Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:15][CH2:16]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CN(CCC2CCNCC2)Cc2ccccc2)cc1
Reactant: Brc1ccncc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc(CN(CCC2CCN(c3ccncc3)CC2)Cc2ccccc2)cc1
Yield: 53 %

Procedure:
N,N-Dibenzyl-2-(piperidin-4-yl)ethanamine (2.4 g, 7.79 mmol, 1 eq) and 4-bromopyridine HBr (1.97 g, 10.12 mmol, 1.3 eq) were dissolved in n-butanol (30 ml) and DIPEA (3.3 ml, 19.47 mmol, 2.5 eq) and the mixture was refluxed for 48 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure and the residue was taken up in dichloromethane (100 ml), washed with water and sat. NaCl solution (in each case 50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 3.5% MeOH in dichloromethane), a white solid was obtained. Yield: 53% (1.6 g, 4.15 mmol).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([NH:14]CC2C=CC=CC=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:14][CH:10]1[CH2:11][C:12](=[O:13])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:22]
Reactant: O=C1CC(NCc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC1CC(=O)N(Cc2ccccc2)C1=O
Yield: 91 %

Procedure:
56.5 g (0.184 mol) of 95% strength 1-benzyl-3-benzylaminopyrrolidine-2,5-dione are dissolved in 700 ml of ethanol and hydrogenated with 2 g of palladium on charcoal (5%) for 4 hours at 70° C. and 60 bar of hydrogen pressure. The catalyst is then filtered off, the filtrate is concentrated, and the residue is dried at 50° C./0.1 mbar. This gives 36.2 g of product with a content of 94%, determined by gas chromatography and corresponding to a yield of 91% of theory. Melting point 74° to 77° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[C:11]([CH3:18])[N:10]=[N:9]1.F[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[CH:17]=2)=[C:11]([CH3:18])[N:10]=[N:9]1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccccc3F)c2)cc1
Temperature: 120 °C
Yield: 1.8 %

Procedure:
A mixture of 1-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-1,2,3-triazole (290 mg, 1.19 mmol), methyl 4-fluorobenzoate (184 mg, 1.19 mmol) and potassium carbonate (330 mg, 2.38 mmol) in DMF (6.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 2 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (8 mg, 2%) as an off white solid. MS: m/e=378.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2=O)c1ccc(Cl)s1
Reactant: Brc1ccccn1
Product: O=C(Nc1cccc2c1C(=O)N(CCC1CCN(c3ccccn3)CC1)C2=O)c1ccc(Cl)s1

Procedure:
can be prepared from 5-chloro-N-{1,3-dioxo-2-[2-(4-piperidinyl)ethyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide and 2-bromopyridine
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH:11]=O.[Cl-].[CH3:14][O:15]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[CH2:10][CH2:11][CH:14]=[O:15]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1=C(CC=O)C(C)(C)CCC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CC1=C(CCC=O)C(C)(C)CCC1
Yield: 80 %

Procedure:
2,6,6-Trimethyl-1-cyclohexene-1-acetaldehyde is reacted with methoxymethyl triphenylphosphonium chloride in the presence of potassium tert-butoxide, followed by conversion to the dimethyl acetal and subsequent hydrolysis, as described in Example 1 above, to provide 3-(2,6,6-trimethyl-1-cyclohexen-1yl)propanal (80% yield) as a colorless oil after distillation in vacuo. This material (6.8 g) is reacted with triethyl 2-phosphonopropionate (10.6 ml) by the method of example 14(B) above, to provide 6.58 g (2E)-2-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-pentenoic acid ethyl ester as a colorless oil after chromatography. This ester is reduced with diisobutylaluminum hydride by the method described in example 14(B) above, to provide (2E)-2-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-pentenol as a colorless oil (93%) after chromatography.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)=O.O=P(Cl)(Cl)[Cl:30]>CN(C=O)C>[CH2:21]([N:19]1[CH:20]=[C:16]([C:14]2[NH:13][C:3]3[C:4](=[O:12])[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([Cl:30])=[N:7][C:2]=3[N:1]=2)[CH:17]=[N:18]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(Cc3ccccc3)c2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Temperature: 127.5 °C
Yield: 8 %

Procedure:
A mixture of 1-benzyl-1H-pyrazole-4-carboxylicacid(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.5 g, 13.5 mmol), POCl3 (10 ml) and DMF (0.1 ml) were heated at 125-130° C. for 20 hours. Reaction mixture was cooled to 20-25° C. It was then concentrated under vacuum. The residue was triturated with diethyl ether, dried. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 2 to 4% methanol in DCM as an eluent to obtain 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.04 g, 8%) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-])[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: Cc1c[n+]([O-])cc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cnc(Cl)c2ccccc12
Yield: 18.75 %

