Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=O)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]2=[O:34])=[CH:22][CH:21]=1)([O-:19])=[O:18].C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:6]=3)[CH2:30][C:29]2=[O:34])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=CCc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Product: O=C1CN(CCc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CCN1CCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
A solution of 1-nitro-4-(prop-2-en-1-yl)-2-(trifluoromethyl)benzene in methanol and cooled to −78° C. Ozone was bubbled through the solution until it turned blue. Excess ozone was removed by bubbling nitrogen through the solution, followed by addition of triphenylphosphine (1.1 g, 4.3 mmol). The mixture was warmed up naturally. TLC showed formation of the desired product. The crude material was adsorbed onto silica gel, and purified by flash chromatography to afford the desired [4-nitro-3-(trifluoromethyl)phenyl]acetaldehyde. The aldehyde (20 mg, 0.070 mmol) was treated with 1-[2-(4-nitrophenyl)ethyl]piperazin-2-one (16 mg, 0.070 mmol) and titanium(IV) isopropoxide (0.20 mL). After stirring the mixture for 15 minutes, ethanol (2 mL) and sodium cyanoborohydride (44 mg, 0.70 mmol) was added into the reaction. The mixture was allowed to stir for 4 hours. LC showed formation of the desired product. The reaction was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated to give the crude product. The crude product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 467 [M+1]+.
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[C:12]([CH3:17])[C:13]([OH:16])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:18](OC(=O)C)(=[O:20])[CH3:19]>S(=O)(=O)(O)O.CCCCCCC>[C:18]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:11][C:12]=1[CH3:17])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCc1ccc(O)c(C)c1
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Product: CCCCCCCCCc1ccc(OC(C)=O)c(C)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
4-Nonyl-2-cresol (1a) (934 g, 3.99 mol) was treated with acetic anhydride (456.6 g, 4.42 mol) in the presence of a few drops of concentrated sulfuric acid at 110° C. for 1 h. After cooling to ambient temperature, the reaction mixture was transferred into a 4-I separatory funnel with aid of heptane (400 mL). The resulting organic phase was washed with aqueous sodium bicarbonate solution and water until the pH became 6 or so. The heptane phase was dried over sodium sulfate and concentrated to obtain 4-nonyl-2-methylphenyl acetate (1098.3 g) in 99.7% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:21]C3CC3)[C:9](=[O:20])[N:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:11][C:5]2=[CH:4][N:3]=1>NC1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:11][C:5]3[C:6](=[N:7][C:2]([NH:10][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:3][CH:4]=3)[N:8]([CH2:21][CH2:5][C:4]#[N:3])[C:9]2=[O:20])=[CH:13][CH:14]=1
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N(CC3CC3)C2=O)cc1
Solvent: Nc1ccccc1
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(CCC#N)C2=O)cc1
Temperature: 120 °C

Procedure:
A mixture of 7-chloro-1-cyclopropylmethyl-3-(4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-one (104 mg, 0.30 mmol) in aniline (2.0 mL) (Aldrich) was heated to 120° C. for 1.5 hours. After cooling, the reaction mixture was washed with hexanes (4×100 mL) and the crude product was purified by recrystallization from methanol-ethyl acetate to give 3-[-3-(4-methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-1-yl]-propionitrile as a white solid. (Yield 111 mg, 91.7%).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO.O>[C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C/CCC#Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/CCC#Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 91.2 %

