Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[SH:28].O[CH:30]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[S:28][CH:30]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37]
Reactant: Sc1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(Sc1cc(Cl)ccc1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 25 %

Procedure:
To a solution of triphenylphosphine (1.97 g), 2,5-dichlorothiophenol (0.90 g) and the product from step (a) (1.48 g) in THF (30 ml) under nitrogen at 0° C. was added diethylazodicarboxylate (1.18 ml) dropwise and the mixture was stirred at 0° C. for 45 minutes, then at room temperature for 72 h. The mixture was concentrated and the residue purified by chromatography (silica, 10% ethyl acetate/isohexane as eluent) to give the sub-title compound as a clear oil (500 mg).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][O:10][SiH:11]([O:14][CH3:15])[O:12][CH3:13]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:11]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: CO[SiH](OC)OC
Reactant: C=CCOCC1CO1
Product: CO[Si](CCCOCC1CO1)(OC)OC

Procedure:
In the example, allyl glycidyl ether was reacted with trimethoxysilane to form 3-glycidyloxypropyltrimethoxysilane. The reaction was carried out continuously by feeding the raw materials (allyl glycidyl ether: 9.6 kg/h and trimethoxysilane: 8 kg/h) together with the Pt Karstedt catalyst in the presence of acetic acid (0.05% by weight, based on the total mass of reactants) into a tube reactor. The concentration of the catalyst based on metallic platinum was 2 ppm. The Pt Karstedt catalyst was dissolved in 3-glycidyloxypropyltrimethoxysilane. The reaction temperature was about 160° C. The reaction was carried out using an excess of allyl glycidyl ether (molar ratio of allyl glycidyl ether:trimethoxysilane=1.28:1). The reaction mixture formed was composed of:
Reaction SMILES: [C:1]([N:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=O)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C(OCC)C>[C:1]([N:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([Cl:24])=[O:22])[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)N(c1ccccc1CC(=O)O)c1c(Cl)cccc1Cl
Solvent: CCOCC
Product: CC(=O)N(c1ccccc1CC(=O)Cl)c1c(Cl)cccc1Cl

Procedure:
2-[N-Acetyl-N-(2,6-dichlorophenyl)amino]phenylacetic acid is reacted with phosphorus pentachloride in diethyl ether to obtain 2-[N-acetyl-N-(2,6-dichlorophenyl)amino]phenylacetic acid chloride. The acid chloride is then reacted with trimethyl phosphite under the conditions described in Example 2, thus producing 2-[N-acetyl-N-(2,6-dichlorophenyl)amino]phenyl-1-hydroxyethene-1-phosphonic acid dimethyl ester; this compound is converted, under the conditions of Example 1, with dimethyl phosphite into 2-[2-(2,6-dichlorophenylamino)phenyl]-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][CH2:2]1.[N:12]([O-])=[O:13].[Na+]>Cl.O>[N:12]([N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3][CH2:4]1)=[O:13]
Reactant: c1ccc2c(c1)NCCCO2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCCOc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a stirred, cold slurry of 2,3,4,5-tetrahydro-1,5-benzoxazepine (13.72 g, 91.96 mmol) in 2N aqueous HCl (105 mL) was added dropwise a solution of NaNO2 (7.30 g, 105.75 mmol) in H2O (16 mL) and stirred at room temperature for 2 hrs. The mixture was taken up in H2O (800 mL), extracted with ether (3×200 mL), dried over MgSO4, and stripped of the solvent under reduced pressure to yield 15.59 g (95%) of 5-nitroso-2,3,4,5-tetrahydro-1,5-benzoxazepine as a tan powder. (M+H)+ 178.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]2=[O:16])=[CH:4][CH:3]=1.CN(C)[CH:19]=[O:20]>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>[O:20]1[C:19]2([CH2:6][CH2:5][C:4]([C:2]3[N:7]=[CH:6][C:5]([N:8]4[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]4=[O:16])=[CH:4][CH:3]=3)=[CH:3][CH2:2]2)[O:10][CH2:11][CH2:12]1
Reactant: CN(C)C=O
Reactant: COCC1CN(c2ccc(Br)nc2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COCC1CN(c2ccc(C3=CCC4(CC3)OCCO4)nc2)C(=O)O1
Reaction time: 22 h

