Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>CN(C=O)C>[CH3:16][N:17]([CH3:19])[CH:18]=[C:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1ccncc1
Reactant: CCOC(OCC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)c1ccncc1
Yield: 100 %

Procedure:
Combined ethyl 2-(pyridin-4-yl)acetate (0.927 mL, 6.05 mmol) and 1,1-diethoxy-N,N-dimethylmethanamine (5.19 mL, 30.3 mmol) in DMF (3.03 mL) and heated to 100° C. for 6 hours. The reaction mixture was concentrated, diluted with 50 mL dichloromethane, and washed twice with 50 mL water. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated to give a residue which was purified on a 60 g NH silica gel column eluted with hexanes and EtOAc to give the title compound (1.333 g, 76%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.13 (t, J=7.1 Hz, 3 H) 2.67 (s, 6 H) 4.06 (q, J=7.1 Hz, 2 H) 6.98-7.12 (m, 2 H) 7.56 (s, 1 H) 8.29-8.53 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.C(N(CC)CC)C.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:19][CH2:20][N:21]([S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])[CH2:22][CH2:23]2)[N:3]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1
Yield: 60.8 %

Procedure:
To a solution of [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone (19.2 mg, 0.0611 mmol, Example 9) in methylene chloride (1.5 mL) were added triethylamine (12.6 mg, 0.124 mmol, Aldrich) in methylene chloride (0.2 mL) and a solution of ethanesulfonyl chloride (8.66 mg, 0.066 mmol, Aldrich 99+%) in methylene chloride (0.2 mL) at room temperature. After ˜30 mins the reaction mixture was concentrated and purified by reversed phase HPLC as described in Example 11 to give [2-Amino-6-(1-ethanesulfonyl-piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone as a white solid (15.1 mg, 60 % yield). HRMS, observed: 407.1533, calcd for (M+H)+: 407.1548.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:35])[C:20]([C:33]#[N:34])=[C:21]4[C:27]=3[O:26][CH:25]([CH3:28])[CH2:24][N:23]([CH:29]3[CH2:32][NH:31][CH2:30]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12.C(N(CC)CC)C.[CH3:43][C:44]1([CH3:47])[CH2:46][O:45]1>CN(C)C=O>[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:35])[C:20]([C:33]#[N:34])=[C:21]4[C:27]=3[O:26][CH:25]([CH3:28])[CH2:24][N:23]([CH:29]3[CH2:32][N:31]([CH2:43][C:44]([OH:45])([CH3:47])[CH3:46])[CH2:30]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CNC2)C3)c2ncnc(N)c12
Reactant: CC1(C)CO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CN(CC(C)(C)O)C2)C3)c2ncnc(N)c12
Temperature: 85 °C
Reaction time: 4 h

Procedure:
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride (0.015 g, 0.034 mmol) was dissolved in N,N-dimethylformamide (1.0 mL) and triethylamine (0.025 mL, 0.18 mmol), and 2,2-dimethyloxirane (0.050 g) was added. The reaction was heated to 85° C. stirred for 4 h. The reaction was concentrated in vacuo, and the product was purified without workup by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compound as two diastereomers: Peak #1 (Example 54) (0.002 g, 13%): LCMS calculated for C26H34ClN8O2 (M+H)+: m/z=525.2; found: 525.2; Peak #2 (Example 55) (0.002 g 13%): LCMS calculated for C26H34ClN8O2 (M+H)+: m/z=525.2; found: 525.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:22][C:23]([F:39])([F:38])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([N:35]1[CH2:34][CH2:33][N:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH2:24][C:23]([F:38])([F:22])[F:39])[CH2:37][CH2:36]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(COCc1ccccc1)C(=O)O
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(COCc1ccccc1)C(=O)N1CCN(c2ccccc2OCC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85333.3 %

