Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C@H:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>C(Cl)Cl>[Br:23][C:24]1[S:28][C:27]([S:29]([N:14]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:9][CH:6]3[CH2:5][CH2:4][O:3][CH2:8][CH2:7]3)[CH2:15]2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: C1CN[C@@H](CC2CCOCC2)CN1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)s1)N1CCN[C@@H](CC2CCOCC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
The (S)-2-((tetrahydro-2H-pyran-4-yl)methyl)piperazine dihydrochloride (390 mg, 1.516 mmol, Intermediate C) was dissolved in CH2Cl2 and the solution was chilled to 0° C. To this solution was added triethylamine (634 μL, 4.55 mmol) followed by 5-bromothiophene-2-sulfonyl chloride (497 mg, 1.90 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was allowed to slowly warm to room temperature and stirring was continued for 2 h. The mixture was concentrated and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give (3S)-1-((5-bromo-2-thiophenyl)sulfonyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)piperazine (520 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][C@@H:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:20]([OH:27])[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:18][C@@H:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:20]([OH:27])[C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(O)C(=O)OC(C)C
Yield: 50.2 %

Procedure:
To a solution of 61 mg of N-benzyloxycarbonyl-L-alanine and 79 mg of isopropyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride in 5 ml of N,N-dimethylformamide were added successively 0.071 ml of diphenylphosphoryl azide and 0.125 ml of triethylamine with stirring under ice-cooling, and the mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified with silica gel flash column chromatography (eluent: chloroform/methanol=20/1 by volume) to obtain 56 mg of isopropyl (2RS, 3S)-3-(N-benzyloxycarbonyl-L-alanyl)amino-2-hydroxy-5-methylhexanoate as a colorless viscous oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].N1C=CC=CC=1>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: COCCOCCOCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COCCOCCOCCCCCCCCS(=O)(=O)c1ccc(C)cc1

Procedure:
A mixture of 40 g of 8-[2-(2-methoxyethoxy)ethoxy]-1-octanol, 35.31 g of tosyl chloride and 200 ml of pyridine was stored in a chill room overnight, then poured into water and extracted with ether. The ether extract was washed successively with water, dilute hydrochloric acid and saturated aqueous sodium bisulfite, dried and the solvent removed, giving the desired compound as an oil which was used without further purification in Example 8.
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](Cl)=[O:18])=[CH:11][CH:10]=1>C(OCC)C>[CH3:5][O:4][P:1]([C:17](=[O:18])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:2])[O:6][CH3:7]
Reactant: COP(OC)OC
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Solvent: CCOCC
Product: COP(=O)(OC)C(=O)CCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 74.8 %

Procedure:
At 0° C., a solution of 3.6 g of trimethyl phosphite in 10 ml of diethyl ether is added dropwise to a solution of 5.1 g of 3-(4-chlorophenyl)propionic acid chloride in 25 ml of diethyl ether. The mixture is first stirred for 2.5 hours at 0° C., then another 2 hours at room temperature. After concentration of the solution, the residue is distilled with the use of a bulb tube at 200°-205° C. and a pressure of 0.02 mm, yielding 5.2 g (74%) of 3-(4-chlorophenyl)-1-oxopropane-1-phosphonic acid dimethyl ester.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[CH3:48])=[CH:19][CH:18]=2)[CH2:15][CH2:14]1>O.C(OCC)(=O)C>[CH:13]1([O:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[CH3:48])=[CH:21][CH:22]=2)[CH2:14][CH2:15]1
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OC3CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.014 g), sodium hydrogen carbonate (0.02 g) and dimethyl sulfoxide (1 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(cyclopropyloxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.097 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-carbonyldiimidazole (0.040 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.040 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.046 g, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.B.Cl>C1COCC1>[OH:13][CH2:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (2.0 g) in THF (30 ml) was added borane-dimethyl sulfide complex (4.0 ml; 10.0 M as borane) under ice-cooled bath, and the mixture was stirred for 8 hours at room temperature. 1 N HCl (10 ml) was added dropwise to the mixture under ice-cooled bath, and THF was removed under reduced pressure. The whole residue was extracted with EtOAc, and the extract was washed with brine and dried over MgSO4. Concentration under reduced pressure gave tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (1.6 g).
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]2[C:12](=[O:13])[CH:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[O:10][C:9]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][S:36]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47]O)=[CH:42][CH:41]=1)(=[O:38])=[O:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:29]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:8]2[C:12](=[O:13])[CH:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:47][CH2:46][C:43]4[CH:42]=[CH:41][C:40]([O:39][S:36]([CH3:35])(=[O:37])=[O:38])=[CH:45][CH:44]=4)=[CH:17][CH:16]=3)[O:10][C:9]2=[O:22])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)Oc1ccc(CCO)cc1
Reactant: O=C1OC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC3OC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Reaction time: 3 h
Yield: 53.3 %