Procedure:
To a solution of ethyl 7-phenylhept-2E-en-6-ynoate (2.5 g) in methanol was added KOH (2.6 g) in water (6 ml). The mixture was stirred at 50° C. under a nitrogen atmosphere for 40 minutes, cooled, diluted with water (20 ml) and washed with ether (15 ml). The aqueous layer was acidified with 10% HCl and extracted with ether. The ether extracts were combined and dried over MgSO4, and the solvent was distilled off (adding dry benzene (4 ml) to form azetrope with traces of water) to give 7-phenylhept-2E-en-6-ynoic acid (2 g) as a colourless oily solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCO>[CH2:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:3][CH2:2][C:1]#[N:4])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CC#N
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCO
Product: N#CCCN1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
Acrylonitrile (9.37 mL, 142 mmol, 2.50 equiv) was added at 0° C. to a solution of 4-benzylpiperidine (10.0 mL, 56.9 mmol, 1.00 equiv, Aldrich) in EtOH (60 mL) and the resulting solution was stirred for 1.5 hours at room temperature. The solvent was removed to give 12.98 g (99%) of colorless oil, which was characterized spectroscopically and used without purification for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:22]=[CH:21][N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[N:19]=3)[CH:16]=2)[N:11]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:10]=1.C([Li])CCC.[C:48](=[O:50])=[O:49]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:22]=[C:21]([C:48]([OH:50])=[O:49])[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:24])=[O:25])[N:19]=3)[CH:16]=2)[N:11]([S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH:10]=1
Reactant: O=C=O
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccn(S(=O)(=O)c4ccc(C)cc4)n3)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(=O)O)n(S(=O)(=O)c4ccc(C)cc4)n3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a cooled solution (−78° C.) of 3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-5-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (458 mg, 0.765 mmol) in dry tetrahydrofuran (7 mL) was added 2.5 M n-butyl lithium (n-BuLi) (336 μL. 0.842 mmol) over 15 min. After 2 h at −78° C., a stream of carbon dioxide gas was added to the mixture for 5 min. The reaction was allowed to warm to room temperature. After stirring 3 h, the reaction was quenched by the addition of saturated ammonium chloride and extracted into ethyl acetate. The organic layer was dried over sodium sulfate and purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford 5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(toluene-4-sulfonyl)-2H-pyrazole-3-carboxylic acid (114 mg, 23%). MS: m/z 643 (M+H+).
Reaction SMILES: BrC1[CH:3]=[N:4]C=C(Cl)C=1C=O.S1C=CN=C1S.[Cl:17][C:18]1C=N[CH:21]=[C:22]([S:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[C:23]=1[CH:24]=[O:25]>ClC1C=C(Cl)C=CN=1>[Cl:17][C:18]1[C:23]([CH:24]=[O:25])=[C:22]([S:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[CH:21]=[CH:3][N:4]=1
Reactant: O=Cc1c(Cl)cncc1Br
Reactant: O=Cc1c(Cl)cncc1Sc1nccs1
Agent: Clc1ccnc(Cl)c1
Agent: Sc1nccs1
Product: O=Cc1c(Sc2nccs2)ccnc1Cl

Procedure:
Introduction of the formyl group in 2,4-dichloro-pyridine according to the synthesis of 3-bromo-5-chloro-pyridine-4-carbaldehyde and subsequent reaction with thiazole-2-thiol according to the synthesis of 3-chloro-5-(thiazol-2-ylsulfanyl)-pyridine-4-carbaldehyde yielded the title compound. MS (m/z): 257.2 [H+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]=[CH:9][CH:10]2[CH2:14][CH2:13][O:12][C:11]2=O)[CH:3]=1.P(Br)(Br)([Br:18])=O>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:11](=[O:12])[C:10]([CH2:14][CH2:13][Br:18])=[CH:9][N:8]=[C:4]2[CH:3]=1
Reactant: O=C1OCCC1C=Nc1cc(Br)ccn1
Reactant: O=P(Br)(Br)Br
Product: O=c1c(CCBr)cnc2cc(Br)ccn12
Temperature: 0 °C
Yield: 86.2 %

