Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=2)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH:26]1(B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.CCO.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].COCCOC.O>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:26]3[CH2:28][CH2:27]3)[CH:18]=2)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C3CC3)c2)N=C1N
Temperature: 165 °C

Procedure:
To a microwave vessel containing 2-amino-4-(3-bromophenyl)-4-(4-(difluoromethoxy)phenyl)-1-methyl-1H-imidazol-5(4H)-one (103 mg, 0.25 mmol) and cyclopropylboronic acid pinacol ester (84 mg, 0.5 mmol) in 4 ml of 1:1:3 ratio of EtOH:water:1,2-dimethoxyethane, palladium(0) teterakis and aqueous sodium carbonate (400 μL of 2N solution) were added. The reaction mixture was heated in CEM microwave at 165° C. (40 mW power) for 8 minutes. The reaction mixture was filtered, and partitioned between DCM and water. The water layer was extracted w/DCM and the combined organic layer was dried (MgSO4) and concentrated under reduced pressure to afford crude product which was purified by reverse chromatography ((M+H)+ 372.4).
Reaction SMILES: C(OC(=O)[N:7]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([Br:26])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:33]1[C:32]2[CH:37]=[CH:38][C:29]([CH2:28][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[C:21]([Br:26])[CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][C:17]4=[O:27])[CH2:10][CH2:9]3)=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(Br)cccc32)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2c(Br)cccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2 mL of a chloroform solution containing 244 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-bromo-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform], to give 143 mg of (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-bromoquinolin-2(1H)-one as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=O.S(Cl)(Cl)=O.Cl.[NH2:18][N:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([NH:18][N:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21])=[O:9]
Reactant: NN1CC(=O)NC1=O
Reactant: O=C(O)C=Cc1cccc(F)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(C=Cc1cccc(F)c1)NN1CC(=O)NC1=O
Reaction time: 8 h

Procedure:
To 99.5 g (0.6 mole) of m-fluorocinnamic acid was added dropwise thionyl chloride (600 ml) followed by heating at reflux for 2 hours. The excess thionyl chloride was removed in vacuo and the residue remaining flushed with dry benzene. The reaction residue was chilled on an ice bath followed by the rapid addition of 1-aminohydantoin hydrochloride (91 g, 0.6 mole). To the cold reaction mixture was added dropwise pyridine (600 ml). After the addition was complete the cold reaction mixture was heated on a steam bath for 3 hours then poured into 6 l. of HCl/ice. Upon standing at room temperature overnight the acidic reaction mixture was filtered and washed with water to give 116 g (73.5%) which after recrystallization from CH3NO2 melted at 294°-296°.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:10](=S)=[S:11].[H-].[Na+].CI.[CH3:17][S:18]([CH3:20])=O>O>[CH3:17][S:18][C:20]([S:11][CH3:10])=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: S=C=S
Reactant: CCOC(=O)CC(C)=O
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)C(C(C)=O)=C(SC)SC

Procedure:
A solution of 6.50 g (50.0 mmol) of ethyl acetoacetate and 4.18 g (3.30 mL, 55.0 mmol) of carbon disulfide in 60 mL of dry dimethylsulfoxide in a flame-dried 300 mL flask was treated portionwise at 16-18° C. with 2.64 g (110 mmol) of oil-free sodium hydride. An additional 100 mL of dimethylsulfoxide was eventually added to facilitate stirring. After the addition was complete, the deep red solution was stirred for 75 minutes and then was quenched with 15.62 g (6.85 mL, 110 mmol) of methyl iodide. The reaction mixture was stirred overnight at room temperature. The solution was poured into water and extracted with ether. The extracts were washed with water, dried and evaporated to give a red oil which was used for subsequent reactions without further purification. 1H-NMR (CDCl3) δ1.24 (3H, t, J=7), 2.28 (3H, s), 2.37 (6H, s), 4.21 (2H, q, J=7).
Reaction SMILES: O.[O:2]([CH2:9][C:10]([NH:12][CH:13]1[C:35](=[O:36])[N:15]2[CH:16]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:17]([CH3:21])([CH3:20])[S:18](=[O:19])[C@H:14]12)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:37]N1C(=O)C2=CC=CC=C2C1=O>C1(C)C=CC=CC=1>[CH3:20][C:17](=[CH2:21])[CH:16]([N:15]1[C:35](=[O:36])[CH:13]([NH:12][C:10](=[O:11])[CH2:9][O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]1[S:18]([Cl:37])=[O:19])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23]
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O
Reactant: O=C1c2ccccc2C(=O)N1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S(=O)Cl