Procedure:
A mixture of 3-benzyloxy-2,2-dimethylpropionic acid (1.6 g, 7.5 mmol), benzene (10 mL) and DMF (2 drops) was cooled to between 0° and 5° C. and then oxalyl chloride (0.98 mL, 11.2 mmol) was added slowly. The mixture was stirred 1.5 hours at between 20° and 25° C. and concentrated. The residue was dissolved in benzene (10 mL) and the solution reconcentrated (repeated once). The residue then was dissolved in benzene (6 mL) and the solution was cooled to 0° C. and added to a cold (0° C.) mixture of 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine (2.1 g, 8.24 mmol) and benzene (6 mL). The mixture was cooled 15 hours at 0° C. and then triethylamine (3 mL, 21.3 mmol) was added. The mixture was stirred an additional 20 minutes, diluted with 10 mL of saturated sodium carbonate and extracted with methylene chloride (3×15 mL). The combined extracts were washed with water (1×10 mL), dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (8:2) to give 3-benzyloxy-2,2-dimethyl-1-{4-[2-(2,2,2-trif-luoroethoxy)phenyl]piperazin-1-yl}-1-propanone (2.8 g, 6.4 mol).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](Cl)=[O:9])[S:4][N:3]=1.[NH3:11]>O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([NH2:11])=[O:9])[S:4][N:3]=1
Reactant: N
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Solvent: O
Product: NC(=O)c1snc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
At 0 to 10° C., 50.1 g (0.2 mol) of 3,4-dichloro-isothiazole-5-carbonyl chloride are added dropwise with stirring over a period of 30 minutes to 82 g (1.2 mol) of concentrated ammonia. After the addition, another 41 g (0.6 mol) of concentrated ammonia are added and the mixture is diluted with 70 ml of water. The mixture is allowed to warm to room temperature and stirred at this temperature for 45 minutes. The resulting precipitate is filtered off with suction, washed successive with water and petroleum ether and dried. In this manner, 32.3 g (81.8% of theory) of 3,4-dichloro-isothiazole-5-carboxamide are obtained in the form of a solid of melting point 156 to 158° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>[Pd].CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(N)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(N)c(N)c1

Procedure:
Five-percent palladium on carbon (0.50 g) was added to a solution of 4.00 g of ethyl 3-amino-4-nitro-benzoate in 100 ml of methanol, and the mixture was stirred in a hydrogen atmosphere at 50° C. for 16 hours. The solid material was separated through filtration, and the filtrate was concentrated to obtain ethyl 3,4-diaminobenzoate. Twenty milliliters of trifluoroacetic acid were added thereto, and the mixture was stirred at 60° C. for 2 hours. The reaction solution was concentrated, and chloroform was added thereto. The crystals precipitated were separated through filtration, and were dried to give 4.46 g of 5-ethoxycarbonyl-2-trifluoromethylbenzimidazole (157).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([C:11]3[NH:12][C:13](=O)[C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][CH2:1][O:2][C:3]=3[CH:4]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc3c(c2)OCCO3)cc2ccccc12
Product: Clc1nc(-c2ccc3c(c2)OCCO3)cc2ccccc12

Procedure:
The resulting 3-(3,4-ethylenedioxyphenyl)isoquinolin-1-one (1.94 g) was reacted with phosphorus oxychloride (20 ml) according to the method of Example 10-2, to give 1-chloro-3-(3,4-ethylenedioxyphenyl)isoquinoline. The resulting compound was reacted, as it was, with N-ethylpiperazine (6 ml) at 100° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The resulting ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1.63 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:12](Cl)([CH3:15])(=[O:14])=[O:13]>N1C(C)=CC(C)=CC=1C.CCCCCC>[CH3:15][S:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCO
Solvent: CCCCCC
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cooled solution of 158.3 grams of 1-decanol in 1.0 liter of collidine is added dropwise 126 grams of mesyl chloride. The resulting mixture is stirred at room temperature for 1.5 hours and then poured onto ice. The reaction mixture is extracted with ether and the ether extracts are washed with 10% hydrochloric acid. The ether extracts are combined, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to leave an oil which solidifies upon cooling. The oil is dissolved in n-hexane and cooled to yield as crystals, decyl methylsulfonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12](Cl)(=[O:18])/[CH:13]=[CH:14]/[C:15](Cl)=[O:16].Cl>C(=S)=S>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]([CH:13]=[CH:14][C:15](=[O:16])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(Cl)/C=C/C(=O)Cl
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(C=CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Yield: 96 %

