Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]([O:13][N:14]=[C:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH3:12]>CCOCC>[CH2:11]([O:13][N:14]=[C:15]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH3:12]
Reactant: c1c[nH]cn1
Reactant: CCON=C(Cl)c1ccccc1SCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCON=C(c1ccccc1SCc1ccc(Cl)cc1)n1ccnc1
Temperature: 170 °C
Reaction time: 21 h
Yield: 14.8 %

Procedure:
DMF (3 ml) and imidazole (0.41 g) were added to α-chloro-2-(4-chlorobenzylthio)benzaldehyde O-ethyloxime (0.68 g), and the mixture was stirred at 170° C. for 21 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography and recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorobenzylthio)-α-(1-imidazolyl)benzaldehyde O-ethyloxime (0.11 g) as colorless crystals. mp. 96.5°-97.5° C.
Reaction SMILES: [CH:1]([C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[N:10][N:11]2C(OC(C)(C)C)=O)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:11]1[C:12]2[C:8](=[C:7]([CH2:6][O:5][C:4]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:3]=3[CH:1]=[O:2])[CH:15]=[CH:14][CH:13]=2)[CH:9]=[N:10]1
Reactant: COc1ccc(OCc2cccc3c2cnn3C(=O)OC(C)(C)C)c(C=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OCc2cccc3[nH]ncc23)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To tert-butyl 4-((2-formyl-4-methoxyphenoxy)methyl)-1H-indazole-1-carboxylate (88 mg, 0.23 mmol) in DCM (5.0 mL) was added TFA (2.0 mL). The mixture was stirred at rt for 2 h and concentrated. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-((1H-indazol-4-yl)methoxy)-5-methoxybenzaldehyde (50 mg, 77%) as a white solid. 1H NMR (400 MHz; CDCl3) δ=10.53 (s, 1H), 8.23 (s, 1H), 7.54 (d, 1H) 7.43 (t, 1H), 7.38 (d, 1H), 7.25 (d, 1H), 7.08-7.15 (m, 2H), 5.51 (s, 2H), 3.82 (s, 3H). LRMS (M+H+) m/z 283.1.
Reaction SMILES: B.O1CC[CH2:4][CH2:3]1.O1CCCC1.ClC1C=CC([C@H]2N3C(SC(C(N4[CH2:47][C@H:46](F)[CH2:45][C@H:33]4[C:34]([N:36]4[CH2:43][C:40]5([CH2:42][CH2:41]5)[NH:39][CH2:38][C@@H:37]4C)=O)=O)=C3C(C)C)=N[C@]2(C2C=NC(Cl)=CC=2)C)=CC=1F.CO>C(OCC)(=O)C>[CH2:34]([N:36]1[CH2:43][C:40]2([CH2:41][CH2:42]2)[NH:39][CH2:38][CH2:37]1)[C:33]1[CH:45]=[CH:46][CH:47]=[CH:4][CH:3]=1
Reactant: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)NC[C@@H]2C)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Reactant: C1CCOC1
Agent: B
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCNC3(CC3)C2)cc1
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A borane-tetrahydrofuran complex (0.93 M tetrahydrofuran solution) (375 ml, 0.35 mol) was added to a tetrahydrofuran (200 ml) solution of the compound (20 g, 86.8 mmol) obtained in Step 2 above under ice cooling and then the resulting mixture was heated to reflux for 19 hours. Methanol (130 ml) was added to the reaction mixture under ice cooling, the resulting mixture was stirred for 60 minutes and then the solvent was concentrated under reduced pressure. Ethanol (450 ml), water (150 ml), and triethylamine (150 ml) were added to the residue obtained, the resulting mixture was heated to reflux for 2 hours and then the solvent was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=10:1 (v/v)] to give the title compound (10.4 g, 59%) as a colorless oil.
Reaction SMILES: [Li+].[OH-].[CH:3]1([CH2:6][N:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([O:15]C)=[O:14])[C:8]2=[O:17])[CH2:5][CH2:4]1.Cl>C1COCC1.CO>[CH:3]1([CH2:6][N:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([OH:15])=[O:14])[C:8]2=[O:17])[CH2:5][CH2:4]1
Reactant: COC(=O)c1nccn(CC2CC2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nccn(CC2CC2)c1=O
Reaction time: 2 h

