Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]([CH2:15][NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[OH:14])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:16]([CH2:15][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1)[OH:14])[C:17]([CH3:20])([CH3:18])[CH3:19])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)NCC(O)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N(CC(O)c1cccc(Cl)c1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (0.21g, 0.15ml) in dichloromethane (5ml) was added dropwise, under nitrogen to a stirred, ice-cooled solution of 3-chloro-α-[[[1,1-dimethylethyl]amino]methyl]benzenemethanol (0.5g) and triethylamine(0.38g, 0.53ml) in dichloromethane (40ml). The reaction mixture was stirred at ambient temperature for 2h., washed with hydrochloric acid (2N), brine, dried (MgSO4), evaporated and chromatographed on silica. Elution with chloroform gave α-chloro-N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[1,1- dimethylethyl]acetamide as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].COS(=O)O[CH2:16][CH2:17][NH:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CN(C=O)C>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:18][CH2:17][CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COS(=O)OCCNc1nc2ccccc2o1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCNc2nc3ccccc3o2)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4-hydroxybenzaldehyde (6.1 g, 50 mmol) in dry DMF (40 mL), was added sodium hydride (2.2 g, 55 mmol, 60% suspension) under stirring, in a nitrogen atmosphere at room temperature. The thick solution was diluted with dry DMF (20 mL). Sulfurous acid 2-(benzooxazol-2-ylamino)-ethyl ester methyl ester [compound of Step III] (14 g, 55 mmol) dissolved in dry DMF was added dropwise to the reaction mixture over a period of 20 min and the resulting mixture was heated to 80° C. for 1 hour. The reaction mixture was poured on crushed ice and then extracted with ethyl acetate (3×200 mL). The ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified using silica gel column and 50% ethyl acetate in petroleum ether to give 4-[2-(benzooxazol-2-ylamino)-ethoxy]-benzaldehyde.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:4]=1[CH:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]([N:26]=[C:27]=[S:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C(N(CC)CC)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:3]([CH2:2][NH:1][C:27]([NH:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[S:28])=[C:4]([CH:5]([OH:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:13]=1
Reactant: NCc1ccc(Cl)cc1C(O)c1ccccc1
Reactant: S=C=NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: OC(c1ccccc1)c1cc(Cl)ccc1CNC(=S)NCCc1ccccc1

Procedure:
2-aminomethyl-5-chlorobenzhydrol (10 g; 0.04 mole) in 100 ml methanol and 2 ml triethylamine was treated dropwise with a solution of phenethyl isothiocyanate (8.6 g; 0.053 mole) in 25 ml of methanol. After 16 hours at room temperature the reaction mixture was evaporated and the residue was extracted with petroleum ether. The residual oil was recrystallized from diisopropyl ether to yield 1-(4-chloro-2-(α-hydroxybenzyl)benzyl)-3-phenethylthiourea as a white powder (M.Pt. 97° -- 101° ).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:10][C@H:9]1[CH:11]([NH:13][O:14][CH3:15])[CH3:12].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:10][C@H:9]1[CH:11]([N:13]([O:14][CH3:15])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31])[CH3:12]
Reactant: CONC(C)[C@@H]1C[C@H]1c1ccccc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
To a stirred solution of trans N-{1-[2-(2-chloro-phenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine (0.30 g; 1.3 mmol) prepared as described in example P12 and triethylamine (0.25 ml; 1.7 mmol) in dichloromethane (5.0 ml) at ambient temperature was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.28 g; 1.3 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (50 ml) and extracted with dichloromethane (3×25 ml). Combined organic layers were washed with water (10 ml), brine and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 1:99) to afford 0.46 g (92% of theory) of trans 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid {1-[2-(2-chloro-phenyl)-cyclopropyl]-ethyl}-methoxy-amide as single diastereomere A in form of a clear viscous oil.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[N:21]([CH2:22][C:23]2[S:27][C:26]3[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=3[CH:24]=2)[C:11]2=[CH:12][N:13]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=[C:10]2[CH:9]=1)=[O:7])C.Cl>O.C1COCC1.CO>[Cl:32][C:29]1[CH:30]=[CH:31][C:25]2[CH:24]=[C:23]([CH2:22][N:21]3[C:11]4=[CH:12][N:13]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=[C:10]4[CH:9]=[C:8]3[C:6]([OH:7])=[O:5])[S:27][C:26]=2[CH:28]=1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2n1Cc1cc2ccc(Cl)cc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cc2cc(C(=O)O)n(Cc3cc4ccc(Cl)cc4s3)c2cn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