Procedure:
A suspension of 8.9 g of (RS)-3-(6-bromo-pyridin-3-yl)-5-methoxymethyl-oxazolidin-2-one, 6.5 g of 8-tributyl-stannyl-1,4-dioxaspiro[4,5]dec-7-ene and 1.4 g of bis(triphenylphosphine)palladium(II) dichloride in 40 ml of dimethylformamide was stirred at 85° under argon for 22 h. Then, the mixture was cooled, filtered over a Celite® pad, the filter cake was washed with a large amount of ethyl acetate and the organic phase was washed several times with semi-saturated sodium chloride solution. The aqueous phases were extracted with ethyl acetate, the organic phases were combined, concentrated to a volume of 250 ml, treated with 250 ml of saturated potassium fluoride solution and stirred for 30 minutes. The mixture was again filtered over a Celite® pad, the phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, concentrated and chromatographed over silica gel 60 with diethyl ether as the eluent. There were obtained 1.2 g of (RS)-3-[6-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-pyridin-3-yl]-5-methoxymethyl-oxazolidin-2-one. 1H-nmr (CDCl3) ppm: 8.48 (s, 1H), 8.19 (d, 1H), 7.56 (d,1H), 6.50 (m, 1H), 4.79 (m, 1H), 4.12 (t, 1H), 4.02 (s, 4H), 3.98 (t, 1H), 3.64 (m, 2H), 3.44 (s, 3H), 2.80 (m, 2H), 2.52 (m, 2H), 1.96 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOCC>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:11][C:21]([NH:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[S:22])[CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccn1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1cccn1NC(=S)NC(=O)c1ccccc1
Reaction time: 8 h
Yield: 50.8 %

Procedure:
1-Amino-1H-pyrrole-2-carboxylic acid ethyl ester (53.0 g, 0.344 mol) was dissolved in Tetrahydrofuran (2000 mL). Benzoyl isothiocyanate (56.1 g, 0.344 mol) was added and the reaction was allowed to stir overnight. The reaction mixture was reduced and 55.47 grams of 1-(3-Benzoyl-thioureido)-1H-pyrrole-2-carboxylic acid ethyl ester was isolated as a white solid via trituration with ether. (M+Na)=339.98. 1H NMR (400 MHz, DMSO, d6) δ 12.91 (s, 1H), 11.94 (s, 1H), 7.98 (d, 1H, J=7.32 Hz), 7.68 (t, 1H, J=7.52 Hz), 7.56 (t, 2H, J=7.64 Hz), 7.16 (m, 1H), 6.89 (m, 1H), 6.19 (m, 1H), 4.14 (q, 2H, J=7.12 Hz), 1.18 (d, 3H, J=14.17 Hz).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][CH2:5][CH2:6][O:7]C1CCCCO1.[Br-].[Mg+2].[Br-]>C(OCC)C>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][CH2:5][CH2:6][OH:7]
Reactant: FC(F)(F)COCCOC1CCCCO1
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Product: OCCOCC(F)(F)F
Reaction time: 24 h

Procedure:
Combine 2-tetrahydropyran-2-yloxyethyl 2,2,2-trifluoroethyl ether (2 mmol) and magnesium bromide (6 mmol) in diethyl ether (10 mL). After 24 hours, extract with water and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give 2-hydroxyethyl 2,2,2-trifluoroethyl ether.
Reaction SMILES: NC1C=CC=CC=1O.[CH3:9][C:10]1[C@@H:15]([OH:16])[CH2:14][CH:13]([C:17]([CH3:19])=[CH2:18])[CH2:12][CH:11]=1>CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Zn+2]>[CH3:9][C:10]1[C:15](=[O:16])[CH2:14][CH:13]([C:17]([CH3:19])=[CH2:18])[CH2:12][CH:11]=1
Reactant: C=C(C)C1CC=C(C)[C@@H](O)C1
Agent: CCCCCCCC(=O)[O-]
Agent: Nc1ccccc1O
Agent: [Zn+2]
Product: C=C(C)C1CC=C(C)C(=O)C1
Temperature: 213 °C
Yield: 8 %