Procedure:
3-((4-bromopyridin-2-ylimino)methyl)dihydrofuran-2(3H)-one (800 mg, 2.97 mmol) and POBr3 (4 g, 13.9 mmol) was stirred at 80° C. for 1.5 hr. After the suspension was poured into ice water, the solution was adjusted to pH 8 and extracted with DCM (3×100 mL). The combined organic layers were washed with brine and concentrated to give 850 mg crude product, which was directly used for the next step without further purification. MS (ESI): 330, 332, 334 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][O:22][C:23]4[C:32]5[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=5)[N:26]=[CH:25][CH:24]=4)=[N:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].O.[OH-].[Li+].Cl.[CH3:39][O:40][CH2:41][CH2:42][NH2:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC1C=C(C2C=CC3N(C(COC4C5C(=CC(OC)=CC=5)N=CC=4)=NN=3)N=2)C=CC=1C(O)=O>C1COCC1.O.CO.CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][O:22][C:23]4[C:32]5[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=5)[N:26]=[CH:25][CH:24]=4)=[N:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:43][CH2:42][CH2:41][O:40][CH3:39])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3n2)cc1F
Reactant: COCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)O)c(F)c5)nn34)ccnc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCNC(=O)c1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3n2)cc1F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoate (0.488 g, 1.06 mmol) (prepared according to General Method A) and lithium hydroxide hydrate (0.223 g, 5.31 mmol) in THF (20 mL), water (5 mL) and MeOH (5 mL) was heated to 40° C. for 3 h. Brought to near neutral pH with 1M HCl. Concentrated. Azeotroped with MeCN (20 mL) and PhMe (20 mL). Used without further purification. A mixture of 2-methoxyethylamine (0.033 ml, 0.38 mmol), HATU (0.24 g, 0.62 mmol), Hunig's Base (0.24 ml, 1.4 mmol), 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoic acid (0.153 g, 0.34 mmol) in DMF was allowed to stir at room temperature for 1 h. Concentrated. Purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate. The volatiles were removed in vacuo and the product was isolated by filtration. Dried under vacuum. MS m/z=503.2 [M+1]+. Calc'd for C26H23FN6O4: 502.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1B(O)O.CC12CC3(C)P(C4C=CC=CC=4)C(C)(CC(C)(O3)O1)O2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:43]1[N:44]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[C:45]([CH3:53])=[C:46]2[C:51]=1[CH2:50][CH2:49][NH:48][C:47]2=[O:52].CC1NC(=O)C2C(=C(C3C=CC=CC=3OC3C=CC=CC=3)NC=2C)N=1.[Cl-].[Na+]>C(OCC)(=O)C.O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:43]1[N:44]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:59])([CH3:61])[CH3:60])[C:45]([CH3:53])=[C:46]2[C:51]=1[CH2:50][CH2:49][NH:48][C:47]2=[O:52]
Reactant: O=[N+]([O-])c1ccc(F)c(B(O)O)c1
Reactant: Cc1c2c(c(Br)n1COCC[Si](C)(C)C)CCNC2=O
Agent: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: Cc1nc2c(-c3ccccc3Oc3ccccc3)[nH]c(C)c2c(=O)[nH]1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c2c(c(-c3cc([N+](=O)[O-])ccc3F)n1COCC[Si](C)(C)C)CCNC2=O
Temperature: 25 °C

Procedure:
2-fluoro-5-nitrophenylboronic acid (0.134 g, 0.725 mmol), tris(dibenzylidineacetone)dipalladium(0) (0.0157 g, 0.017 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.0165 g, 0.056 mmol) and tris-potassium phosphate (0.280 g, 1.319 mmol) were combined in a sealed 5 mL microwave tube with stir bar and sparged with nitrogen for 15 minutes. A solution of Example 93g (0.173 g, 0.481 mmol) in a degassed mixture of 4:1 dioxane/water (5.0 mL) was added by syringe into the reaction vessel which was heated at 110° C. for 25 minutes in a Biotage Initiator 2 monomode microwave reactor, then cooled to ambient temperature. The reaction mixture was shaken in a separatory funnel with 75 mL ethyl acetate and 40 mL saturated aqueous sodium chloride. The organics were dried over anhydrous sodium sulfate. Filtration and solvent removal gave a yellow oil which was chromatographed on a 40 g silica gel cartridge eluting with 0-100% ethyl acetate/heptane to provide the title compound.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH3:18][C:19]1([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][C:19]1([CH3:25])[CH2:24][CH2:23][N:22]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:21][CH2:20]1
Reactant: CC1(C)CCNCC1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: CC1(C)CCN(c2nc(Cc3ccsc3)[nH]c(=O)c2C#N)CC1

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 430 mg (3.80 mmol) of 4,4-dimethylpiperidine to give 42 mg (34% of theory) of the title compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].OC(C(F)(F)F)=O.[NH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([OH:38])=[O:37].C[O-].[Na+]>CCO.C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([OH:38])=[O:37])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 63.4 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (83 mg, 0.36 mmol) and NaOMe (39 mg, 0.72 mmol) in 2 mL of EtOH was heated at 150° C. for 3 h in a CEM microwave reactor. The solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-40% EtOAc/hexanes+2% AcOH) to give a crude solid. The solid was dissolved in saturated NaHCO3 and washed with ether. 1 M HCl was added to the aqueous layer until pH was about 2, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 24 mg of the title compound. MS: (+) m/z 421.02 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH:9]([B-](F)(F)F)=[CH2:10].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC1CCCO1.O.C(OC)(C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:7]1[C:2]([CH:9]=[CH2:10])=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: Fc1cncnc1Br
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COC(C)(C)C
Solvent: CC1CCCO1
Solvent: O
Product: C=Cc1ncncc1F
Temperature: 75 °C
Yield: 41 %

