Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:27][N:28]1C(=O)CCC1.C([Cu])#N.CN(C=O)C>O>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:27]#[N:28])=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: CN1CCCC1=O
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
Agent: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(C#N)n5c4)n3n2)cn1
Temperature: 200 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 55 mg, 0.135 mmol) was introduced in a microwave reactor with NMP (150 μL) and CuCN (15.7 mg, 0.175 mmol). The RM was heated at 200° C. for 10+15 min. The black solid obtained was taken up with DMF. Water was added to the mixture and it was extracted with EtOAc/MeOH (9:1) twice. Combined organic layers was washed with 10% ammonia solution. The organic layer was dried over Na2SO4 filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated. The white solid obtained was a repurified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound as a white solid (tR 0.8 min (conditions 2), MH+=355).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].[Br:8][C:9]1[CH:10]=[CH:11][C:12](F)=[N:13][CH:14]=1>CN(C=O)C.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])=[N:13][CH:14]=1
Reactant: CC(C)CO
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(Br)cn1
Yield: 86.3 %

Procedure:
To 2-methyl-propan-1-ol (10 g, 0.41 mol) was added NaH (60%, 8.2 g, 0.204 mol) portionwise under a nitrogen atmosphere at room temperature over 10 minutes. The mixture was refluxed for 30 minutes. A solution of 5-bromo-2-fluoro-pyridine (24 g, 0.136 mol) in DMF (400 mL) was added dropwise and the mixture refluxed for 18 hours. The reaction mixture was then diluted with water (1 L) and extracted with EtOAc (3×500 mL). The combined organics were washed with brine (3×300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue obtained was purified by flash column chromatography eluting with petroleum ether to yield the title compound as a colourless oil (27 g).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@H:7]([OH:20])[CH2:8][O:9][C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:37]3[CH2:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[OH:20][C@H:7]([CH2:8][O:9][C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:6][NH:5][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[CH:29]=[CH:30][C:31]([S:34]([N:37]3[CH2:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])(=[O:36])=[O:35])=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1CN(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)C(=O)N1
Reaction time: 0.33 h
Yield: 39.5 %

Procedure:
Acetic acid (0.14 mL, 2.38 mmol) was added dropwise into a mixture of 4-{[(2S)-3-amino-2-hydroxypropyl]oxy}-1,3-dihydro-2H-benzimidazol-2-one (265 mg, 1.19 mmol), 1-[[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl]-2,4-imidazolidinedione (400 mg, 1.19 mmol) and N,N-dimethylformamide (5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (303 mg, 1.43 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 3/1) to produce a brown solid (256 mg, 40% yield): mp 230° C. (decomposed); 1H NMR (400 MHz, DMSO-d6): δ 1.52-1.63 (m, 2H), 2.04-2.15 (m, 2H), 2.48 (m, 2H), 2.9-3.0 (m, 2H), 3.13-3.15 (m, 1H), 3.2-3.4 (m, 3H), 4.0-4.1 (m, 5H), 4.42 (s, 2H), 6.6-6.63 (m, 2H), 6.8-6.85 (m, 1H), 7.03-7.05 (m, 2H), 7.78-7.8 (m, 2H), 10.6 (s, 1H), 10.7 (s, 1H); MS m/e 543 (M−H)+;
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)=[CH:9][CH:8]=1)(=O)=O.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26].C(N(CC)CC)C>CN(C=O)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>[CH2:29]([O:28][C:24]([CH:25]=[CH:26][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)=[CH:9][CH:8]=1)=[O:27])[CH3:30]
Reactant: C=CC(=O)OCC
Reactant: O=S(=O)(Oc1ccc(C2OCCO2)c2ccccc12)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C2OCCO2)c2ccccc12
Temperature: 90 °C
Yield: 53.7 %