Procedure:
A mixture of 1000 parts of trans-1,2-limonene oxide, 4 parts of zinc octoate (contains 18% zinc) and 2 parts of 2-aminophenol was refluxed at 200-226° C. for 3 hours in a three-necked flask equipped agitator, Dean-Stark trap, and temperature probe. After cooling 998 part of the mixture containing 67% carveol and 8% carvone was obtained. This mixture can be further processed to carvone according to example 58, or fractionated to obtain pure cis-carveol.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH2:11])[CH2:4][CH2:3]1.F[C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:11][C:21]2[CH:22]=[N:23][CH:24]=[CH:16][C:17]=2[C:18]([OH:20])=[O:19])[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1cccc(OCC2CC2)c1
Agent: Cl
Product: O=C(O)c1ccncc1NCc1cccc(OCC2CC2)c1
Yield: 7 %

Procedure:
The title compound was prepared in 7% yield from 3-cyclopropylmethoxy-benzylamine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 8.07 (s, 1H), 7.79 (d, 1H, J=5.0 Hz), 7.57 (d, 1H, J=5.0 Hz), 7.23 (t, 1H, J=8.0 Hz), 6.89-6.95 (m, 2H), 6.79 (d, 1H, J=7.6 Hz), 4.49 (s, 2H), 3.78 (d, 2H, J=6.9 Hz), 1.15-1.21 (m, 1H), 0.51-0.57 (m, 2H), 0.27-0.32 (m, 2H). [M+H] calc'd for C17H18N2O3, 299. Found 299.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH:14](C)[CH2:13][CH:12](C)[CH2:11]2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH3:22])=[O:20].Br>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH3:22])=[O:20]
Reactant: CNC(=O)Nc1cc(CCN2CC(C)CC(C)C2)ccc1O
Agent: Br
Product: CNC(=O)Nc1cc(CCN2CCCCC2)ccc1O

Procedure:
1-(2-hydroxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]phenyl-3-methylurea.HBr;
Reaction SMILES: CCOCC.Br[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Li]CCCC.[CH3:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1>[Cl-].[Na+].O>[CH3:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Brc1cccs1
Reactant: Cc1ccnc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(-c2cccs2)nc2ccccc12
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A two necked round-bottom flask (250 mL) containing a stir bar fitted with a reflux condenser was evacuated and purged with nitrogen gas. Dry ether (50 mL) and 2-bromothiophene (0.0191 mol, 3.06 g) was added to the flask followed by the slow addition of n-BuLi (0.0229 mol, 9.17 mL) via a syringe pump. The reaction mixture was stirred at room temperature for 30 min to 40 min and then 4-methylquinoline (0.0191 mol, 2.72 g) was slowly added. The reaction mixture was refluxed for an additional 2 to 3 hr. The reaction mixture was then cooled to room temperature and diluted with an aqueous brine solution and extracted with ether (3×30 mL). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using hexanes/CH2Cl2 as eluent to afford 2.77 g of 4-methyl-(2-thiophenyl)quinoline (65% yield).
Reaction SMILES: [CH:1]1([C:5]2[N:10]=[C:9]([CH:11](OC)[O:12]C)[CH:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>Cl.O>[CH:1]1([C:5]2[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(OC)c1ccnc(C2CCC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=Cc1ccnc(C2CCC2)n1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A solution of 2-cyclobutyl-4-(dimethoxymethyl)pyrimidine (300 mg, 1.4 mmol) in aqueous hydrochloric acid (3N, 5 mL) was heated to 50° C. for 16 h. The reaction mixture was cooled to room temperature, then was diluted with water, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as a brown colored liquid (200 mg). MS (ES+) (M+H) 163.16.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:22]2[C:23]([CH3:39])=[C:24]([NH:28]C(=O)OCC4C=CC=CC=4)[CH:25]=[CH:26][CH:27]=2)=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=3)(=[O:3])[NH2:2]>O1CCCC1.CO.[Pd]>[NH2:28][C:24]1[C:23]([CH3:39])=[C:22]([C:7]2[C:8]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3C)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3C)c12
Temperature: 25 °C
Yield: 102.3 %