Procedure:
LiOH (0.84 mL, 0.84 mmol, 1.0 M) was added to a solution of methyl 4-(cyclopropylmethyl)-3-oxo-3,4-dihydropyrazine-2-carboxylate (87 mg, 0.42 mmol) in a mixture of THF-MeOH (3:1 ratio, 2 mL) at room temperature. After stirring for 2 hours, the reaction mixture was acidified to pH 1 with aq. 1N HCl solution (0.14 mL) and then concentrated to afford the desired product salt. 1H NMR (400 MHz, CD3OD) δ 7.67 (d, 1H), 7.37 (m, 1H), 3.86 (d, 2H), 1.32 (m, 1H), 0.61 (m, 2H), 0.45 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].C1C(=O)N([I:24])C(=O)C1>CN(C=O)C>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:5][C:6]([CH2:9][CH3:10])=[C:7]([I:24])[N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(NC(CC)CC)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CCc1nc(NC(CC)CC)c(CC)nc1I
Yield: 74 %

Procedure:
A solution of 3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine, NIS (5.37 g, 23.9 mmol) and anhydrous DMF (100 mL) under N2 was heated at 50° C. for 4 h. The solution was partitioned between ethyl acetate and H2O and separated. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with H2O, brine and dried (MgSO4). The mixture was filtered and concentrated to give a brown oil which was purified by flash chromatography (20% ethyl acetate in heptane) to give 5.57 g (74%) of 3,6-diethyl-N-(1-ethylpropyl)-5-iodopyrazin-2-amine as a light brown oil. 1H NMR (400 MHz, CDCl3) δ 4.02 (m, 2 H), 2.76 (q, 2 H), 2.57 (q, 2 H), 1.60-1.70 (m, 2 H), 1.45-1.55 (m, 2 H) 1.20-1.30 (m, 6 H), 0.92 (q, 6 H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([CH2:18][NH:19][OH:20])=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[O:23]([C:25]#[N:26])[K]>O.C(O)(=O)C>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]([OH:20])[C:25]([NH2:26])=[O:23])=[CH:21][CH:22]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(CNO)cc1
Reactant: N#CO[K]
Solvent: CC(=O)O
Solvent: O
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(CN(O)C(N)=O)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a stirred solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl hydroxylamine (303 mg, 1.0 mmol) (obtained from preparation 18) in a mixture of water (2 ml) and acetic acid (0.5 ml) was added a solution of KOCN (343 mg, 3.0 mmol) in water (1 ml) and stirred for 1 h at 30° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the compound (295 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>O1CCCC1.[Ni].O>[F:11][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([F:1])[C:3]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(F)c(N2CCSCC2)c(F)c1
Reaction time: 24 h