Procedure:
Toluene (425 ml.) was heated in equipment containing a Dean-Stark water trap to azeotropically remove any moisture which may be present, and 25 ml. of toluene were removed thereby. To the remaining toluene were added 10.0 g. (20 mmol.) of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide, the toluene being maintained at a temperature slightly below reflux. Toluene (200 ml.) was separately distilled, and 4.0 g. (22 mmol.) of N-chlorophthalimide were added. The resulting solution (warm) was added dropwise to the solution of the penicillin sulfoxide ester over a period of 30 minutes. The mixture remained a light yellow solution throughout addition. The mixture then was refluxed for 55 minutes after which time a sample was removed, and nmr (CDCl3) analysis of the sample indicated virtually entire conversion of the penicillin sulfoxide ester to the title compound.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11](=[O:30])[CH:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[CH:4]1([S:7]([NH:10][C:11](=[O:30])[CH:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])(=[O:9])=[O:8])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 141.3 %

Procedure:
To a suspension of the compound (1.37 g) obtained in Example 188 (2) in methylene chloride (50 mL) were added oxalyl chloride (800 μL) and DMF in catalytic amount under ice-cooling, and the mixture was stirred at room temperature for 1.5 hr. After concentration under reduced pressure, methylene chloride (8 mL) was added to the residue. Under ice-cooling, the solution was added dropwise to a mixture of the above-mentioned compound (760 mg) in THF (50 mL) and 4-dimethylaminopyridine (1.71 g). After stirring at room temperature for 17 hr, dilute hydrochloric acid (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL×2). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound (1.67 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:5])([Cl:4])F.[Cl:6][C:7]([F:11])=[C:8]([F:10])[Cl:9].ClC(F)=C(F)[F:15]>C(Cl)(Cl)(Cl)Cl>[F:10][C:8]([Cl:9])([F:15])[C:7]([Cl:6])([F:11])[C:2]([Cl:5])([Cl:4])[Cl:1]
Reactant: FC(F)=C(F)Cl
Reactant: FC(Cl)=C(F)Cl
Reactant: FC(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(Cl)C(F)(Cl)C(Cl)(Cl)Cl