8 mL of a 1M LiOH solution in water were added to solution of 890 mg (2 mmol) 1-(6-Chloro-benzo[b]thiophen-2-ylmethyl)-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester in 30 mL THF and 15 mL MeOH and the mixture was stirred for 1 h at 50° C. 16 mL of 1N HCl were added, the organic solvent removed in vacuo and the residue extracted with ethyl acetate. The organic phase was dried over MgSO4. After filtration the solvent was evaporated yielding the desired product. Yield: 810 mg.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.BrCC1C=C([N+]([O-])=O)C=C2C=1N=[C:25](OC)[C:26]([O:35]C)=N2.C(OC(=O)C)(=O)C.C(N(CC)CC)C>C(N(CC)C=O)C.C(OCC)C>[CH3:17][O:16][C:7]1[C:6]([O:18][CH3:19])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][NH:1][C:26](=[O:35])[CH3:25])[N:8]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Agent: CCN(C=O)CC
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1nc2cc([N+](=O)[O-])cc(CNC(C)=O)c2nc1OC

Procedure:
111 mg (0.437 mmol) of 5-aminomethyl-2,3-dimethoxy-7-nitro-quinoxaline, obtainable in a manner analogous to that described in Example 9 but starting from 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, are stirred with 0.046 ml (1.1 equiv.) of acetic anhydride and 0.073 ml (1.2 equiv.) of triethylamine in 5 ml of N,N-diethylformamide at room temperature for 24 hours. The reaction mixture is diluted with diethyl ether, and the solid is filtered off, washed with diethyl ether and dried.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:57]2[CH2:67][CH2:66][C:60]3([C:64](=[O:65])[O:63][CH2:62][CH2:61]3)[CH2:59][CH:58]=2)O1>>[O:42]=[S:38]1(=[O:41])[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][NH:32][C@:16]23[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]2[C@@H:18]2[C@@:13]([CH3:43])([CH2:14][CH2:15]3)[C@@:12]3([CH3:44])[C@@H:21]([C@:22]4([CH3:25])[C@@H:9]([CH2:10][CH2:11]3)[C:8]([CH3:45])([CH3:46])[C:7]([C:57]3[CH2:67][CH2:66][C:60]5([C:64](=[O:65])[O:63][CH2:62][CH2:61]5)[CH2:59][CH:58]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:36][CH2:37]1
Reactant: CC1(C)OB(C2=CCC3(CCOC3=O)CC2)OC1(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC7(CCOC7=O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the procedure described in general procedure Step 5, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-oxaspiro[4.5]dec-7-en-1-one as reactants and 85° C. The product was obtained as a mixture of diasteroisomers and was used without further purification in the next step. MS: m/e 721 (M+H)+, 2.72 min (method 4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[I:23]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:23])=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1cc(F)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture of tert-butyl 4-(2-fluoro-4-methoxyphenyl)piperidine-1-carboxylate (Step A; 255 mg; 0.825 mmol) in MeOH (15 mL) was treated with iodine (345 mg; 1.107 mmol) and silver sulfate (281 mg; 1.107 mmol). The reaction was stirred at room temperature for 2 h. The reaction was filtered through Celite and the filtrate was concentrated in vacuo. The residue was redissolved in ether (50 mL) and washed with H2O (50 mL). The aqueous layer was extracted with ether (3×50 mL) and the combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% EtOAc/hexanes gradient) to afford tert-butyl 4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidine-1-carboxylate as a colorless glass. The aqueous layer was then re-extracted with EtOAc (3×100 mL) and the combined extracts were dried (MgSO4), filtered, and the solvent was removed under reduced pressure until a precipitate formed. This solid was collected by filtration and dried in a vacuum oven to afford 4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidine as a off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30]CC)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)(O)[O-].[Na+].C(O)(=O)C>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 51.3 %

Procedure:
A mixture of 7-[2-(2-aminothiazol-4-yl)-2ethoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.45 g) and sodium bicarbonate (0.63 g) in water (15 ml) was stirred at ambient temperature for 7 days. The reaction mixture was adjusted to pH 6.0 with acetic acid. The solution was subjected to column chromatography on macroporous nonionic adsorption resin "Diaion HP-20 " (30 ml) and eluted with water. The eluate was acidified to pH 2.2 with 10% hydrochloric acid under ice-cooling. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.7 g), which was identified by comparing the physico-chemical data with those of the object compound in Example 90.
