Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH:13]=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[F:15][C:16]1[CH:21]=[C:20]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]3[CH2:31][CH2:30][CH2:29][C@@H:28]3[CH3:32])[CH2:23]2)[CH:19]=[CH:18][C:17]=1[NH2:33].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH2:13][NH:33][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[CH2:23]3)=[CH:21][C:16]=2[F:15])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc(N)c(F)c2)C1
Reactant: COC(=O)C1(CCC=O)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)C1(CCCNc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)cc2F)CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(3-Oxo-propyl)tetrahydro-pyran-4-carboxylic acid methyl ester (135 mg, 0.515 mmol, 1 eq) was dissolved in 2.4 mL of 1,2-dichloroethane. To this was added 2-Fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine (103 mg, 0.515 mmol, 1 eq) in 6.2 mL of 1,2-dichloroethane. To the combined mixture was added glacial acetic acid (96 mg, 1.6 mmol, 3.1 eq) followed by NaBH(OAc)3 (330 mg, 1.55 mmol, 3 eq). The reaction mixture was stirred at rt for 15 h. The reaction mixture was quenched with water, transferred to a separatory funnel and extracted with CH-2Cl2 (2×100 mL). The combined organics were dried over Na2SO4, concentrated under vacuum and purified by column chromatography on silica gel (40 g column, 6% MeOH in CH2Cl2; 35 mL/min). This gave 130 mg (61%) of the title compound as a beige semi-solid.
Reaction SMILES: C(O)(=O)C.O=[C:6]1[CH2:23][CH2:22][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.[N:24]1[CH:25]=[N:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]=12.[Na]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N:24]1[CH:25]=[N:26][N:27]2[CH2:32][CH2:31][N:30]([CH:6]3[CH2:23][CH2:22][C:9]4([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]4)[CH2:8][CH2:7]3)[CH2:29][C:28]=12
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: c1nc2n(n1)CCNC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N3CCn4ncnc4C3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Acetic acid (2.34 eq.) was added to a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1.122 mmol, 1 eq.) and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (1.14 eq.) in methylene chloride (7 ml). Sodium triacetoxyborhydride (1.4 eq) was then added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and sat. NaHCO3 solution. The aqueous phase was washed with methylene chloride (2×20 ml), and the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica, ethyl acetate/ethanol 10:1) to obtain the desired product. Yield: 62%
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19]O)[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][Cl:3])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cc(OCc2ccccc2)ccn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cc(OCc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.76 ml (24.16 mmol) of thionyl chloride are added to 2 g (9.29 mmol) of [4-(benzyloxy)pyridin-2-yl]methanol [described in J. Org. Chem., (1996), 61(8), 2624] in 46 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 18 hours and then concentrated under reduced pressure. The residue obtained is taken up in a saturated aqueous sodium carbonate solution and then extracted with dichloromethane. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. 2.1 g of a brown oil are collected. Mass spectrometry (ES+ Mode): MH+=234
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][NH:11][C:10](=O)[C:9]=3[CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>C(#N)C>[Cl:22][CH:10]1[C:9]2[CH:8]=[CH:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:14]=2[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][NH:11]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c[nH]c(=O)c2ccn(C3CCCC3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COC(=O)C1=CNC(Cl)c2ccn(C3CCCC3)c21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (1.83 g) obtained in Step D of Example 29 in acetonitrile (20 mL) was added phosphoryl chloride (4 mL), and the mixture was stirred at 80° C. for 4 hr. To the reaction mixture was added 8N aqueous sodium hydroxide solution at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.37 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH2:13][CH2:14]1)[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCC
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C

Procedure:
To 1 g (3.19 mmol) trans-5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-pentanoic acid in 37 ml CH2Cl2 was added 0.5 ml (4.8 mmol, 1.5 eq) diethylamine and 0.53 ml (4.79 mmol, 1.5 eq) NMM. The solution was cooled to 0° C. and 795 mg (4.15 mmol, 1.3 eq) EDCI and 98 mg (6.4 mmol) HOBT were added. The mixture was stirred at RT over night, partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The organic phase was washed with KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with EtOAc/hexane 1:1 gave 1.05 g (86%) trans-[4-(4-Diethylcarbamoyl-butyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester as colorless liquid MS: 369 (MH+).
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1Cl)[CH2:2][CH2:3][CH3:4].[CH2:15]([Mg]Br)[CH3:16]>O1CCCC1.CCOCC>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:15][CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Mg]Br
Reactant: CCCC/N=C/c1c(F)cccc1Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC/N=C/c1c(F)cccc1CC