Procedure:
4-Bromo-5-fluoropyrimidine (5 g) was reacted with potassium vinyltrifluorborate (1.05 equivalents) in the presence of (PPh3)2PdCl2 (0.02 eq), PPh3 (0.02 eq), and Cs2CO3 (3 equivalents) in a mixture of methyl tetrahydrofuran (85 ml) and water (8.5 ml). The reaction was heated at 75° C. for about 5.5 hours. The reaction mixture was then diluted with methyl tert-butyl ether (50 ml), followed by aqueous extraction. The crude product was purified by distillation at 170 mbar (90-110° C.). The product was obtained as a colourless oil (1.44 g, 41% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]([OH:21])=O)[NH:16][C:15]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C[N:25](C)CCCN=C=NCC.O.N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.N.C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl>[NH2:25][C:19]([C:17]1[NH:16][C:15](=[O:22])[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH:18]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)[nH]c2=O)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(N)=O)[nH]c2=O)CC1
Reaction time: 3 h
Yield: 37.2 %

Procedure:
A solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (210 mg, 0.675 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (388 mg, 2.02 mmol), 1H-1,2,3-benzotriazol-1-ol hydrate (273 mg, 2.02 mmol), N,N-diisopropylethylamine (0.352 mL, 2.02 mmol), and ammonia (0.5 M, 2.02 mmol, 4.05 mL) were stirred at room temperature in dimethylformamide (10 mL). After 3 h, the reaction was worked up with dichloromethane and saturated sodium bicarbonate. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→15% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (78 mg). MS 255.2 (M+1-tert butyl)
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH2:5][O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[CH:11]1>CO>[NH2:23][C:14]1[C:13]2[N:12]=[CH:11][N:10]([CH2:9][CH2:8][CH2:7][O:6][N:5]=[C:2]([CH3:4])[CH3:1])[C:22]=2[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CC(C)=O
Reactant: NOCCCn1cnc2c(N)nc3cccnc3c21
Solvent: CO
Product: CC(C)=NOCCCn1cnc2c(N)nc3cccnc3c21
Reaction time: 6 h

Procedure:
Acetone (1 mL) was added to a suspension of 1-[3-(aminooxy)propyl]-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.237 g, 0.92 mmol) in methanol (6 mL) at room temperature. The mixture was stirred and eventually a solution formed. After 6 hours, the volatiles were removed and the crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-25% CMA in chloroform) to give a white powder that was crystallized from acetonitrile to yield 0.110 g of acetone O-[3-(4-amino-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propyl]oxime as white needles, mp 120-121° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][C:34]=1[O:35][C:36](=[O:38])[CH3:37])[C:8]([O:10][CH2:11][C:12]1[CH2:19][S:18][CH:17]2[N:14]([C:15](=[O:28])[CH:16]2[NH:20]C(OC(C)(C)C)=O)[C:13]=1[C:29]([OH:31])=[O:30])=[O:9])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][C:34]=1[O:35][C:36](=[O:38])[CH3:37])[C:8]([O:10][CH2:11][C:12]1[CH2:19][S:18][C@H:17]2[N:14]([C:15](=[O:28])[C@H:16]2[NH2:20])[C:13]=1[C:29]([OH:31])=[O:30])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)OCC2=C(C(=O)O)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)cc1OC(C)=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)OCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)cc1OC(C)=O
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a magnetically stirred 500 mL flask under argon at room temperature (about 23° C.) was added 25.69 g of (6R-trans)-3-[[[3,4-bis(acetyloxy)-benzoyl]oxy]methyl-7-[[1,1dimethylethoxycarbonyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 250 mL of methylene chloride. This was followed by the addition of 25 mL of anisole and 250 mL of trifluoroacetic acid. Stirring was continued for 3 hours and then the solvents removed in vacuo. To the oil residue was added 200 mL of ethyl acetate and stirred for 20 minutes causing precipitation. 650 mL of anhydrous ether was added to this suspension and stirred for 10 minutes. The mixture was filtered on a Buchner funnel and dried under high vacuum to give 20.25 g (76.9%) of the named product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][C@H:17]([OH:26])[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][C:9]=2[CH:34]=1)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[C:30]([O:29][C:27]([N:15]([CH:11]1[CH2:10][C:9]2[CH:34]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[CH2:14][CH2:13][CH2:12]1)[CH2:16][C@H:17]([OH:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)c1ccc2c(c1)CC(N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(C(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.6 %

Procedure:
To a solution of 8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (4.5 g) in methanol (45 ml) and tetrahydrofuran (15 ml) was added 1N sodium hydroxide aqueous solution. After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure, neutralized with 1N hydrochloric acid solution under ice-cooling. The product was extracted with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid (4.48 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Reactant: Cc1ccnc(Br)n1
Product: Cc1ccnc(-c2cc(C)c(Br)c(C)c2)n1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-4-methyl-pyrimidine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.08 min; Mass spectrum (ESI+): m/z=277/279 (Br) [M+H]+.