Procedure:
A solution of 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine (3.00 g, 11.5 mmol) in tetrahydrofuran (60 mL) is added to a Parr bottle containing a mixture of Raney nickel (1 g) in water (15 mL) under N2, and the reaction mixture is shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for 24 hrs. The catalyst is removed by filtration through Celite, rinsing with tetrahydrofuran and water, the filtrate is diluted with water (50 mL) and EtOAc (50 mL), and the layers are separated. The organic phase is washed with saline (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting oil is chromatogtaphed on a Flash 40M 90 g silica gel cartridge eluting with EtOAc/heptane (15/85). Pooling and concentration of those fractions with an Rf=0.19 by TLC (EtOAc/hexanes, 25/75) gives the title compound, mp 85-86° C.; MS (ESI+) for C10H12N2F2S m/z 231 (M+H)+.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]2)[CH2:2]1.[CH2:13]([NH2:15])[CH3:14]>>[CH2:13]([NH:15][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1)[CH3:14]
Reactant: CCN
Reactant: COC(=O)N1CCCC2(CO2)C1
Product: CCNCC1(O)CCCN(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.3 g (54.3 mmol) of methyl 5-aza-1-oxaspiro[2,5]octane-5-carboxylate are added dropwise to 50 ml of ethylamine solution (50% strength in water) and the mixture is stirred overnight at room temperature. It is then concentrated and the residue is distilled.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[SH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:14][CH2:15][C:16]2[CH:21]=[N:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: FC(F)(F)COc1ccc(CS)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)n1ncc(SCc2ccc(OCC(F)(F)F)nc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
In 40 ml of methanol were dissolved 2.2 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone and 2.4 g of 5-mercaptomethyl(2,2,2-trifluoro-ethoxy)-pyridine, and thereto was added 1.2 g of sodium carbonate. The reaction mixture was stirred overnight at room temperature and then poured into water. Then, procedures similar to those in Preparation Example 24 were conducted to obtain 3.6 g of 2-t-butyl-4-chloro-5-[{6-(2,2,2-trifluoroethoxy)-3-pyridyl}-methylthio]-3(2H)-pyridazinone, m.p. 109.0°~110.0° C.
Reaction SMILES: [F:1][C:2]([F:16])([CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:6]([O:5][C:3]([C:2]([F:16])([F:1])[CH:8]([O:15][C:27]([C:17]12[CH2:26][CH:21]3[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]3)[CH2:24]1)[CH2:18]2)=[O:28])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4])[CH3:7]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C(F)(F)C(O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(F)(F)C(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Ethyl 2,2-difluoro-3-hydroxy-3-phenylpropionate acid (9 g) prepared in Synthesis Example 1-4 and 1-adamantanecarbonyl chloride (9.5 g) were dissolved in methylene chloride (60 g), and a mixed solution of triethyl amine (6 g), 4-dimethyl aminopyridine (0.5 g) and methylene chloride (20 g) was dropped into the obtained solution under ice cooling. After aging overnight, 5% by mass hydrochloric acid was added to the product and quenched, and then the reaction solution was washed with water, and concentrated. Methylisobutyl ketone was added to the concentrated solution, and was concentrated again to obtain a target compound, or 1-adamantane carboxylic acid 2-ethoxycarbonyl-2,2-difluoro-1-phenyl-ethyl ester (15 g) as a colorless oily matter (yield: 68%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[C:2]1=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>O>[NH:16]1[C:2]2[NH:1][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[N:12]=[N:13][C:14]1=[S:15]
Reactant: NNC(N)=S
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: S=c1nnc2c([nH]1)[nH]c1ccccc12
Temperature: 25 °C

Procedure:
To a solution of indole-2,3-dione 14b (74 mmol, 1 equiv.) in water (600 mL) is added thiosemicarbazide 14a (81.4 mmol, 1.1 equiv.) and potassium carbonate (11 mmol, 1.5 equiv.) as disclosed in Gladych, J. M. Z.; Hornby, R.; Hunt, J. H.; Jack, D.; Boyle, J. J.; Ferlauto, R. J.; Haff, R. F.; Kornendy, C. G; Standfield, F. J.; Stewart, R. C. J. Med. Chem. 1972, 15, 277-281 and references cited therein. The solution is stirred and refluxed for 7 hours. The red-orange solution is allowed to cool to room temperature overnight. The solution is acidified with acetic acid, and a yellow precipitate forms. The precipitate is filtered and washed with water, and dried under vacuum for 15 hours to yield 1,9-Dihydro-1,3,4,9-tetraaza-fluorene-2-thione 14c as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.N1C=CC=CC=1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>ClCCl>[F:1][C:2]([F:9])([F:8])[C:3]1([O:7][C:17](=[O:18])[O:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: OC1(C(F)(F)F)CCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1(C(F)(F)F)CCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.1 %