Procedure:
Prepared as described in Example 58(a) as by-product of reaction between butyl-[1-(2-chloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine and ethylmagnesium bromide in tetrahydrofuran and ether. MS (ISP): 208.3 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:31]=1)[C:19]([N:21]=[S@@:22]([CH3:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>>[C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:31]=2)[C:19]([N:21]=[S@@:22]([CH3:30])(=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:8]=[CH:7][CH:6]=1)(=[O:12])[CH3:11]
Reactant: C#Cc1cccc(NC(C)=O)c1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: CC(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)c1
Yield: 67.8 %

Procedure:
In a manner similar to that described in Example 449, N-(3-ethynyl-phenyl)-acetamide (0.0469 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (83 mg, 0.20 mmol, 67%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C(N(C(C)C)CC)(C)C.[N:24]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[OH:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][N:27]2[CH2:26][CH2:25][N:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][CH2:28]2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CCOC(=O)N1CCNCC1
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(Cc2ccc(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
To a mixture of 5-chloromethyl-8-hydroxyquinoline hydrochloride (A2) (2.36 g, 10.2 mmol) and diisopropylethylamine (3.6 ml, 20.4 mmol, 2 eq) in 50 ml CHCl3 at 0° C., ethyl 1-piperazinecarboxylate (1.5 ml, 10.2 mmol, 1 eq) was added. The mixture was stirred for 24 h at room temperature, and then 100 ml of CHCl3 was added and the solution was washed with 5% NaHCO3 (3×50 ml), brine (2×50 ml), and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was crystallized from a mixture of benzene-hexane (1:1) to yield the title compound HLA16 as white solid. (1.38 g, 42% yield, m.p.=92-93° C.). H1 NMR (250 MHz, CDCl3), 1.25 (dd, J=7.1, 7.1 Hz 3H), 2.42 (s, 4H), 3.43 (s, 4H), 3.81 (s, 2H), 4.14 (dd, j=14.21, 7.12 Hz, 2H), 7.08 (d, J=7.72 Hz, 1H), 7.31 (m, 1H), 7.47 (dd, J=8.52, 4.20 Hz, 1H), 8.66 (dd, J=8.56, 1.58 Hz, 1H), 8.79 (dd, J=4.18. 1.54 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:19][C:9]1[C:2]([F:1])=[CH:3][C:4]([O:10][CH3:11])=[C:5]([CH:8]=1)[C:6]#[N:7]
Reactant: COc1cc(F)ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(Br)cc1C#N
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a 500 mL flask was added 4-fluoro-2-methoxybenzonitrile (9.00 g, 59.5 mmol), NBS (12.7 g, 71.5 mmol) and TFA (40 mL); the resulting mixture was stirred for 4 h at 65° C. Analysis of the reaction by LC indicated completion of the reaction. The reaction mixture was concentrated to dryness, treated with EtOAc (200 mL) and washed with brine and water, dried (Na2SO4), filtered and concentrated to dryness. The resulting organic residue was purified by MPLC with the solvent systems of hexanes/EtOAc=1/1 to furnish the desired product: LC/MS: [(M+2)]+=232;
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=1[C:19]([OH:21])=[O:20]>O1CCCC1>[CH3:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]2[C:13]([O:21][C:19](=[O:20])[C:11]=12)=[O:15]
Reactant: COc1cccc(C(=O)O)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cccc2c1C(=O)OC2=O
Temperature: 25 °C
Yield: 99.1 %

Procedure:
Acetic anhydride (70 ml) was added to a mixture of 3-methoxyphthalic acid (51.0 g, 0.26 mol) in anhydrous tetrahydrofuran (250 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo and the resulting solid material was dried in a vacuum oven at 50° C. overnight to afford 3-methoxyphthalic anhydride (45.9 g, 99%) as a colourless solid. 1H NMR (DMSO-d6) 7.97 (1H, dd), 7.63 (1H, d), 7.60 (1H, d), 4.02 (3H, s). MS: [M+H]+ 179.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CN=C1>CN(C=O)C>[Si:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:4]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1c1cc(O)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc(O)c(N2C(=O)c3ccccc3C2=O)c1)(c1ccccc1)c1ccccc1
Yield: 68.1 %