Procedure:
A solution of 4-methylisoquinoline 2-oxide (0.65 g, 4.08 mmol) in POCl3 (6 ml) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified with solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.17 g, 18.75%) as oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.14-8.12 (d, J=8 Hz, 1H), 7.97 (s, 1H), 7.95-7.93 (d, J=8 Hz, 1H), 7.86 (t, J=4 Hz, 1H), 7.84(t, J=8 Hz, 1H), 2.59 (s, 3H); MS: MS m/z 178.2 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:5]3[CH:4]=[CH:3][C:2]([N:29]4[CH2:30][CH2:31][N:27]([CH3:26])[C:28]4=[O:32])=[CH:9][C:6]=3[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[C:21]([CH3:25])[CH:22]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3C#N)CC2)c(C)c1
Yield: 77.2 %

Procedure:
Using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (399 mg) described in Preparation Example 187 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (323 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:33][C:34]1[C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=[CH:36][N:35]=1>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:39]4[C:34]([CH3:33])=[N:35][CH:36]=[CH:37][CH:38]=4)=[O:41])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Cc1ncccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a stirred solution of 1.0 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 3 ml of N,N-diisopropylethylamine in 100 ml of methylene chloride is slowly added 600 mg of 2-methylpyridine-3-carbonyl chloride dissolved in 15 ml of methylene chloride. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with water and the organic layer washed well with water. The organic layer is dried(MgSO4), filtered and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane to give 800 mg of the desired product as a pale yellow residue. M+ =422.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[C@H:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH3:5].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[Mg]Br.[Cl-].[NH4+].O>C1COCC1>[Cl:1][CH2:2][C:3]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][C:20]=1[F:22])([OH:14])[CH:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 0.69 g (3.0 mmol) of (R)-1-chloro-3-(tert-butyldimethylsilyloxy)butan-2-one in 5 mL of THF was cooled to −20° C., and 5.3 mL (3.3 mmol) of a solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise over a period of 15 minutes. After the completion of the dropwise addition, stirring was continued for another 2 hours, and then 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added thereto, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 3). Thereby, the title compound was obtained in a yield of 68% ((2S,3R):(2R,3R)=92:8).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:33]1[CH2:36][CH2:35][CH2:34]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:33]2[CH2:36][CH2:35][CH2:34]2)[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: BrC1CCC1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a suspension of 2-(2-hydroxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (3) (400 mg, 1.18 mmol), anhydrous Cs2CO3 (769 mg, 2.36 mmol), and KI (40 mg, 0.24 mmol) in DMF (10 mL) is added bromo-cyclobutane (130 μL, 1.42 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (20 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10-40% EtOAc in heptane) to give a pure product (8) as white solid (320 mg, 69%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N+:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:6]([O:8][CH3:9])=[O:7])([O-:14])=[O:13]
Reactant: NCC1CCOCC1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: COC(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from methyl 4-chloro-3-nitrobenzoate (Lancaster Synthesis Ltd.) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:16]3[C:17](=[O:25])[N:18]([CH3:24])[C:19]([S:22][CH3:23])=[N:20][CH:21]=3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1.O>[CH3:24][N:18]1[C:17](=[O:25])[C:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:30]4[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)=[CH:21][N:20]=[C:19]1[S:22][CH3:23]
Reactant: CSc1ncc(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(=O)n1C
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)n1C
Temperature: 90 °C
Yield: 34.3 %

Procedure:
A mixture of 5-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (0.52 g, 0.97 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.22 g, 1.07 mmol), and K2CO3 (0.40 g, 2.9 mmol) in 5:1 dioxane/water (6 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.12 g, 0.10 mmol), sparged again with Ar and heated at 90° C. overnight. The solids were removed via filtration, the filtrate treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(methylthio)pyrimidin-4(3H)-one (140 mg, 34%). MS (ESI) m/z: 421.1 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[NH:10][C:9]2[C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)=[O:4].[H][H]>CO.[Pd]>[NH2:15][C:11]1[C:9]2[NH:10][C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)([C:3]([NH:2][CH3:1])=[O:4])[CH2:6][O:7][C:8]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CNC(=O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)C1(c2ccccn2)COc2cccc(N)c2N1
Reaction time: 2 h
Yield: 22 %

