Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH3:20][S:17]([C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:18])=[O:19]
Reactant: COC(=O)c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2ccc(C(=O)O)cc2)c1

Procedure:
Procedure HH: To a stirring solution of 3′-Methanesulfonyl-biphenyl-4-carboxylic acid methyl ester (1.0 mmol) in 1:1 methanol/tetrahydrofuran (0.15M), add 2N sodium hydroxide (3.0 mmol) and heat to reflux for 1 hour. After this time, remove the heat and concentrate in vacuo. Wash with 1N hydrochloric acid and water while extracting with 10% isopropanol/dichloromethane. Concentrate the organic layer in vacuo to yield the title compound. MS (m/e): 275.1 (M−1)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:16])([CH3:15])[CH3:14])[C:6]=2[N:5]=1.Br[CH2:18][C:19]1[CH:38]=[CH:37][C:22]2/[C:23](=[C:33](/[CH3:36])\[C:34]#[N:35])/[C:24]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:25]=3[O:26][CH2:27][C:21]=2[CH:20]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:24]2=[C:25]([CH:28]=1)[O:26][CH2:27][C:21]1[CH:20]=[C:19]([CH2:18][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:16])([CH3:14])[CH3:15])[C:6]=4[N:5]=[C:4]3[CH2:3][O:2][CH3:1])[CH:38]=[CH:37][C:22]=1/[C:23]/2=[C:33](/[CH3:36])\[C:34]#[N:35]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: COCc1nc2c(C(C)(C)O)cccc2[nH]1
Product: COCc1nc2c(C(C)(C)O)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 99.6 %

Procedure:
[step 2] Using 2-[2-(methoxymethyl)-1H-benzo[d]imidazol-4-yl]propan-2-ol (74 mg, 0.34 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (166 mg, 99%) was obtained.
Reaction SMILES: [N:1](=[C:3]1[S:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:8][N:9]([S:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:10](F)=[O:11].C(N(CC)CC)C>O1CCOCC1>[CH3:8][N:9]([S:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]([O:2][N:1]=[C:3]1[S:7][CH2:6][CH2:5][S:4]1)=[O:11]
Reactant: CN(SSC(C)(C)C)C(=O)F
Reactant: ON=C1SCCS1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(SSC(C)(C)C)C(=O)ON=C1SCCS1

Procedure:
2-[[O-[N-Methyl-N-(tert-butylthiosulfenyl)carbamoyl]oximino]]-1,3-dithiolane was prepared according to the procedure described in Example I, by reacting 2.9 g (0.0214 m) of 2-oximino-1,3-dithiolane, 4.23 g (0.0214 m) of N-methyl-N-(tert-butylthiosulfenyl)carbamoyl fluoride and 2.17 g (0.0214 m) of triethylamine in 50 ml of dioxane. 2-[[O-[N-Methyl-N-tert-butylthiosulfenyl)carbamoyl]oximino]]-1,3-dithiolane crystallized from methylene chloride isopropyl ether to yield 4.0 g of a white solid. It was then recrystallized from ethyl acetate to yield a solid, m.p. 112°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Sn](C)(C)C)=[CH:5][N:4]=1.FC(F)(F)S(O[C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[CH:23]=2)(=O)=O.[Cl-].[Li+]>O1CCOCC1.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[CH:23]=3)=[CH:5][N:4]=1
Reactant: COc1cc2cc(OS(=O)(=O)C(F)(F)F)cnc2cc1OC
Reactant: COc1ccc([Sn](C)(C)C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc3cc(OC)c(OC)cc3c2)cn1

Procedure:
A mixture of 800 mg (2.94 mmol) of 2-methoxy-5-trimethylstannylpyridine, 994 mg (2.94 mmol) of 6,7-dimethoxyquinolin-3-yl trifluoromethane sulfonate, 374 mg (8.82 mmol) of anhydrous lithium chloride and 170 mg (0.147 mmol) of Pd(PPh3)4 in 15 mL of anhydrous dioxane is flushed thoroughly with nitrogen and refluxed for 6 hours. The mixture is diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 (75 mL), dried (Na2SO4) and evaporated. The resulting residue is chromatographed on silica gel (eluting with chloroform) to give a solid material which is recrystallized from ethyl acetate to give 3-(2-methoxypyrid-5-yl)-6,7-dimethoxyquinoline (m.p. 170.5°-171.5° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH3:12][C:13]1[S:14][C:15]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][N:17]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[NH:21][NH:20][C:18]([C:15]1[S:14][C:13]([CH3:12])=[N:17][CH:16]=1)=[O:19]
Reactant: Cc1ccc(N=C=O)c(C)c1
Reactant: Cc1ncc(C(=O)NN)s1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)NNC(=O)c2cnc(C)s2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared from a mixture 2,4-dimethylphenylisocyanate (50 mg, 0.34 mmol) and 2-methylthiazole-5-carboxylic acid hydrazide (59 mg, 0.37 mmol) in methylenedichloride (10 mL). The mixture was stirred at room temperature for 2 h, and the resultant precipitate was collected by filtration and isolated as pale white solid (66 mg, 64%). 1H NMR (DMSO-d6): 10.00 (s, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 6.99 (s, 1H), 6.87 (d, J=8.1 Hz, 1H), 2.72 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].[NH2:6][CH2:7][CH2:8][C:9]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:10]1>C(OC(=O)C)(=O)C>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:12]2[CH2:11][CH2:10][C:9]([CH2:8][CH2:7][NH:6][C:1](=[O:3])[CH3:2])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:14][C:13]2=[O:15])[CH:17]=1
Reactant: CC(=O)[O-]
Reactant: NCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Reaction time: 2 h
Yield: 32.1 %