Procedure:
A mixture of Example 73B (5.31 g, 20.81 mmol), tert-butyldiphenylsilyl chloride (5.68 mL, 21.85 mmol), imidazole (2.83 g, 41.62 mmol) in anhydrous DMF (100 mL) was heated at 50° C. for 2 days. The solvent was removed via vacuum pump. THF (200 mL) was added. The mixture was ultrosonicated. The suspension was filtered. The solution was dried with silica gel powder (20 g). 20% ethyl acetate in hexanes (1 L) and 30% ethyl acetate in hexanes (1 L) were used to perform flash chromatography to give the title compound (7 g, 68%). MS (APCI) m/z 492.19 (M−H)−; 1H NMR (500 MHz, CDCl3) δ ppm 1.10 (s, 9H) 6.64 (dd, J=8.73, 2.81 Hz, 1 H) 6.78 (d, J=8.73 Hz, 1 H) 6.86 (d, J=2.81 Hz, 1 H) 7.34–7.45 (m, 6 H) 7.70–7.75 (m, 4 H) 7.78 (dd, J=5.46, 2.96 Hz, 2 H) 7.92 (dd, J=5.30, 3.12 Hz, 2 H).
Reaction SMILES: C(O)C.Cl.[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[OH:19])([CH3:8])([CH3:7])[CH3:6].[N:20]([O-])=[O:21].[Na+]>O>[N:20]([C:13]1[CH:14]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:10]([OH:19])=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=1)=[O:21]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
Ethanol (75 ml) was cooled to 15° C and saturated with hydrogen chloride gas. This solution was diluted by addition of another 400 ml of ethanol. To this alcoholic solution was added 82.4 grams of 2,6-di-tert-butylphenol. After it was dissolved, a solution of 30.4 grams of sodium nitrite in 40 ml of water was added at 15°-20° C over a period of one hour with stirring. Stirring was continued for another two hours with the temperature allowed to rise to room temperature. The solution was diluted with 200 ml of water, and the product formed was collected by filtration and washed well with water. The filter cake was then slurried in 300 ml of petroleum ether, filtered, washed with another 100 ml of petroleum ether and dried in a vacuum oven at 70°-80° C to yield the desired intermediate 4-nitroso-2,6-di-tert-butylphenol, melting at 219° C.
Reaction SMILES: N#N.[C:3]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-:22]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].C(=O)(OCC)O[CH2:39][CH3:40]>CO>[F:36][C:33]([F:34])([F:35])[S:30]([N-:22][S:23]([C:26]([F:27])([F:28])[F:29])(=[O:24])=[O:25])(=[O:31])=[O:32].[CH2:39]([P+:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:40]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)OCC
Agent: N#N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 10 °C

Procedure:
In a reactor wherein air was replaced by N2, 300.0 g of (1.1 mol) triphenyl phosphine and 500 mL of methanol were added and cooled to 10° C. by a ice-bath. 320.3 g (1.14 mol) of trifluoromethanesulfonimide was then added dropwise under strong stirring, and 264.3 g (2.2 mol) of diethyl carbonate was also added after 1 hour of reaction. The reaction mixture was transferred to an autoclave, wherein air was removed prior to heating. After 2 hours of reaction at temperature of 180° C. and at pressure of from 1.4 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 599.5 g of ethyl triphenyl phosphonium bis(trifluoromethyl sulfonyl) amide was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11]C(=O)OC(C)(C)C)[N:10]=2)[N:7]=1.Cl.C(OCC)(=O)C.C(OCC)C>C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Nc1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
To a suspension of tert-butyl (6-iodoimidazo[1,2-b]pyridazin-2-yl)carbamate (10.2 g, 28.3 mmol) in ethyl acetate (50 mL) was added 4N hydrochloric acid/ethyl acetate (75 mL), and the mixture was stirred at room temperature for 4 hr. Diethyl ether (200 mL) was added to the reaction mixture, and the precipitate was filtrated. After washing with saturated aqueous sodium hydrogencarbonate solution, the filtrate was washed with water, acetonitrile and diethyl ether to give the title compound (4.9 g, 67%) as a green powder.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:25]=[N:24][N:23]([CH:26]4[CH2:30][CH2:29][CH:28]([OH:31])[CH:27]4[OH:32])[C:13]=3[N:14]=[C:15]([S:17]([CH2:20]CC)(=O)=O)[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[S-].[Na+]>O1CCCC1.O>[C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:25]=[N:24][N:23]([CH:26]4[CH2:30][CH2:29][CH:28]([OH:31])[CH:27]4[OH:32])[C:13]=3[N:14]=[C:15]([S:17][CH3:20])[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCS(=O)(=O)c1nc(NC2CC2c2ccccc2)c2nnn(C3CCC(O)C3O)c2n1
Agent: C[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CCC(O)C3O)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of product from step b) (0.15 g) in tetrahydrofuran (10 ml) was treated with sodium methanethiolate (0.046 g) in water (1 ml). The solution was stirred at room temperature overnight. The solution was concentrated in vacuo and residue was purified by chromatography (SiO2, ethyl acetate:dichloromethane 1:1 as eluant) to afford the title compound (0.095 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1.[CH3:16][CH:17]([CH3:26])[CH2:18][C@@H:19]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH2:20]>>[CH3:16][CH:17]([CH3:26])[CH2:18][C@H:19]([NH:20][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:21]1[S:22][CH:23]=[CH:24][N:25]=1
Reactant: CC(C)C[C@H](N)c1nccs1
Reactant: Cc1ccc(C(=O)O)nc1OCC1CC1
Product: Cc1ccc(C(=O)N[C@@H](CC(C)C)c2nccs2)nc1OCC1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36 d) and (S)-α-(2-methylpropyl)-2-thiazolemethanamine (Example 56 d) as starting materials, MS (EI): m/e=360.2 [M+H]+.
Reaction SMILES: C(O)C.[H][H].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([O-])=O>[Pd].C1C=CC=CC=1>[NH2:6][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: *O[SiH2]*
Solvent: c1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2ccc(N)cc2)cc1
Yield: 123.9 %