Procedure:
Nitrogen was passed through a solution of 2-(4-trifluoromethylsulfonyloxynaphthyl) dioxolane (2.46 g, 7.06 mmol), ethyl acrylate (2.3 mL, 2.1 g, 21.2 mmol), triethylamine (4.3 g, 42.3 mmol) in DMF (6 mL) for 15 min, and bis(triphenylphosphine)palladium dichloride was added. The well stirred solution was heated at 90° C. for 8 hr, and concentrated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (2×50 mL), dried (Na2SO4), and concentrated. Purification by flash chromatography using hexane/ethyl acetate 9:1 as eluent provided a yellow solid (1.13 g, 53%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:25]=[C:26](I)[C:27]([NH2:30])=[N:28][CH:29]=1>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>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:26]2[C:27]([NH2:30])=[N:28][CH:29]=[C:24]([Br:23])[CH:25]=2)=[CH:15][CH:14]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Nc1ncc(Br)cc1I
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: Nc1ccc(-c2cc(Br)cnc2N)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium (1.16 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.48 g) and potassium carbonate (4.15 g) were added to a solution of 5-bromo-3-iodopyridin-2-amine (2.99 g) in 1,4-dioxane (40 ml) and water (10 ml) at room temperature. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel chromatography [chloroform:methanol=9:1 (v/v)] to give 2.48 g of the title compound as a solid.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]([CH3:40])([CH3:39])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]([N:26]([C:34](=[O:36])[CH3:35])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:18][C@@H:17]2[CH3:37])=[O:15])=[CH:10][C:9]=1[F:38].[OH-].[Li+].Cl>CO.C1COCC1>[C:34]([N:26]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C@H:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][C:4]([CH3:40])([CH3:39])[C:3]([OH:41])=[O:2])=[C:9]([F:38])[CH:10]=2)=[O:15])[C@@H:17]([CH3:37])[CH2:18]1)(=[O:36])[CH3:35]
Reactant: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)c(F)c2)c2ccccc21
Reaction time: 1 h

Procedure:
(2S,4R)-4-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-2-fluoro-phenoxy)-2,2-dimethyl-butyric acid methyl ester (100 mg) was dissolved in methanol/THF (1:1, 5 mL), and lithium hydroxide (1.0N, 1 mL) was added. After 1 hour, the reaction was acidified (HCl) and extracted from with methylene chloride. The organic layer was dried, filtered, and concentrated. The crude residue was purified by silica gel chromatography ethyl acetate-5% MeOH/ethylacetate gradient) to afford the product.
Reaction SMILES: [N:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH2:26][CH:27]3[CH2:29][O:28]3)[C:17]3[C:22]([C:23]=2[CH:24]=1)=[CH:21][C:20]([Br:25])=[CH:19][CH:18]=3.[Li+].[Br-]>C1COCC1>[N:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:29][CH:27]([OH:28])[CH2:26][N:16]2[C:17]3[CH:18]=[CH:19][C:20]([Br:25])=[CH:21][C:22]=3[C:23]3[C:15]2=[CH:14][CH:13]=[C:12]([Br:11])[CH:24]=3)=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1ccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 23 %

Procedure:
4-Azidoaniline (0.038 g, 0.283 mmol) was added to a solution of 3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (0.100 g, 0.262 mmol) in THF (0.10 mL). LiBr (0.001 g, 0.013 mmol) was added and the reaction was stirred at room temperature for 3 days. The reaction was purified directly by chromatography (SiO2, 0-25% EtOAc/Hexane) to afford the desired product (31 mg, 23%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O.[OH-].[Na+].Cl>O.C(O)C>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])/[CH:10]=[CH:17]/[C:16]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:14]([Cl:13])[CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1cc(C)cc(Br)c1O
Reactant: COc1ccc(C=O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(/C=C/C(=O)c2cc(C)cc(Br)c2O)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
1-(3-Bromo-2-hydroxy-5-methylphenyl)-1-ethanone (10 g, 43.7 mmol) and 3-chloro-4-methoxybenzaldehyde (9.0 g, 1.2 molar eq.) were introduced into 80% aqueous ethanol solution (150 ml), sodium hydroxide (NaOH; 5.2 g, 3.0 molar eq.) was added thereto, and the resulting mixture was stirred for 17 hours at room temperature. After completion of reaction, the reaction solution was neutralized by 2N aqueous hydrochloric acid solution and diluted with water (150 ml). The yellow solid thus precipitated was washed with water and methanol to give 14.2 g (Yield 85%) of the purified title compound.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]1([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:17]Br>>[Br:17][C:15]1[CH:14]=[N:13][N:12]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:16]=1
Reactant: BrBr
Reactant: c1cnn(C2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Brc1cnn(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a suspension of Na2CO3 (13 g, 124 mmol) in CH2OH2 (100 mL) was added 1-cyclopentyl-1 H-pyrazole (8.35 g, 62 mmol) and Br2 (3.2 mL). The resulting mixture was stirred at RT overnight. The solid was removed by filtration and the filter cake was washed with DCM. The combined filtrates were washed with water, brine and dried over anhydrous MgSO4. The solvent was concentrated to dryness to give 4-bromo-1-cyclopentyl-1 H-pyrazole (14 g, 93%). 1H NMR (300 MHz, CDCl3): δ7.46 (s, 1 H), 7.44 (s, 1 H), 4.64 (m, 1 H), 2.18-1.67(m, 8 H); MS (ESI) m/z: 215.0 [M+H]+.
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[SH:39]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:39][C:33]2[C:34]([Cl:38])=[CH:35][CH:36]=[CH:37][C:32]=2[Cl:31])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Reactant: Sc1c(Cl)cccc1Cl
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](Sc2c(Cl)cccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mesylate from experiment A2 with 2,6-dichlorothiophenol yielded (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(2,6-dichloro-phenylsulfanyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a white solid. MS: 454.4 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.[Si](N=C=S)(N=C=S)(N=C=S)[N:18]=[C:19]=[S:20].C(N)=S>C1C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:19](=[S:20])[NH2:18])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: S=C=N[Si](N=C=S)(N=C=S)N=C=S
Agent: NC=S
Agent: [Li]CCCC
Solvent: O
Solvent: c1ccccc1
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Reaction time: 0.5 h