Procedure:
In a 5 dram vial, sodium acetate (3 mg, 0.04 mmol) was added to 6-(2-aminoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (5.13 mg, 0.013 mmol) in acetic anhydride (0.5 mL). The reaction was stirred for 2 h. The solvent was evaporated and the crude residue purified via prep HPLC to afford 1.88 mg of N-(2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)acetamide. LC-MS Method 1 m/z=451 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C@H:27]([OH:49])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[CH:31]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]([CH2:26][C@H:27]([OH:49])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[CH:31]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)ccc1OCc1ccccc1

Procedure:
A mixture of 4.48 g (5.71 mmol) of ethyl trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoate and of 38 ml of a 1N aqueous sodium hydroxide solution in 114 ml of ethanol is heated overnight at 50° C. The solvents are evaporated, the residue is taken up in water and a 1N hydrochloric acid solution is gently added to pH=1. The precipitate is filtered off and dried under vacuum. The title compound is thus obtained in the form of a white solid (4.05 g, 94%)
Reaction SMILES: Cl.C([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@@H:7]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[O:35])[CH2:27][CH2:26]2)=[O:24])[CH2:6]1)=O.C(=O)([O-])O.[Na+]>O1CCOCC1>[OH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@@H:7]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[O:35])[CH2:27][CH2:26]2)=[O:24])[CH2:6]1
Reactant: O=CO[C@H]1C[C@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(OCCN1CCN(C(=O)[C@H]2C[C@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
28 ml of a 10% w/v methanolic solution of hydrogen chloride were added dropwise to a solution of 1.42 g of (2R,4S)-4-formyloxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in 14 ml of 1,4-dioxane, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with water. The aqueous mixture thus obtained was made alkaline by the addition of a saturated aqueous solution of sodium hydrogencarbonate, and then the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 9:1 by volume mixture of ethyl acetate and methanol as the eluent to give 1.33 g of the title compound, as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:40])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[C:22]=1[CH2:37][CH2:38][CH3:39])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:40])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:22]=1[CH2:37][CH2:38][CH3:39])[CH3:16]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 59.1 %

Procedure:
A mixture of 3.0 g of 1-[2,4-dihydroxy-3-propylphenyl)ethanone, 6.65 g of [4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]acetic acid ethyl ester and 4.3 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 24 hours. The reaction mixture was concentrated in vacuo to a red oil which was purified by high pressure liquid chromatography using 25% ethyl acetate-hexane to yield 4.95 g (59%) of [4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy] acetic acid ethyl ester as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].Br[C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1>COCCOC.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>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1ncccc1Br
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of sodium carbonate (1.31 g), tetrakis(triphenylphosphine)palladium(0) (0.357 g), 4-tert-butylphenylboronic acid (1.43 g) and 3-bromopyridin-2-amine (1.069 g) in 1,2-dimethoxyethane (50 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.274 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[CH2:3][CH:4]=[O:5].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C.O>[CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[CH2:3][CH2:4][OH:5]
Reactant: C=CCC(C)(C)CC=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C=CCC(C)(C)CCO
Temperature: 5 °C
Reaction time: 1 h

Procedure:
In a 1-L 4-necked round-bottom flask, 3,3-dimethylhex-5-enal (14.20 g; 0.113 mol) was dissolved in absolute ethanol (420 mL). Then the mixture was cooled to 5° C. in an ice-bath and, under nitrogen atmosphere, sodium borohydride (3.3 g; 0.087 mol) was added cautiously in 10 minutes. After the mixture had been stirred for 1 hour, it was poured into 5% ammonium chloride, diluted with water, and extracted with dichloromethane. Extracts were dried over sodium sulfate and evaporated, then the white solid was filtered away, while the pale yellow oil was distilled at 55-56° C. (4 mmHg) to give the title compound as a foul smelling, colorless liquid.
Reaction SMILES: O[CH:2]([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:19][CH:2]([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: CC(O)CCCCCc1nc2ccccc2[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Br)CCCCCc1nc2ccccc2[nH]1
Yield: 75.8 %