Procedure:
a process wherein trichlorofluoromethane is added to 1,2-dichlorodifluoroethylene or carbon tetrachloride is added to chlorotrifluoroethylene to obtain 1,1,2-trifluoropentachloropropane, which is then oxidized and esterified to form a 2,3-dichlorotrifluoropropionic acid ester, followed by dechlorination of the ester; (2) a process wherein bromine is added to chlorotrifluoroethylene to obtain 1,2-dibromo-1-chlorotrifluoroethylene, which is then subjected to an addition reaction with propylene, followed by dehydrobromination to obtain 5-bromo-4-chloro-4,5,5-trifluoropentene-2 (CF2BrCFClCH=CHCH3), which is then oxidized and esterified to form a 3-bromo-2-chlorotrifluoropropionic acid ester, which is in turn dehalogenated; and (3) a process wherein chlorotrifluoroethylene is subjected to an addition reaction with hydrogen bromide, followed by dehalogenation to obtain trifluoroethylene, which is then subjected to an addition reaction with ICl, followed by dehydrochlorination to obtain trifluoroiodoethylene, which is then reacted with metallic magnesium in ether to form an organomagnesium intermediate, which is in turn reacted with carbon dioxide, followed by hydrolysis to obtain perfluoroacrylic acid, which is then esterified.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[F:23][C:24]([F:30])([F:29])[S:25](Cl)(=[O:27])=[O:26].O>O1CCCC1>[CH3:12][C:11]1[C:2]([O:1][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])=[C:3]([CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1O
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Methyl 2-hydroxy-3-methyl-5-nitrobenzoate (Reference Compound No. 1-4-(2), 6.0 g, 28.4 mmol) was dissolved in tetrahydrofuran (200 mL), then triethylamine (16.7 mL, 120 mmol) and trifluorometanesulfonyl chloride (6.23 mL, 58.5 mmol) were added thereto, and then the reaction mixture was stirred at room temperature overnight. Water (500 mL) was added to the reaction mixture, then the whole was extracted with ethyl acetate (500 mL). The organic layer was washed with 0.2N aqueous NaOH solution (200 mL, twice) and saturated brine (200 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (9.32 g) as a pale yellow oil. (Yield 96%)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:34][C:33]2=[O:47])=[CH:28][C:27]=1[NH:48][CH3:49].C(N(CC)C(C)C)(C)C.[CH3:59][CH:60]1[CH2:62][CH:61]1[C:63](O)=O>CN(C=O)C>[F:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][O:38][C:35]2[CH:36]=[CH:37][N:32]([C:29]3[CH:30]=[CH:31][C:26]4[N:25]=[C:63]([CH:61]5[CH2:62][CH:60]5[CH3:59])[N:48]([CH3:49])[C:27]=4[CH:28]=3)[C:33](=[O:47])[CH:34]=2)=[CH:45][CH:44]=1
Reactant: CC1CC1C(=O)O
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CC1c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HATU (235 mg) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (200 mg), N,N-diisopropylethylamine (0.308 ml) and 2-methylcyclopropanecarboxylic acid (0.057 ml) in DMF (3 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with brine and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue in AcOH (1 ml) was stirred at 80° C. for 1 h. After evaporation of the solvent, the residue was passed through NH silica pad and concentrated in vacuo. The resulting solid was recrystallized from THF to give the title compound as a white solid.
Reaction SMILES: ClC1C=C(C2C=[C:10]([C:20]([N:22]3[CH2:27][CH2:26]NC(=O)C3)=O)[O:11]C=2C2C=CC(F)=CC=2)C=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]=[C:39]([C:50](O)=[O:51])[O:40][C:41]=2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[N:49])[CH:43]=2)[CH:33]=[C:34]([F:36])[CH:35]=1.N1CC[C@@H](O)C1>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]=[C:39]([C:50]([N:22]3[CH2:27][CH2:26][C@@H:10]([OH:11])[CH2:20]3)=[O:51])[O:40][C:41]=2[C:42]2[CH:43]=[C:44]([C:48]#[N:49])[CH:45]=[CH:46][CH:47]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: N#Cc1cccc(-c2oc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)cc3)o2)CCN1
Agent: O[C@@H]1CCNC1
Product: N#Cc1cccc(-c2oc(C(=O)N3CC[C@@H](O)C3)cc2-c2cc(F)cc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 6 starting with the compound from Example 20A. 1.1 equivalents of (3R)-pyrrolidin-3-ol are used. 51.0 mg (85% of theory) of the title compound are obtained.
Reaction SMILES: C[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3]1.Cl.Cl.NCC1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[C:22]([C:33]([NH2:35])=[O:34])=[CH:21][N:20]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>O>[C:6]([NH:2][CH2:3][C:4]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[C:22]([C:33]([NH2:35])=[O:34])=[CH:21][N:20]=2)=[CH:14][CH:13]=1)(=[O:7])[CH3:5]
Reactant: CN1CCCC1=O
Reactant: Cc1cccc(Nc2nc(Nc3ccc(CN)cc3)ncc2C(N)=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NCc1ccc(Nc2ncc(C(N)=O)c(Nc3cccc(C)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 10 ml portion of NMP solution containing 500 mg of 2-{[4-(aminomethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide dihydrochloride synthesized by the method described in Example 8 of WO 99/31073 was mixed with 0.53 ml of triethylamine and 0.12 ml of acetic anhydride, followed by stirring overnight at room temperature. The reaction mixture was mixed with water and extracted with ethyl acetate, the organic layer was washed with saturated brine and then the solvent was evaporated. The resulting residue was triturated with methanol, and washed to obtain 270 mg of 2-({4-[(acetylamino)methyl]phenyl}amino)-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide as a pale yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:35]=[C:34]6[C:29]([CH:30]=[CH:31][CH:32]=[N:33]6)=[CH:28][CH:27]=5)=[CH:22][C:21]=4[F:36])[C:16]([O:18]C)=O)[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:37])[CH2:3][CH2:2]1.[OH-:38].[K+].[NH2:40]O>CO.O1CCCC1>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:35]=[C:34]6[C:29]([CH:30]=[CH:31][CH:32]=[N:33]6)=[CH:28][CH:27]=5)=[CH:22][C:21]=4[F:36])[C:16]([NH:40][OH:38])=[O:18])[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:37])[CH2:2][CH2:3]1
Reactant: [OH-]
Reactant: COC(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: NO
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.1 %