Procedure:
To 1-trifluoromethyl-cyclobutanol (2.2 g, 15 mmol) in dichloromethane (7.5 mL, 2M) was added pyridine (3 mL) and 4-nitrophenyl chloroformate (4 g, 18.3 mmol). The flask was sealed and stirred at room temperature for 2 days. The reaction was diluted with dichloromethane (50 mL) and washed with 1M KHSO4(aq), saturated sodium bicarbonate, water, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (gradient elution with 10% to 40% EtOAc in hexane) gave 2.2 g (48% yield) of carbonic acid 4-nitro-phenyl ester 1-trifluoromethyl-cyclobutyl ester as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.35 (d, 2H), 7.50 (d, 1H), 2.78-2.85 (m, 2H), 2.58-2.70 (m, 2H), 1.9-2.1 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:13])[C:5]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:6]=2[N:7]=1.[CH2:14]([Sn](CC)(CC)CC)[CH3:15]>COCCOC.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>[CH2:14]([C:2]1[N:3]=[N+:4]([O-:13])[C:5]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:6]=2[N:7]=1)[CH3:15]
Reactant: CC[Sn](CC)(CC)CC
Reactant: [O-][n+]1nc(Cl)nc2cc(F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc2cc(F)ccc2[n+]([O-])n1
Yield: 89.8 %

Procedure:
Pd(PPh3)4 (196 mg, 0.17 mmol) was added to a stirred solution of chloride 27 (329 mg, 1.7 mmol) and tetraethyltin (0.7 mL, 3.3 mmol) in DME (20 mL), the solution degassed, and stirred under N2 at reflux temperature for 16 h. The solvent was evaporated and the residue purified by chromatography, eluting with 20% EtOAc/pet. ether to give an oil which was further purified by chromatography, eluting with 5% EtOAc/DCM, to give 1-oxide 28 (295 mg, 93%) as a white solid, mp (EtOAc/pet. ether) 122-124° C.; 1H NMR δ 8.48 (dd, J=9.5, 5.5 Hz, 1 H, H-8), 7.60 (dd, J=8.7, 2.6 Hz, 1 H, H-5), 7.38 (m, 1 H, H-7), 3.04 (q, J=7.6 Hz, 2 H, CH2), 1.43 (t, J=7.6 Hz, 3 H, CH3); 13C NMR δ 168.6 (q, J=175 Hz), 165.1, 149.5(d, J=15 Hz), 130.5, 123.2 (d, J=11 Hz), 120.0 (d, J=26 Hz), 112.7 (d, J=22 Hz), 30.7, 12.2. Anal. Calcd for C9H8FN3O: C, 56.0; H, 4.2; N, 21.8. Found: C, 56.0; H, 4.2; N, 21.8%.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([C:15]#[N:16])[C@H:10]([CH3:17])[CH2:9]1)=O)(C)(C)C.[ClH:18].O1CCOCC1>C1COCC1>[ClH:18].[CH3:17][C@H:10]1[CH2:9][NH:8][CH2:13][C@@H:12]([CH3:14])[N:11]1[C:15]#[N:16]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[C@@H]1CNC[C@H](C)N1C#N
Reaction time: 5 h

Procedure:
4-Cyano-cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.0 g) in 10 mL THF was treated with 4.0 N HCl/dioxane (25 mL), stirred for five hours and concentrated to provide 1.1 g of the title compound. 1H NMR (DMSO-D6, 300 MHz) δ ppm 1.24 (d, 6H, J=6.6 Hz), 2.65 (q, 2H, J=11.1 Hz), 3.27 (d, 2H, J=12.2 Hz), 3.63 (m, 2H); 13C (DMSO, 75 MHz) 16.73 (2C), 46.81 (2C), 50.80 (2C), 104.20.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)(=[O:5])=[O:4])[CH3:2].C([Li])CCC.CCCCCC.[CH2:25]([Sn:29](Cl)([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28].[Cl-].[NH4+]>C1COCC1>[CH2:1]([S:3]([C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[C:12]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])[S:11][C:10]=12)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(=O)(=O)CC)c2s1
Reaction time: 0.25 h