Reaction SMILES: [C:1]([C:9](=[CH:15]OCC)[C:10]([O:12]CC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([N:25]2[C:29]([NH2:30])=[CH:28][CH:27]=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[OH:12][C:10]1[C:9]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[CH:15][N:30]=[C:29]2[N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:26]=[CH:27][C:28]=12
Reactant: Nc1ccnn1-c1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1O
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
A mixture of ethyl 2-benzoyl-3-ethoxyacrylate (0.99 g, 4.0 mmol) and 1-phenyl-1H-pyrazol-5-amine (0.64 g, 4.0 mmol) was stirred at 120° C. for 1.5 hr under argon and then cooled. After diphenyl ether (5 g) was added, the mixture was stirred at 240° C. for 2 hr under argon. Flash chromatography and crystallization in heptane and ethyl acetate mixture gave (4-hydroxy-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (0.53 g, 1.7 mmol, 42% yield) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.Cl>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C=Cc2ccc(N)cc2)cc1
Temperature: 60 °C

Procedure:
A portion (20.27 grams, 0.075 mole) of 4,4'-dinitrostilbene from A above, concentrated hydrochloric acid (150 milliliters) and ethanol (300 milliliters) are added to a beaker and heated to provide a 60° C. stirred solution. Over the next eight hour period, 325 mesh powdered iron is added to the reaction mixture in aliquots until a total of 33.51 grams (0.60 mole) has been added. After completion of the iron addition, the mixture is heated for 16 hours at 60° C. then diluted with ethanol (250 milliliters) and deionized water (250 milliliters). After cooling to 25° C., the product is filtered. The resultant solution is treated with 50% aqueous sodium hydroxide sufficient to induce precipitation of a pale tan colored product which is recovered by filtration. The recovered filter cake is washed with deionized water (500 milliliters) then dried in a vacuum oven at 100° C. and 2 mm Hg to a constant weight of 11.3 grams. The product is recovered as a pale tan colored solid. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product confirms the product structure: Disappearance of the absorbances observed for the conjugated nitro group, appearance of --NH2 stretching absorbances at 3436 (3462 shoulder) and 3356 (3376 shoulder) cm-1, a --NH2 bending absorbance at 1616 cm-1 (1603 cm-1 shoulder due to aromatic ring absorbance), an out-of-plane C--H deformation at 970 cm-1 due to the trans substituted ethylene group and a C--H out-of-plane bending vibration at 832 cm-1 due to the para-disubstituted aromatic rings. Proton nuclear magnetic resonance spectroscopy further confirms the product structure.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].C[O-].[Na+].CO.[CH3:10][C:11]([CH3:20])([CH3:19])[C:12](=O)[CH2:13][C:14](OC)=[O:15]>C(O)(=O)C.O>[C:11]([C:12]1[CH:13]=[C:14]([OH:15])[N:4]=[CH:2][N:3]=1)([CH3:20])([CH3:19])[CH3:10]
Reactant: COC(=O)CC(=O)C(C)(C)C
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
First, 7.2 g of formamidine hydrochloride, 7.5 g of sodium methoxide, and 70 mL of methanol were put into a 100 mL three-neck flask. Then, 10 g of methyl 4,4-dimethyl-3-oxovalerate was added to this mixed solution. The mixture was stirred at room temperature for 24 hours. After that, a mixed solution of 17 mL of water and 7.2 mL of acetic acid was added to the reacted solution, and the mixture was stirred at room temperature. This mixture was concentrated, and the resulting residue was dissolved in water. The solution was subjected to extraction with ethyl acetate. The obtained solution of the extract was washed with saturated brine, and magnesium sulfate was added for drying. After the drying, the solution was filtered. After the solvent of this solution was distilled off, the obtained solid was washed with ethyl acetate, so that the pyrimidine derivative to be produced was obtained as a white solid in a yield of 49%. A synthesis scheme of Step 1 is shown in (k-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperazine-1-carboxylate (0.0394 g, 0.0983 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0131 g, 0.0894 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-ynyl)piperazine-1-carboxylate (0.0315 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:31]=[CH:32][N:33]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].C(O)(C(F)(F)F)=O>ClCCl>[NH2:23][CH:20]1[CH2:21][CH2:22][N:18]([C:16]2[CH:17]=[C:12]([NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[N:7]=3)[C:13]3[N:14]([CH:31]=[CH:32][N:33]=3)[N:15]=2)[CH2:19]1