Procedure:
0.28 g (0.623 mmole) 3-triphenylmethyl-5-([4-hydroxyphenyl]methyl)oxazolidine-2,4-dione was under argon atmosphere added to a cooled solution of 0.148 g (0.685 mmole) 2-[4-(methylsulfonyloxy)phenyl]-1-ethanol, 0.173 g (0.685 mmole) 1,1′-(azodicarbonyl)-dipiperidine and 0.18 g (0.685 mmole) triphenylphosphine in 6 ml dichloromethane. After stirring for 3 hours the reaction mixture was filtered and the crude product was purified by chromatography on silica gel using heptane:ethyl acetate (2:2) as eluent to give 0.215 g (yield 53%) of 3-triphenylmethyl-5-([4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl]methyl)oxazolidine-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]1[O:6][C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C:17](Cl)=[O:18].[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH2:28])[CH3:24].Cl>C1C=CC=CC=1>[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH:28][C:17]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[O:6][C:5]([C:4]1[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[CH:3]=1)=[C:14]([CH3:15])[C:13]2=[O:16])=[O:18])[CH3:24]
Reactant: Cc1c(-c2cccc(Cl)c2)oc2c(C(=O)Cl)cccc2c1=O
Reactant: CCN(CC)CCN
Agent: Cl
Solvent: c1ccccc1
Product: CCN(CC)CCNC(=O)c1cccc2c(=O)c(C)c(-c3cccc(Cl)c3)oc12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 33.3 %

Procedure:
To a solution of 3'-chloro-3-methylflavone-8-carboxylic acid chloride (prepared from 1.00 g of 3'-chloro-3-methylflavone-8-carboxylic acid and 0.46 ml of thionyl chloride) in 40 ml of benzene were added 0.33 g of N,N-diethylethylenediamine and the solution was stirred for 80 minutes at room temperature. To the reaction mixture was added aqueous HCl solution and shaken. The water layer was separated and made alkaline with potassium carbonate and extracted with chloroform. The extract was washed with water, dried, and evaporated. The residue was purified by column chromatography (adsorbent: silica gel, eluted with chloroform and chloroform containing 1% of methanol) to give 0.39 g of yellow crystals, which were recrystallized from isopropyl ether as colorless plates, m.p. 116°-117° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.BrC1C2N(C(C(NC3C=CN=CC=3F)=O)=CN=2)N=C(Cl)C=1.[CH3:43][O:44][C:45]1[CH:55]=[CH:54][C:48]([CH2:49][NH:50][CH:51]2[CH2:53][CH2:52]2)=[CH:47][CH:46]=1.C(N(CC)C(C)C)(C)C.[NH2:65][C@H:66]1[CH2:71][CH2:70][C@H:69]([NH2:72])[CH2:68][CH2:67]1>CN(C=O)C.O>[NH2:65][C@H:66]1[CH2:71][CH2:70][C@H:69]([NH:72][C:2]2[CH:3]=[C:4]([N:50]([CH:51]3[CH2:53][CH2:52]3)[CH2:49][C:48]3[CH:54]=[CH:55][C:45]([O:44][CH3:43])=[CH:46][CH:47]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:68][CH2:67]1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Cl)cc(Cl)nn12
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(CNC2CC2)cc1
Agent: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Temperature: 80 °C