Procedure:
N-Methyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide (25 mg, 0.080 mmol) was dissolved in methanol (5 mL) in a Parr bottle and degassed with nitrogen, followed by addition of palladium (10% on carbon) (5 mg, 0.05 mmol). The reaction vessel was charged to 50 PSI hydrogen and shaken for 2 h. The reaction mixture was filtered and concentrated in vacuo to give crude 5-amino-N-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide (0.005 g. 100%). LCMS calculated for C15H17N4O2 (M+H)+: m/z=285.1. found: 285.0.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[C:30]([Si:34]([CH3:45])([CH3:44])[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([Si:34]([CH3:45])([CH3:44])[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH:43][C:13](=[O:14])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:28][CH:27]=[CH:26][C:25]=3[F:29])[CH:6]=[N:7]2)[CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:39]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C(O)C(Cc1c(F)cccc1F)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(Cc2c(F)cccc2F)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 65 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-propionic acid (Intermediate 34) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-propionamide as a light yellow solid (690 mg, 65%); ES+-HRMS m/e calcd for C30H33N5O4SiF4 [M+H+] 632.2311 found 632.2311. 1H NMR (300 MHz, DMSO-d6) δ ppm −0.08 (s, 6H) 0.80 (s, 9H) 3.24-3.34 (m, 1H) 3.49 (dd, J=14.5, 5.7 Hz, 1H) 3.83 (t, J=5.1 Hz, 2H) 4.00-4.10 (m, 2H) 5.69 (dd, J=9.8, 5.6 Hz, 1H) 5.89 (d, J=2.7 Hz, 1H) 6.43 (d, J=2.1 Hz, 1H) 6.96 (t, J=8.0 Hz, 2H) 7.18-7.52 (m, 4H) 7.54 (d, J=2.1 Hz, 1H) 8.20 (d, J=2.7 Hz, 1H) 10.67 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]2([CH2:26][C:27]3[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=3)[NH:12][C:11](=[S:13])[N:10]([CH2:14][CH:15]3[CH2:20][CH:19]4[CH2:21][CH:17]([C:18]4([CH3:23])[CH3:22])[CH:16]3[CH3:24])[C:9]2=[O:25])=[CH:5][N:4]=[CH:3]1.[C:33]([C:35]1[CH:44]=[CH:43][C:38]([C:39](=[O:42])[CH2:40]Br)=[CH:37][CH:36]=1)#[N:34].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>>[CH3:32][N:28]1[C:27]([CH2:26][C:8]2([CH2:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)[C:9](=[O:25])[N:10]([CH2:14][CH:15]3[CH2:20][CH:19]4[CH2:21][CH:17]([C:18]4([CH3:22])[CH3:23])[CH:16]3[CH3:24])[C:11]([S:13][CH2:40][C:39]([C:38]3[CH:43]=[CH:44][C:35]([C:33]#[N:34])=[CH:36][CH:37]=3)=[O:42])=[N:12]2)=[CH:31][N:30]=[CH:29]1
Reactant: CC1C(CN2C(=O)C(Cc3cncn3C)(Cc3cncn3C)NC2=S)CC2CC1C2(C)C
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CC1C(CN2C(=O)C(Cc3cncn3C)(Cc3cncn3C)N=C2SCC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C

Procedure:
Using the same procedure as described in example 1D, the title compound of 3C (0.355 g, 0.78 mmol) and 4-cyanophenacyl bromide (193 mg, 0.86 mmol) in the presence of potassium bis(trimethylsilyl)-amide (193 mg, 0.86 mmol) reacted to yield 0.232 g (0.39 mmol, 50% yield) of the title compound of example 3D after chromatographic purification. Cl-Ms: m/z 598.3 [M+1].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](OCC)=[O:23]>C1(C)C=CC=CC=1>[C:4]1([C:1](=[O:3])[CH2:2][C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[O:23])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccccn1
Reactant: CC(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CC(=O)c1ccccn1)c1ccccc1
Yield: 68.6 %

Procedure:
Acetophenone (11.6 mL, 99 mmol), was added to a suspension of potassium tert-butoxide (12.34 g 110 mmol) in toluene (150 mL) and stirred under argon. The flask was then charged with ethyl picolinate (13.4 mL, 99 mmol) and the mixture stirred overnight. The toluene was removed by rotary evaporation and 200 mL of both diethylether and deionised water added. With stirring the mixture was acidified with dilute HCl until the ether layer was dark orange˜pH 7). The ether layer was separated, washed with deionised water (3×100 mL), dried over magnesium sulfate and filtered. The solvent was removed and the solid recrystallised from hot ethanol to yield 1-phenyl-3-pyridin-2-ylpropane-1,3-dione (1) as a pale yellow crystalline solid (15.3 g, 69%).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1([NH:41][C:42]([C:44]2([C:47](O)=[O:48])[CH2:46][CH2:45]2)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:47]([C:44]4([C:42](=[O:43])[NH:41][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:45][CH2:46]4)=[O:48])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1F
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A crude product of [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (219 mg) was dissolved in N,N-dimethylformamide (5 ml). 1-(Phenylcarbamoyl)cyclopropanecarboxylic acid (196 mg), triethylamine (0.133 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (422 mg) were added under a nitrogen atmosphere at room temperature, followed by stirring overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:2) to provide the titled compound as white powder (271 mg).