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (1.43 g, 0.01 mole) in benzene (20 ml) was treated with n-butyl-lithium (15% w/w, 4.5 ml, 0.01 mole) and the solution was allowed to stand at room temperature for 0.5 hours. The solution was then treated with a suspension of silicon tetraisothiocyanate (1.3 g, 0.005 mole) in benzene (5 ml) at 0° C. After 10 minutes, water (50 ml.) was added to the solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-lithio-N-(tri-isothiocyanato) silyl)thiocarboxamide causing hydrolysis to 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-tri-isothiocyanato)silyl) thiocarboxamide and subsequent hydrolysis to the title compound, and the mixture was stirred for 0.5 h at room temperature and then acidified with conc. HCl. The aqueous layer was separated, washed with ethyl acetate and the pH was adjusted to 10 with solid Na2CO3. The basic mixture was extracted with ethyl acetate (3 × 50 ml) and the combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was triturated with n-hexane to give 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (0.2 g, 10%).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[Na+].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([NH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCNC(=O)CCl
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a rapidly stirred mixture of oleylamine (118.5 g), diether (200 mL), Na2CO3 (50.29 g) and water (500 mL) is added chloroacetyl chloride (54.16 g) dropwise over 60 min. Intermittent cooling is applied to maintain temperature between 10-15° C. After completion of addition, the mixture is stirred for 60 min, and the phases are allowed to separate. Analysis (H-NMR) of a sample of the upper ether layer indicates that a small amount of amine is not reacted. Additional Na2CO3 (7 g) and water (50 mL) is added, followed by chloroacetyl chloride (7 g). The upper ether phase is removed, the aqueous phase extracted with additional ether (200 mL), and the combined organic phase is washed with water (2×125 mL portions), saturated NaCl (125 mL), dried over anh. Na2SO4, and the solvent removed in vacuo to give 149 g of 2-chloro-N-oleylacetamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:5]=1[NH2:22])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:6]1[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=[C:4]([NH2:1])[C:5]=1[NH2:22]
Reactant: Nc1c(-c2ccccn2)cc(-c2cccnc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cccnc2)cc(-c2ccccn2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of 2-nitro-6-pyridin-2-yl-4-pyridin-3-yl-phenylamine (75 mg, 0.26 mmol) in ethyl acetate (20 mL) was added 10% palladium on carbon (50 mg). The resulting suspension was placed in a Parr hydrogenation apparatus under 40 psi hydrogen gas while shaking at ambient temperature for one hour. The catalyst was removed by filtration and the filtrate concentrated in vacuo to afford compound the title compound (50 mg, 0.19 mmol).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Br:5][C:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:25]=[C:24]([CH3:26])[O:23][C:22](=O)[C:21]=3[CH:28]=2)=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:5][C:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:28]=[C:21]3[C:20](=[CH:19][CH:18]=2)[N:25]=[C:24]([CH3:26])[N:4]([CH2:1][CH2:2][CH3:3])[C:22]3=[O:23])=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: CCCN
Reactant: Cc1nc2ccc(C(=O)c3nc(Br)c4ccccn34)cc2c(=O)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCn1c(C)nc2ccc(C(=O)c3nc(Br)c4ccccn34)cc2c1=O
Temperature: 160 °C
Yield: 71.6 %