Procedure:
A solution of 669 mg of 7-ethanesulfonylimidazo[5,1-b]thiazole in 30 ml of THF was cooled to −40° C. in an argon atmosphere. A 1.6 N n-butyllithium/n-hexane solution (4.3 ml) was added dropwise thereto at the same temperature. The mixture was stirred for 15 min. Tri-n-butylstannyl chloride (0.88 ml) was added thereto, followed by stirring at the same temperature for 10 min. A saturated aqueous ammonium chloride solution was added thereto. The mixture was extracted twice with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1). The title compound (1.54 g) was obtained from the fraction of Rf=0.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([NH:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)CN1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
A mixture of 1-benzyl-piperazine (1.0 g, 5.67 mmol), 2-chloro-N-methylacetamide (671.2 mg, 6.24 mmol, 1.1 eq.), and potassium carbonate (941 mg, 6.81 mmol, 1.2 eq.) in anhydrous THF (23 mL) was stirred at 60° C. under N2 for 18 h. The mixture was cooled to rt and poured into EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (Biotage®, gradient elution 1:4:5 v/v MeOH:Acetone:DCM) to give 1.16 g (83%) of the product as a white solid. 1H-NMR (300 MHz, DMSO-d6) 7.62 to 7.56 (broad d, 1H), 7.33 to 7.20 (m, 5H), 3.45 (s, 2H), 2.85 (s, 2H), 2.58 (d, 3H), 2.44 to 2.33 (broad s, 8H); ES-MS m/z 248.2 [M+H]+, RT (min) 0.33.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([N:10]=[C:11]=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[C:26]=2[N+:32]([O-:34])=[O:33])=[CH:22][C:21]=1[F:37]>>[NH2:31][C:27]1[C:26]([N+:32]([O-:34])=[O:33])=[C:25]([O:24][C:23]2[CH:35]=[CH:36][C:20]([NH:19][C:11]([NH:10][C:8]3[N:7]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=3)=[O:12])=[C:21]([F:37])[CH:22]=2)[CH:30]=[CH:29][N:28]=1
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1F
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(N)c3[N+](=O)[O-])cc2F)n(-c2ccccc2)n1

Procedure:
Using Method F3 with -tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole (15 mL, 4.05 mmol) and 4-(4-amino-3-fluorophenoxy)-3-nitropyridin-2-amine (893 mg, 3.38 mmol) the title compound was obtained in quantitative yield (1.71 g) as a yellow solid after column chromatography with 5% to 50% EtOAc in CH2Cl2.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([F:16])[C:13]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[CH:12][C:11]=2[F:22])=[CH:6][N:5]=[C:4]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:19]1([CH2:18][O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([C:9]3[O:23][C:2]4[CH:3]=[C:4]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[N:5]=[CH:6][C:7]=4[N:8]=3)=[C:11]([F:22])[CH:12]=2)[CH2:21][CH2:20]1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2cc(F)c(OCC3CC3)cc2F)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc2oc(-c3cc(F)c(OCC4CC4)cc3F)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((4-(cyclopropylmethoxy)-2,5-difluorobenzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (5.39 g), potassium carbonate (2.91 g) and copper(I) iodide (201 mg) in DMF (30 mL) was stirred at 160° C. for 4 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.64 g).
Reaction SMILES: [F:1][C:2]1([C:29]2[CH:34]=C[CH:32]=[CH:31][N:30]=2)[N:6]([O:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:4]=2[NH:3]1.[N:35]1C=CN=CC=1C(O)=O>>[F:1][C:2]1([C:29]2[CH:34]=[N:35][CH:32]=[CH:31][N:30]=2)[N:6]([O:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:4]=2[NH:3]1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3c(c2)N(Oc2cccnc2)C(F)(c2ccccn2)N3)cn1
Reactant: O=C(O)c1cnccn1
Product: CS(=O)(=O)c1ccc(Oc2ccc3c(c2)N(Oc2cccnc2)C(F)(c2cnccn2)N3)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2-fluoro-pyridin-3-yloxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 211 and pyrazine-2-carboxylic acid.