Procedure:
A ˜1:1 mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8A (3 g, 8.6 mmol), N-(4-methoxybenzyl)cyclopropanamine (1.79 g, 10.12 mmol) and N,N-diisopropylethylamine (2.41 mL, 13.80 mmol) were suspended in DMF (30 mL) and heated at 80° C. for 1 hr. The reaction mixture was concentrated, dried under reduced pressure for 16 hrs, suspended in methanol (20 mL) and an off-white solid collected via Buchner filtration (2×10 mL methanol rinse) and taken to the next step without further purification. The reaction mixture was combined with trans-1,4-diaminocyclohexane (16.28 g, 143 mmol) and heated at 160° C. for 2.5 hours. The reaction was cooled to room temperature, and water (40 mL) was added, and the solid collected via Buchner filtration. The crude product was purified with silica gel chromatography using a stepwise gradient of 10% methanol/chloroform to 25% methanol/chloroform/1% triethylamine to isolated a foamy solid. The solid was suspended in water (50 mL) and collected with Buchner filtration (2×25 mL water wash) and dried for 16 hrs under reduced pressure to isolate 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (3.2 g, 5.58 mmol, 63% yield) as a off white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.68 (M+H=545.22).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:5][C:4]2[C:13]([CH2:21][CH2:22][CH3:23])=[C:14]3[C:19](=[CH:20][C:3]1=2)[CH2:18][CH2:17][CH2:16][CH2:15]3.[N+:24]([O-])([OH:26])=[O:25].O>S(=O)(=O)(O)O>[N+:24]([C:20]1[C:3]2[C:2](=[O:1])[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:5][C:4]=2[C:13]([CH2:21][CH2:22][CH3:23])=[C:14]2[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]2)([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: CCCc1c2c(cc3c(=O)cc(C(=O)OCC)oc13)CCCC2
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1c2c(c([N+](=O)[O-])c3c(=O)cc(C(=O)OCC)oc13)CCCC2
Temperature: 25 °C
Yield: 79 %

Procedure:
Ethyl 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (9.4 g) was dissolved in concentrated sulphuric acid (100 ml) and cooled to room temperature, and fuming nitric acid (3 ml) was added dropwise, with stirring. The resulting mixture was stirred for a further 3 hours and then poured into water (2 l). The resulting yellow semi-solid was extracted into ether. The organic layer was washed with water, dried (sodium sulphate) and evaporated to give a yellow solid of moderately pure ethyl 6,7,8,9-tetrahydro-5-nitro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (8.5 g; 79%). An analytically pure sample (5 g) was obtained on recrystallisation from cyclohexane, mp 140°-2°.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.[NH2:27][C:28]1[S:29][CH:30]=[C:31]([CH3:33])[N:32]=1>>[CH3:33][C:31]1[N:32]=[C:28]([NH:27][C:2]2[N:3]=[CH:4][C:5]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([C:15]([F:26])([F:25])[F:14])[CH:21]=3)=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[S:29][CH:30]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1csc(N)n1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Product: Cc1csc(Nc2ncc(-c3cccc(C(F)(F)F)c3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=401.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-(trifluoromethyl)phenylboronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[O:40][CH:41]=[CH:42][N:43]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[O:40][CH:41]=[CH:42][N:43]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: O=C1CCC(O)(c2ncco2)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4ncco4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-oxazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C:7](=O)[C:8](=O)[CH3:9])([CH3:4])([CH3:3])[CH3:2].IC1C=CN=C(OC)C=1C=O.C(OC(C1[NH:30][C:31]([C:35]2[C:36]([O:42][CH3:43])=[N:37][CH:38]=[CH:39][C:40]=2[I:41])=[N:32]C=1C)=O)C>>[I:41][C:40]1[CH:39]=[CH:38][N:37]=[C:36]([O:42][CH3:43])[C:35]=1[C:31]1[NH:30][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12])=[C:8]([CH3:9])[N:32]=1
Reactant: CC(=O)C(=O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1[nH]c(-c2c(I)ccnc2OC)nc1C
Agent: COc1nccc(I)c1C=O
Product: COc1nccc(I)c1-c1nc(C)c(C(=O)OC(C)(C)C)[nH]1
Yield: 47 %

Procedure:
2,3-Dioxo-butyric acid tert-butyl ester (0.293 g, 1.54 mmol) and 4-iodo-2-methoxy-pyridine-3-carbaldehyde (0.405 g, 1.54 mmol) were reacted as described for the synthesis of 2-(4-iodo-2-methoxy-pyridin-3-yl)-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester to give the title material (0.303 g, 47%). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 1.58 (s, 9H) 2.46 (s, 3H) 3.85 (s, 3H) 7.64 (d, J=5.31 Hz, 1H) 8.00 (d, J=5.31 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:16][C:15](C=O)([C:17]#[N:18])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[CH2:21]([OH:24])[CH2:22][OH:23].[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:12]2[C:16]([CH:25]3[O:24][CH2:21][CH2:22][O:23]3)=[C:15]([C:17]#[N:18])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: Cn1nc(N2CC(C#N)(C=O)C=N2)c(Cl)c1OC(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nc(-n2ncc(C#N)c2C2OCCO2)c(Cl)c1OC(F)F