Procedure:
To a solution of fluorobenzene (0.52 mols, 50 g, 48.83 mL) in carbon disulfide (500 mL) was added aluminium chloride (0.651 mmol, 86.8 g). The resulting suspension was gently refluxed under an atmosphere of nitrogen. Fumaryl chloride (0.26 mols, 28.2 mL) was added over a period of 15-20 minutes. The resulting dark orange reaction mixture was refluxed for 18 h and the residue was poured into crushed ice (1 Kg) and concentrated hydrochloric acid (15.0 mL). The semi-solid was filtered off, washed with ether and ethanol, digested in ethanol, and recrystallized from ethyl acetate/ethanol to give pale yellow needles of compound 1 in 96% yield, m.p. 115°-116° C. 1H NMR: 7.14-7.18 (t, 2H, Jmeta =1.9 Hz, C6H4), 7.96 (s, 2H, CH=CH), 8.05-8.12 (q, 6H, J=2.2 Hz, C6H4); ms m/e (Cl with NH3 ), 290(NH3 +H+M), 273(M+1), 272(M); HRMS m/e calcd for C16H10O2F2 273.0727, found 273.0727.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>CCOCC>[CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC1=CC(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Cc1cc(O)c2ccccc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-[1,4]-naphthoquinone (5 g, 29 mmol) and ether (200 ml) were mixed in a reaction vessel replaced with argon, and this solution was cooled to -10° C. A suspension (40 ml) of lithium aluminum hydride (1.0 g, 26.3 mmol) in ether was added dropwise to this solution over 40 minutes, and the mixture was stirred at room temperature for 0.5 hour. To the reaction mixture was added dropwise 1N hydrochloric acid (100 ml) to stop the reaction. The aqueous layer was extracted twice with ethyl acetate (100 ml). The organic layers were combined, washed twice with saturated brine (50 ml), 3 times with a saturated aqueous sodium hydrogencarbonate solution (30 ml) and twice with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. Water (10 ml) and conc. hydrochloric acid (10 ml) were added to the obtained residue, and the mixture was refluxed under heating for 2 hours. Water (50 ml) was added to this reaction mixture, and the aqueous layer was extracted twice with ether (50 ml). The organic layer was washed with water (30 ml), washed twice with a saturated aqueous sodium hydrogencarbonate solution (30 ml) and twice with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=30/1-10/1) to give 3-methylnaphthalen-1-ol in a mixture of compounds structurally unidentified. The mixture was not further purified, but used for the next reaction.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:6]1[O:8][CH2:7]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:7][CH:6]([OH:8])[CH2:5][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NCCO
Reactant: CCCCC(CC)COCCCCCCCCCCOCC1CO1
Solvent: CCO
Product: CCCCC(CC)COCCCCCCCCCCOCC(O)CNCCO
Temperature: 80 °C
Yield: 68.4 %

Procedure:
A 200-ml two-necked flask equipped with a stirrer, reflux tube and dropping funnel was charged with 32.7 g (0.54 mol) of ethanolamine and 10.1 g of ethanol. While heating and stirring the mixture at 80° C., 1.76 g (5.14 mmol) of 10-(2-ethylhexyloxy)decyl glycidyl ether were added dropwise over 2 hours. After the resultant mixture was heated and stirred further for 18 hours, it was concentrated under reduced pressure, and the resultant residue was purified by column chromatography on silica gel, thereby obtaining 1.42 g (yield: 68%) of the title compound (Ia-14).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8]P(OC)(OC)=O)=[O:7])([CH3:4])[CH3:3].[H-].[Na+].[CH:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=O>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19](/[CH:17]=[CH:8]/[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 118.3 %

Procedure:
To a solution of tert-butyl P,P-dimethylphosphonoacetate (Fluka, 1.43 g, 6.4 mmol) in THF (40 mL) was added NaH (Alderich, 60%, 536 mg, 13.4 mmol) portionwise at rt over 30 min. Methyl 4-formylbenzoate (Alderich, 1.0 g, 6.09 mmol) was then added and the reaction mixture was stirred at rt for 4 hrs. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, and dried over Na2SO4. The mixture was then concentrated to give the crude 4-((E)-2-tert-butoxycarbonyl-vinyl)-benzoic acid methyl ester (1.89 g, 118%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]([F:12])([F:24])[F:25])[CH:16]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Clc1ccc2ncc(Br)n2n1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
3-bromo-6-chloroimidazo[1,2-b]pyridazine was prepared according to procedures described in U.S. Pat. No. 7,750,007, which is hereby incorporated by reference in its entirety. To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (5 g, 21.5 mmol) and 3-(trifluoromethoxy)phenylboronic acid (4.43 g, 21.5 mmol) in dioxane/H2O (100 mL, 4:1) was added K2CO3 (6.8 g, 64.5 mmol) and Pd(PPh3)4 (1.9 g, 2.58 mmol), the mixture was stirred at 110° C. for 3 h. The solution was concentrated, partitioned in EtOAc/H2O. The aqueous layer was washed with EtOAc (50 mL) for 3 times. The collected organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (3.2 g, with 63% purity, yield 30%) as a brown solid.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[O:16])=[C:4]([I:23])[C:3]=1[NH:24][C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26].[OH-].[Na+].Br[CH2:54][CH:55]([OH:58])[CH2:56][OH:57]>O>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[O:16])=[C:4]([I:23])[C:3]=1[N:24]([CH2:54][CH:55]([OH:58])[CH2:56][OH:57])[C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26]
Reactant: OCC(O)CBr
Reactant: O=C(Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c1I)Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCO)c1c(I)c(NC(=O)N(CC(O)CO)c2c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c2I)c(I)c(C(=O)NC(CO)CO)c1I
Reaction time: 96 h
Yield: 14 %

