CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=C[CH:4]=1.Cl.[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47](C(C)(C)C)=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([O:2][CH2:3][CH3:4])=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: CCOc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 358 (M−15,0.1), 253 (17), 252 (100), 163 (6), 121 (21), 114 (8), 108 (8).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CCOCC.C([Li])CCC.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:35]=1)[CH:33]=[O:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCCCCC>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:33]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[OH:34])[CH:35]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(Br)cn1
Reactant: COc1ccc(OCc2ccccc2)cc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc(C(O)c2cc(OCc3ccccc3)ccc2OC)cn1
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
5-Bromo-2-methoxypyridine (15.87 g) was dissolved in dry tetrahydrofuran (50 ml) and the solution cooled with mechanical stirring under nitrogen to -100° (ether/liquid nitrogen). A solution of n-butyl lithium in hexane (53 ml of a 1.6M solution) was added dropwise, maintaining the temperature below -90°; a white precipitate appeared. After 5 minutes, 5-benzyloxy-2-methoxybenzaldehyde (17.04 g) in dry tetrahydrofuran (150 ml) was added dropwise, maintaining the temperature below -95°. After the addition was complete, the mixture was stirred to 5°. The dark solution was quenched with excess saturated ammonium chloride, the organic layer removed, the aqueous extracted with ethyl acetate, then the combined organics dried with anhydrous magnesium sulphate and evaporated. The residue crystallised from ether/petroleum spirit to give 1-(5-benzyloxy-2-methoxyphenyl)-1-(6-methoxy-3-pyridyl)methanol (17.83 g, 72%), m.p. 80°-82°.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[Cl:8][CH2:9][CH2:10][OH:11].[CH2:12]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C.S(Cl)(=O)(=O)N>ClCCl>[CH2:12]([C:20]1[CH:21]=[CH:22][C:23]([NH:24][S:2]([NH:5][C:6](=[O:7])[O:11][CH2:10][CH2:9][Cl:8])(=[O:4])=[O:3])=[CH:25][CH:26]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: OCCCl
Agent: NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(NS(=O)(=O)NC(=O)OCCCl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
A solution of chlorosulfonyl isocyanate (1.41 g, 10 mmol) in dichloromethane (5 mL) was treated with 2-chloroethanol (810 mg, 10 mmol) and stirred for 10 min at rt. The resulting solution was stored at ˜5° C.; aliquots were used as required. For example a solution of 4-n-octylaniline (2.05 g, 10 mmol) and triethylamine (1.54 mL, 11 mmol) in dichloromethane (20 mL) at 0° C. was treated dropwise with the solution of sulfamoyl chloride prepared as described above. After the addition was complete, the resulting mixture was stirred for 60 min at 0° C. and diluted with dichloromethane (40 mL). The dichloromethane solution was washed with 0.1 N HCl (20 mL), dried (Na2SO4) and concentrated to reduce the volume. The resultant white precipitate was collected by suction filtration to give the title compound (1.60 g) as white solid. Further concentration of the filtrate yielded an additional batch (1.02 g) as white solid. Total yield was 2.62 g (67%). 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 7.20-7.10 (m, 4H), 7.11 (s, 1H), 4.46 (s, 2H), 3.71 (s, 2H), 2.60 (t, 2H, J=6.8 Hz), 1.58 (s, 2H), 1.37-1.20 (m, 10H), 0.88 (t, 3H, J=6.4 Hz).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([O:13]CC)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C(O)CO.Cl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cnn(C(C)(C)C)c(=O)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1c(O)cnn(C(C)(C)C)c1=O
Yield: 88.2 %

Procedure:
The resulting 2-tert.-butyl-5-ethoxy-4-methyl-3(2H)-pyridazinone (1.7 g) and potassium hydroxide (6.0 g) were added to 30 ml of ethyleneglycol, and the mixture was stirred under reflux for 3 hours. The reaction mixture was poured into 200 ml of water and added with 30 ml of 6N-hydrochloric acid. The crystals thus precipitated was collected by filtration. After drying, the crystals were washed with hot hexane to give 1.3 g of 2-tert.-butyl-5-hydroxy-4-methyl-3(2H)-pyridazinone. The melting point and the result of NMR analysis of this product were identical with those of the product obtained by the Method A.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:39]([NH2:41])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:95]=[C:96]1[CH:100]=[CH:99][C:98](=[O:101])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH2:110])=[O:108]>CN(C=O)C>[O:101]=[C:98]1[CH:99]=[CH:100][C:96](=[O:95])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH:110][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:39]([NH2:41])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:108]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
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: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15 mg (18 μmol) of (N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 3.8 ml of DMF and then admixed with 27 mg (70 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 12 μl of N,N-diisopropylethylamine and with 14 mg (53 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The reaction mixture was stirred at RT for 1 h. This was followed by concentration under high vacuum and purification of the remaining residue by means of preparative HPLC. Thus, 6.2 mg (33% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:28][CH:27]=[N:26][CH:25]=1)CCC.CCOC(C)=O.[F-].[K+]>C1(C)C=CC=CC=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>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:24]3[S:28][CH:27]=[N:26][CH:25]=3)[CH:7]=2)=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[N:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cncs2)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
A solution of Example A4 (0.35 g, 1.318 mmol) in toluene (8 mL) was sparged with Ar, treated with 5-(tributylstannyl)thiazole (0.493 g, 1.318 mmol) and Pd(PPh3)4 (0.152 g, 0.132 mmol), heated at 110° C. for 16 h, then cooled to RT. The mixture was treated with EtOAc and 10% aq. KF solution, stirred for 1 h and the solids were removed via filtration through diatomaceous earth. The layers of the filtrate were separated, the aqueous layer extracted with additional EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 5-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (270 mg, 65%) as a pale orange solid. 1H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.62 (s, 1H), 8.53 (d, J=5.7 Hz, 1H), 8.24 (d, J=8.7 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.06 (dd, J=5.7, 2.4 Hz, 1H), 2.51 (s, 3H); MS (ESI) m/z: 315.1 (M+H+).