Procedure:
0.6 g (2.0 mmol) 1-(4-chlor-5-difluormethoxy-1-methyl-3-pyrazolyl)-4-formyl-4pyrazol-carbonitrile is dissolved in 30 ml toluene and 0.14 g (2.2 mmol) ethylene glycol and a catalytic amount of p-toluene sulphonic acid are added. The mixture is heated for 2 hours on the water-separator, the cooled solution is washed with sodium chloride solution, and it is then dried and concentrated.
Reaction SMILES: [C:1]1(O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=1.COC.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N>CO>[C:12]1([NH:18][N:19]=[C:1]2[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccccc1
Reactant: OC1=NCCCCC1
Agent: COC
Agent: N
Solvent: CO
Product: c1ccc(NN=C2CCCCCN2)cc1
Yield: 45.3 %

Procedure:
When a mixture of 127 g (1 mole) of caprolactim-methylether and 108 g (1 mole) of phenylhydrazine was heated from 140° to 200°C over the course of 6 hours, 34 g (theoretically 32 g of methanol) of a distillate with a pungent smell of ammonia passed over at boiling point 60° to 140°C. The distillation of the reaction product yielded, in addition to a first runnings of starting material and 35 g of distillation residue, 92 g of caprolactam-phenylhydrazone of boiling point 125°C/0.1 mm Hg, in the form of a yellow crystalline mass which assumed a resinous brown discoloration in air. The yield was only 45.5% of theory.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:3]=1.Cl.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH:23]([C:28](OC)=O)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-:32].[NH4+]>C(O)(=O)C>[CH2:14]([N:21]1[CH2:26][C:25](=[O:32])[C:24]2[N:1]=[C:2]3[N:3]=[C:4]([N:7]4[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)[NH:5][N:6]3[CH2:28][C:23]=2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: Nc1nc(N2CCOCC2)n[nH]1
Reactant: [OH-]
Agent: Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C1CN(Cc2ccccc2)CC2=C1N=C1N=C(N3CCOCC3)NN1C2
Reaction time: 6 h
Yield: 72 %

Procedure:
A mixture of 50.76 g (0.3 mole) of 5-amino-3-morpholino-1H-1,2,4-triazole, 85.13 g (0.3 mole) of 1-benzyl-3-carbomethoxy-4-piperidone-hydrochloride and 175 ml of acetic acid is heated to boiling for 6 hours. After cooling 400 ml of concentrated ammonium hydroxide solution are added to the reaction mixture, which is then allowed to stand at room temperature for 16 hours. The precipitated crystals are filtered and washed with 200 ml of water. The product is heated to boiling in 500 ml of methanol for 15 minutes, filtered, washed with 400 ml of methanol, dissolved in hot dimethyl formamide, precipitated by adding acetonitrile, filtered and washed with acetonitrile. Thus 78.81 g of 7-benzyl-2-morpholino-6,7,8,9-tetrahydro-pyrido[4,3-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained, yield 72%, m.p.: 291°-293° C. The crystals precipitated from the methanol solution are filtered, washed with methanol, dissolved in 60 ml of hot dimethyl formamide, precipitated by adding 60 ml of acetonitrile, filtered and washed with acetonitrile. Thus 6.63 g of 7-benzyl-2-morpholino-6,7,8,9-tetrahydro-pyrido[4,3-d]-1,2,4-triazolo[1,5-a]pyrimidine-6(10H)-one are obtained, yield 6%, m.p.: 252°-254° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[C:14]1[CH2:25][CH2:26][CH2:27][CH3:28].[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>ClCCl>[OH2:37].[NH2:24][C:17]1[C:16]2[N:15]=[C:14]([CH2:25][CH2:26][CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][S:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[C:21]=2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=1
Reactant: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCN
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNS(=O)(=O)c1ccc(F)cc1
Product: O
Temperature: 25 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
Triethylamine (0.07 mL, 0.5 mmol) was added to a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (150 mL). The reaction mixture was cooled in an ice bath. 4-fluorobenzenesulfonyl chloride (113 mg, 0.5 mmol) was added and the reaction mixture was removed from the ice bath. The reaction mixture was stirred at ambient temperature for 48 hours. The reaction mixture was washed with water (2×150 mL) and then concentrated under reduced pressure. The resulting residue was recrystallized from methyl acetate and then dried in an Abderhalden drying apparatus to provide 50 mg of N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-fluorobenzenesulfonamide hydrate as a white crystalline solid, m.p. 133.1-133.7° C.