Procedure:
270 mg of 5%-Pd/C was suspended in 14 mL of a 1:1 mixed solvent of ethanol and benzene. While passing hydrogen through the system, a solution was added that consisted of 3.21 g of the 4,4'-dinitrobiphenyl-containing polysiloxane (average value of n: 14.4) synthesized in Reference Example 2 dissolved in 14 mL of the same mixed solvent. Hydrogen was injected into the system for 3 hours while stirring. The catalyst was then filtered off and the solvent was distilled under reduced pressure to give 3.00 g of the 4,4'-diaminobiphenyl-terminated polysiloxane as a viscous yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]=[C:17]=[S:18])=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:20][C:21]1[C:22]([NH2:45])=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([CH:39]=1)[C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]1)=[O:27]>CN(C=O)C.O>[Cl:1][C:2]1[C:15]([NH:16][C:17]([NH:20][C:21]2[CH:39]=[C:25]([C:26](=[O:27])[NH:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([C:35]([F:38])([F:36])[F:37])[CH2:33][CH2:34]3)[C:24]([O:40][CH2:41][CH:42]([F:43])[F:44])=[N:23][C:22]=2[NH2:45])=[S:18])=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCC(F)F)nc1N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(NC(=S)Nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)nc2N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2,4-Dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (100 mg, 0.30 mmol) is added to 5,6-diamino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (120 mg, 0.30 mmol) in DMF (5 mL) and it is stirred at rt overnight. The reaction mixture is diluted with water, extracted with EtOAc, the organic layer is washed with water, dried and concentrated to give the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH2:12].[Cl:13][C:14]1[C:19]2[C:20](=[O:24])[O:21][CH:22](O)[C:18]=2[C:17]([F:25])=[C:16]([Cl:26])[N:15]=1>CO>[Cl:13][C:14]1[N:15]=[C:16]([Cl:26])[C:17]([F:25])=[C:18](/[CH:22]=[N:12]/[CH2:11][C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[C:19]=1[C:20]([OH:24])=[O:21]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C1OC(O)c2c(F)c(Cl)nc(Cl)c21
Solvent: CO
Product: COc1ccc(C/N=C/c2c(F)c(Cl)nc(Cl)c2C(=O)O)c(OC)c1
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of (2,4-dimethoxyphenyl)methanamine (40.5 g, 242.0 mmol) in MeOH (250 mL) was added 4,6-dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one (55.0 g, 231.0 mmol). The mixture was stirred for 0.5 h, filtered, and washed with petroleum ether to give the title compound as a white solid (73.0 g, 82%). 1H NMR (CDCl3, 400 MHz) δ ppm 3.75 (s, 3H), 3.79 (s, 3H), 3.93 (s, 2H), 6.30 (s, 1H), 6.40-6.42 (m, 2H), 7.12 (d, J=8.4 Hz, 1H). [M+H] calc'd for C16H13Cl2FN2O4, 387. found, 387.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[OH:15].O>CN(C)C=O>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([CH:14]([OH:15])[CH2:13][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:17][CH:18]=1)[CH3:23]
Reactant: CCc1ccc(C(O)CBr)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
Into a solution of 9.635 kg (72.99 mol) of 4-hydroxy benzaldehyde dissolved in 50 lit. dimethylformamide was added 5.675 kg (236.45 mol) of sodium hydride in 5 lit. dimethylformamide and stirred for 15 min. To this was added 15 Kg (65.22 mol) of 2-bromo-1-(5-ethyl pyridin-2-yl)-ethanol dissolved in 500 lit dimethylformamide and stirring was continued for 1 hr. at 25 to 30° C. Reaction mixture was heated at 80 to 90° C. for 14 hr., allowed to cool to 25° C. and excess of water was added into it. Product was extracted with diethyl ether. Organic layer was dried (magnesium sulfate) and concentrated to obtain crude product, which was purified in methyl tert-butyl ether as described in example 17 to obtain 12.195 Kg (69%) pure 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde. m.p. 83° C.