Procedure:
2.18 g of the compound obtained in Example 19a, 4.97g of carbon tetrabromide and 3.93 g of triphenylphosphine were added to 30 ml of tetrahydrofuran and the mixture was reacted overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 2.10 g of the title compound as pale yellow solid (yield: 75%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].[OH-].C[N+](C)(C)CC1C=CC=CC=1.CO>C(Cl)(Cl)Cl>[CH3:28][O:27][C:23]([CH2:24][CH2:25][N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4]1)=[O:26]
Reactant: C=CC(=O)OC
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Yield: 66.3 %

Procedure:
A mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.43 g), methyl acrylate (1.29 g), 40% methanolic trimethylbenzylammonium hydroxide (0.4 ml) and methanol (2 ml) in chloroform (8 ml) was refluxed for 40 minutes and then evaporated in vacuo. To the residue were added methylene chloride (30 ml) and water (30 ml), and the organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and diethyl ether to give 3-[2-(2-methoxycarbonylethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.37 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH3:38][CH:39]([OH:52])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>>[CH3:38][CH:39]([O:52][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCC(C)O
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCCCCCCCC(C)OC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with 1-methyl-tridecanol.
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: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
Reactant: CN1CCCC1=O
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: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:12][C:11]([CH3:14])([CH3:13])[N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]2[CH2:22][F:23])=[CH:4][CH:3]=1.[CH3:24][S:25]SC.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[C:18]([O:17][C:15]([N:10]1[C@H:9]([CH2:22][F:23])[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([S:25][CH3:24])=[CH:3][CH:4]=2)[O:12][C:11]1([CH3:14])[CH3:13])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(Br)cc2)OC1(C)C
Reactant: CSSC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-butyl lithium (n-BuLi), (1.78 g, 28 mmol, 1.2 eq) was added to a solution of tert-butyl (4S,5R)-5-(4-bromophenyl)-4-(fluoromethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (9.0 g, 23 mmol) in 30 ml of anhydrous tetrahydrofuran (THF) at −78° C. in 30 min, and the reaction mixture was stirred for 30 minutes under N2. 3.1 ml of dimethyldisulfide (1.5 eq) was added, and stirred for 30 min. The reaction mixture was warmed up to room temperature and stirred for 1 hour. A saturated solution of ammonium chloride (50 ml) and ethyl acetate (50 ml) was added and stirred for 30 min. The organic layer was washed with brine (50 ml) and dried over sodium sulfate. After purification, via a column, 8.15 g of white solid of the desired product was obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:13][NH:14][CH:15]([C:31](=[O:37])[NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.[ClH:46]>C(Cl)Cl.C(OCC)C>[ClH:46].[ClH:46].[NH2:7][CH:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:13][NH:14][CH:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:22]=1)[C:31]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:37]
Reactant: CC(C)CC(CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC(N)CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reaction time: 0.42 h
Yield: 59 %

Procedure:
To a solution of (1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester (0.4 g, 0.76 mmol, Example 8, Step A) in CH2Cl2 (7.5 mL) was added trifluoroacetic acid (2.5 mL) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 25 minutes, then concentrated in vacuo. The viscous oil obtained was dissolved in 40 mL of CH2Cl2 and successively washed with saturated aqueous NaHCO3 solution (2×40 mL), brine (2×40 mL), and was dried over Na2SO4. The CH2Cl2 solution of free amine was concentrated in vacuo to afford the crude product as a viscous oil which was then dissolved in 10 mL of ethyl ether. To this solution was added saturated HCl solution in ethyl ether until no more white precipitate formed. Filtration and drying overnight under vacuum afforded 0.15 g (59%) of titled compound as a yellow solid; mp 228-230° C.
Reaction SMILES: [Na].[N:2](=[C:4]([C:10]#[N:11])[C:5](OCC)=[O:6])[OH:3].Cl.[CH2:13]([O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH2:28])=[NH:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CO>[NH2:11][C:10]1[N:27]=[C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[NH:28][C:5](=[O:6])[C:4]=1[N:2]=[O:3]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: CCCCCCCCCCOc1ccccc1C(=N)N
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCOc1ccccc1-c1nc(N)c(N=O)c(=O)[nH]1
Reaction time: 4 h

Procedure:
Sodium (7.35 g.) was dissolved in anhydrous methanol (130 ml.), treated with ethyl α-oximinocyanoacetate (11.4 g.) and 2-decyloxybenzamidine hydrochloride (25 g.) and heated to reflux, with stirring, for 4 hours. The mixture was allowed to stand at room temperature overnight and the solid which separated was filtered off, washed with water and dried at 75° C. to give the crude sodium salt of 4-amino-2-(2-decyloxyphenyl)-5-nitrosopyrimid-6-one, pure enough for use in the next stage of the preparation. An aliquot was treated with dilute acetic acid and the solid obtained recrystallised from dilute acetic acid and then from methanol to give pure 4-amino-2-(2-decyloxyphenyl)-5-nitrosopyrimid-6-one, m.p. 144°-146° C.