Procedure:
N,N'-bis[2,4,6-triiodo-3-(2-hydroxyethylaminocarbonyl)-5-(1,3-dihydroxyprop-2-ylaminocarbonyl)-phenyl]urea (0.25 g, 0.18 mmol) was dissolved in water (5 ml) followed by 2M aqueous NaOH (2.1 ml) and, after 5 min, bromopropane-2,3-diol (0.196 ml) was added. The solution was stirred for 4 days, neutralized with a strongly acidic cation exchange resin and evaporated to dryness. Purification by preparative HPLC gave 38 mg (14%) of the product as a white solid. MS (ESP, m/e): 1450 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9]2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[O:3]1.C(N1C=CN=C1)(N1[CH:27]=[CH:26]N=C1)=O.C(=O)=O.[O-]CC.[Na+]>CN(C)C=O.C(O)C>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([N:8]2[C:12]([C:13]([O:15][CH2:26][CH3:27])=[O:14])=[CH:11][N:10]=[CH:9]2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[O:3]1
Reactant: CC1(C)CC(n2cncc2C(=O)O)c2ccccc2O1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cncn1C1CC(C)(C)Oc2ccccc21
Yield: 63.5 %

Procedure:
A solution of 3.3 parts of 1-(2,3-dihydro-2,2-dimethyl-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylic acid in 45 parts in warm N,N-dimethylformamide was cooled to room temperature and then 2 parts of 1,1'-carbonylbis[1H-imidazole] were added. The whole was stirred at room temperature till CO2 evolution had ceased (±30 minutes). The mixture was heated to ±70° C. and 2.4 parts of ethanol and 0.1 parts of sodium ethoxide were added. Stirring was continued over weekend at ±70° C. After evaporation, the residue was taken up in water and trichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from hexane. The product was filtered off and dried, yielding 2.36 parts (63.5%) of ethyl 1-(2,3-dihydro-2,2-dimethyl-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylate; mp. 80.9° C. (compound 1.138).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C1COCC1.C(N(CC)CC)C.[F:23][C:24]1[CH:34]=[C:33](F)[C:32]([N+:36]([O-:38])=[O:37])=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:33]1[CH:34]=[C:24]([F:23])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][C:32]=1[N+:36]([O-:38])=[O:37])([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NCC(=O)OC(C)(C)C)cc1F
Yield: 86.7 %

Procedure:
By using 3.63 g of glycine tert-butyl ester hydrochloride, 25 ml of THF, 3.03 g of triethylamine, 5 ml of DMF and 5.0 g (21.6 mmol) of ethyl 2,4-difluoro-5-nitrobenzoate, 6.41 g (87%) of N-(4-ethoxycarbonyl-5-fluoro-2-nitrophenyl)glycine tert-butyl ester was obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[N:39]=[N:38]2)[CH:32]=1.NC1C=NC=CC=1.Cl.[Cl:57][C:58]1[CH:68]=[CH:67][CH:66]=[CH:65][C:59]=1[O:60][CH:61]1[CH2:64][NH:63][CH2:62]1>CN(C=O)C>[Cl:57][C:58]1[CH:68]=[CH:67][CH:66]=[CH:65][C:59]=1[O:60][CH:61]1[CH2:64][N:63]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:40]2[N:39]=[N:38][N:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[CH:41]=2)=[O:43])[CH2:62]1
Reactant: Clc1ccccc1OC1CNC1
Reactant: O=C(O)CNC(=O)c1cn(-c2cccnc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CC(Oc2ccccc2Cl)C1)c1cn(-c2cccnc2)nn1
Reaction time: 0.03 h
Yield: 29.4 %

Procedure:
DIPEA (141 mg, 1.1 mmol) followed by HOBt (39 mg, 0.29 mmol) and EDCI (56 mg, 0.29 mmol) were added to a stirred solution of [(1-pyridin-3-yl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 3-aminopyridine, and subsequently, application of Step 3 of the General Scheme) (67.5 mg, 0.27 mmol) in DMF (3 mL). After 2 minutes of stirring, 3-(2-chloro-phenoxy)-azetidine hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (60 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC afforded 33 mg (29.4% Yield) of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[3-(2-chloro-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 413, 98.7%. 1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.2 (d, 1H), 8.7 (m, 2H), 8.4 (m, 1H), 7.64 (m, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.0 (t, 1H), 6.9 (d, 1H), 5.12 (m, 1H), 4.68 (m, 1H), 4.38 (m, 1H), 4.24 (m, 1H), 3.96 (m, 1H), 3.84 (m, 1H).