Procedure:
1.32 g (22.4 mmol) of n-propylamine are added, at 0° C. under an inert atmosphere, to 0.9 g (2.2 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-methyl-4H-3,1-benzoxazin-4-one in 15 ml of glacial acetic acid. The reaction medium is microwave-heated for 45 minutes at 160° C. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with a saturated aqueous solution of sodium carbonate. The precipitate obtained is filtered off and then dried under reduced pressure at 50° C. overnight. 0.67 g of a yellow solid is obtained.
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:38]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:32]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][Br:38])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture of N-triphenylmethyl-5 (4'-methylbiphenyl-2-yl)tetrazole (Example 11, 12.7 g), N-bromosuccinimide (4.6 g), carbon tetrachloride (300 mL), and benzoyl peroxide (75 mg) was heated at reflux for 2.5 hours. The cooled suspension was filtered and the filtrate was evaporated to give the title compound as a crystalline solid. 1H-NMR (CDCl3) δ8.2-6.7 (complex, 23H), 4.3 (s, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]1[N:20]=[C:21]([NH2:24])[O:22][CH:23]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:24][C:21]1[O:22][CH:23]=[C:19]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][C:9]=2[OH:8])[N:20]=1
Reactant: [H][H]
Reactant: Nc1nc(-c2c(OCc3ccccc3)ccc3ccccc23)co1
Agent: [Pd]
Solvent: CCO
Product: Nc1nc(-c2c(O)ccc3ccccc23)co1
Yield: 40.6 %

Procedure:
4-(2-Benzyloxy-naphthalen-1-yl)-oxazol-2-ylamine (12, 1.0 g) was dissolved in ethanol and then palladium, 10% on carbon (390 mg) was added. The mixture was stirred under 1 atmosphere of hydrogen for 48 hours. The mixture was filtered through a pad of hyflo and washed with industrial methylated spirits. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to afford 1-(2-amino-oxazol-4-yl)-naphthalen-2-ol (22) (290 mg, 41%) as a glassy orange foam. 1H NMR (DMSO-D6): 6.6 (2H, br s), 6.85 (1H, s), 7.2 (1H, d, J=9.0 Hz), 7.25 (1H, m), 7.4 (1H, m), 7.75 (2H, m), 7.9 (1H, m), 9.9 (1H, br s). Mass Spectrum (m/z): 227 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:16])=[C:5]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:6]([O:8]CC)=[O:7])#[N:2].Cl.O>C(O)(=O)C>[C:1]([C:3]1[C:4]([F:16])=[C:5]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCOC(=O)c1cc(F)c(F)c(C#N)c1F
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
Ethyl 3-cyano-2,4,5-trifluorobenzoate (3.35 g, 14.6 mmol) was suspended in glacial acetic acid (5 mL). Concentrated hydrochloric acid (10 mL) was added thereto, and the mixture was stirred at 100° C. for 4 hours. While cooling with ice, water (100 mL) was added to the reaction mixture. Subsequently, the resultant mixture was extracted with chloroform (100 mL×4), followed by drying with sodium sulfate anhydrate. After filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform/n-hexane, to thereby yield the title compound as a white solid (2.86 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.F[B-](F)(F)F.[CH3:18][O+](C)C.[OH-].[Na+]>ClCCl>[CH3:18][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=1
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2cc(Br)ccc2n1

Procedure:
A mixture of 6-bromo-2-[1H]-quinolone (2.90 g) and trimethyloxoniumtetrafluoroborate (2.10 g) was stirred in dichloromethane (50 cm3) for 48 hours under nitrogen. Aqueous 10% sodium hydroxide (20 cm3) was added and the aqueous phase was extracted with dichloromethane (2×40 cm3). The dried (MgSO4) extracts were evaporated and the residue was crystallised from petroleum ether (b.p. 60°-80°) to yield 2-methoxy-6-bromoquinoline, m.p. 90°-94°, (2.16 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][N:12]=[C:11]3O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:30]>C1(C)C=CC=CC=1>[Cl:30][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccc(-c3ccc(F)cc3)cc12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Yield: 90.2 %

Procedure:
To a suspension of the product of example 7 (720 mg, 3 mmol) in toluene (20 ml) was added diisopropylethylamine (1.5 ml, 9 mmol) and POCl3 (0.84 ml, 9 mmol). The mixture was refluxed for 1 hour. The solvents were evaporated in vacuo. The residue was redissolved in dichloromethane and the organic layer was washed with ice water till pH 6-7. The combined organic layers were dried over MgSO4 and concentrated to yield the title compound as a yellow solid (700 mg, yield: 90%) which was characterized by its mass spectrum as follows: MS (m/z): 259 ([M+H]+, 100).