Procedure:
A solution of methyl 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetate (0.560 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with potassium hydroxide (1.782 mmol) and hydroxylamine (50% w/v in water, 8.16 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction solution was then concentrated to dryness under a stream of nitrogen. Purification of the residue by reverse phase HPLC (20-60% acetonitrile/water with 0.1% NH4OH) followed by chiral HPLC (Chiralpak AS-H column, acetonitrile:methanol 98:2) and lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid (20 mg, 6%). MS(ES)+ m/e 504.9 [M+H]+, >99% ee, αD=+17 deg (c=0.02, acetonitrile:methanol 98:2).
Reaction SMILES: Cl.Cl[C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[NH:17]1[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:9][C:8]1[C:3]([N:17]2[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1cncnc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(c2ncncc2Cl)CC1
Reaction time: 0.5 h
Yield: 19.3 %

Procedure:
To a solution of 4,5-dichloropyrimidne hydrochloride 20 (0.20 g, 1.1 mmol) in DMF (4 mL) was added triethylamine (1.5 mL, 10 mmol). After stirring for 30 min, a solution of isonipecotamide (0.42 mg, 3.3 mmol) in DMF (4 mL) was added and the mixture was stirred at r.t. for a further 16 h. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, gradient 98:2-96:4) to furnish the title compound as a white solid (51 mg, 20%), m.p. 201-202° C.; umax (CHCl3)/cm−1 3023, 3014, 1724, 1682, 1448, 1360, 1219, 1037; m/z (ESI) C10H14CN4O requires 241.0851, found [M+H]+ 241.0851.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH3:13])[CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[N:20]2[N:21]=[C:22](F)[CH:23]=[CH:24][C:19]2=[N:18][CH:17]=1.C(N(CC)CC)C>C(O)(C)C>[C:1]([O:5][C:6](=[O:14])[N:7]([CH:8]1[CH2:12][CH2:11][N:10]([C:22]2[CH:23]=[CH:24][C:19]3[N:20]([C:16]([Br:15])=[CH:17][N:18]=3)[N:21]=2)[CH2:9]1)[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: Fc1ccc2ncc(Br)n2n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(Br)n3n2)C1
Temperature: 140 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A mixture of methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.2 g, 6 mmol), 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (648 mg, 3 mmol), and triethylamine (1.67 ml, 12 mmol) in isopropyl alcohol (3 ml) was heated in a microwave at 140° C. for 20 min. The reaction mixture was allowed to stand for overnight and the white solid was collected by filtration and washed with MeOH to give the titled compound (750 mg). The filtrate was concentrated and the residue was subjected to ISCO (40 g column), to give further titled compound (360 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45-1.52 (m, 9H) 2.03-2.27 (m, 2H) 2.83 (s, 3H) 3.39-3.54 (m, 2H) 3.69-3.77 (m, 2H) 6.58 (d, J=9.92 Hz, 1H) 7.49 (s, 1H) 7.65 (d, J=9.70 Hz, 1H). LRMS (ESI) m/z 396.1 and 398 [(M+H)]+, calc'd for C16H22BrN6O2: 396.29.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.O[NH:19][C:20](=O)[CH3:21].C[N:24](C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([O:6]/[N:19]=[C:20](\[NH2:24])/[CH3:21])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1c(F)cccc1I
Reactant: CC(=O)NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C/C(N)=N/OC(=O)c1c(F)cccc1I

Procedure:
Alternately, acid (XXXa) is prepared by first converting 2-fluoro-6-iodobenzoic acid to the acid chloride by reaction with a chlorinating agent such as oxalyl chloride, in a solvent such as DCM, with a catalytic amount of DMF, at a temperature of 0° C. Subsequent reaction of the acid chloride with N-hydroxyacetamide in a solvent such as CH2Cl2 provides (Z)—N′-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide. 5-(2-Fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole is prepared by reacting (Z)—N′-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide with sodium acetate, in a solvent such as tert-butanol, at temperatures ranging from 100° C. to 110° C. 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (XXXa) is prepared by reacting 5-(2-fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole with a grignard reagent such as i-PrMgCl, in a suitable solvent such as THF and the like, at a temperature of −78° C. Subsequent addition of CO2 gas, at a temperature of −78° C. provides 3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (XXXa).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:42])=[O:41]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCNCC3)cnc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCN(S(C)(=O)=O)CC3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Piperidin-4-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.073 g, 0.158 mmol) was suspended in DCM (1 mL) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol) was added. Methanesulfonyl chloride (0.015 mL, 0.19 mmol) was added and the resulting solution stirred at RT overnight. The solvent was evaporated. The remaining semi-solid was purified by SiO2 chromatography (12 g SiO2, DCM/MeOH 0-4% MeOH). Obtained 0.065 g of 1-(1-methanesulfonyl-piperidin-4-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as an off-white solid (88% yield).