Reactant: COc1ccc(Nc2cc(N3CCC(NC(=O)OC(C)(C)C)C3)nn3ccnc23)nc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2cc(N3CCC(N)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 126.6 %

Procedure:
A suspension of tert-butyl 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamate (180 mg, 0.40 mmol) and TFA (2 mL) in dichloromethane (5 mL) was stirred at 25° C. for 6 h. The residue was concentrated to give 6-(3-aminopyrrolidin-1-yl)-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (180 mg, crude) as a red liquid. This was used directly without purification. LC-MS: 356 [M+1]+, tR=1.187 min.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:6][C:5]=2[NH:4][N:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:6][C:5]2[NH:4][N:3]=[C:2]([CH3:1])[C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccccc1C1CC(=O)c2c(C)n[nH]c2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)n[nH]c2C1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
A mixture of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindazol-4-one (0.15 g), aminoguanidine hydrochloride (0.072 g), concentrated hydrochloric acid (0.062 ml), water (0.062 ml) and ethanol (30 ml) was stirred at 50° C. for 3 hours and at 80° C. for 1.5 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with diethylether. To the aqueous layer was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and to the residue was added 1N hydrochloric acid (1.5 ml). Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 20) (0.18 g) as colorless crystals.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[CH2:16][CH2:15][CH2:14][NH:13][C:12]=3[N:11]=2)[CH2:6][CH2:5][N:4]1[CH2:20][C:21]([OH:23])=O.CN1CCOCC1.CC#N.F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:45]2C=CC=[CH:49][C:44]=2N=N1.[CH3:61][CH2:62][O:63][C:64]([CH3:66])=[O:65]>>[CH2:62]([O:63][C:64](=[O:65])[CH2:66][C@@H:45]([C:44]#[CH:49])[NH:41][C:21](=[O:23])[CH2:20][N:4]1[CH2:5][CH2:6][CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[CH2:16][CH2:15][CH2:14][NH:13][C:12]=3[N:11]=2)[C:3]1=[O:2])[CH3:61]
Reactant: O=C(O)CN1CCC(CCc2ccc3c(n2)NCCC3)C1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCOC(C)=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: C#C[C@H](CC(=O)OCC)NC(=O)CN1CCC(CCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 20 h

Procedure:
To a stirred solution of 2-8 (50 mg, 0.15 mmol), 2-9 (29 mg, 0.17 mmol) (Zablocki et al., J. Med Chem., 1995, 38, 2378), NMM (83 μL, 0.75 mmol), and CH3CN (1 mL) was added BOP (74 mg, 0.17 mmol). After 20 h, the reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3, H2O and brine, dried (MgSO4), and concentrated to give 2-11 as a yellow oil.
Reaction SMILES: C(O)C.[OH-].[K+].[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[C:22]([Br:39])[N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([O:36]CC)=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH:16]=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]>O>[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[C:22]([Br:39])[N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([OH:36])=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH:16]=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)c(Br)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nn(-c3ccccc3C(=O)O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Ethanol (1.2 ml ), ion-exchanged water (0.3 ml ), and potassium hydroxide (28 mg) were added to 2-butyl4-chloro-1-[3-bromo-2- (2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-1 H-imidazole-5-carbaldehyde (101 mg, 0.186 mmol) as obtained in Example 1, and the mixture was stirred at room temperature for one day. The mixture was concentrated in an evaporator, and partitioned by ion-exchanged water (2.5 ml) and diethyl ether (5 ml). The water layer was separated and conc. hydrochloric acid was dropwise added thereto to adjust its pH to 5. The resultant solid was filtered off and washed three times with ion-exchanged water (1 ml). The solid was dried in vacuo overnight at 37° C. to give 72 mg of 2-butyl-4-chloro-1-[3-bromo-2-(2-carboxyphenyl)-2H-indazol-5-yl]methyl-1H-imidazole-5-carbaldehyde.