Procedure:
A mixture of benzyl 3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate (0.226 g, 0.431 mmol) and Pd/C (60 mg, 0.056 mmol) in tetrahydrofuran (12 mL) and methanol (18 mL) was stirred at room temperature under H2, provided with a H2 balloon, for 1.5 hr. The catalyst was removed by suction filtration, and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate (80 mL) and dried over anhydrous MgSO4. Removal of the solvent under vacuum provided the desired product (0.172 g, 0.441 mmol, 102% yield) as a beige solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH:11]=[CH:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.S(=O)(=O)(O)O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C=CC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(CCCc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
Under an argon atmosphere, to a mixture of 5.0 g of methyl 4-[3-(4-nitrophenyl)-3-oxoprop-1-en-1-yl]benzoate and 150 mL of methanol was added dropwise 5.0 mL of concentrated sulfuric acid under ice-cooling. Under an argon atmosphere, to the reaction mixture was added 500 mg of palladium on carbon under ice-cooling, followed by replacing with hydrogen (3 atm) at room temperature and then stirring at room temperature for 24 hours. The insoluble materials were filtered off on a celite layer and the filtrate was concentrated under reduced pressure. The residue was neutralized by the addition of a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform) to obtain 2.9 g of methyl 4-[3-(4-aminophenyl)propyl]benzoate as a pink oil.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])[CH:4]([CH:17]=[CH2:18])[CH2:3]1>C(O)(=O)C.[Zn]>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])[CH:4]([CH:17]=[CH2:18])[CH2:3]1
Reactant: C=CC1CC(=O)C=CN1C(=O)OCC[Si](C)(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: C=CC1CC(=O)CCN1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(trimethylsilyl)ethyl 4-oxo-2-vinyl-3,4-dihydropyridine-1(2H)-carboxylate (29.1 g, 109 mmol) in acetic acid (500 ml) was added zinc dust (42.7 g, 652 mmol). The solution stirred at room temperature for 2 hrs and was filtered through a pad of celite. The solvent was evaporated under reduced pressure and the product was purified by column chromatography on silica gel Biotage 65i, eluting with 20% ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][CH:18]4[CH2:27][CH2:26][C:21]5(OCC[O:22]5)[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][CH:18]4[CH2:19][CH2:20][C:21](=[O:22])[CH2:26][CH2:27]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2cnc3ccc(NC4CCC5(CC4)OCCO5)nn23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
To a solution of 3-(3-chlorophenyl)-N-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[1,2-b]pyridazin-6-amine (210 mg, 0.55 mmol) in THF (3 mL) was added 3 N HCl (3 mL). The resulting mixture was stirred at room temperature for 2 h. TLC (EtOAc) showed the reaction was complete. The mixture was poured into sat. NaHCO3 (aq) and extracted with EtOAc (100 mL×3). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanone (190 mg, 102%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[O:13]1[CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]1>CN(C=O)C>[OH:13][CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][O:6][C:5]1[C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[O:8][C:2](=[O:1])[C:3]=1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CCCCC1CO1
Solvent: CN(C)C=O
Product: CCCCC(O)COC1=C(O)C(=O)O[C@@H]1[C@@H](O)CO
Temperature: 80 °C
Reaction time: 24 h
Yield: 24.6 %

Procedure:
Under an argon atmosphere, 30 ml of DMF was added to L-ascorbic acid (5.00 g), and further, 1,2-epoxyhexane (3.45 g) was added thereto. The mixture was heated up to 80° C. and stirred for 24 hours, then, extracted with ethyl acetate. The extracted liquid was dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. Thereafter, 7.56 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:20/3/0.3), and concentration was performed under reduced pressure to obtain 3-O-(2-hydroxyhexyl) ascorbic acid (1.93 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[C:11](=[O:13])[N:12]=2)[CH2:4][CH2:3]1.[OH:28][C@@H:29]([CH2:42][NH2:43])[CH2:30][O:31][C:32]1[C:40]2[NH:39][C:38](=[O:41])[NH:37][C:36]=2[CH:35]=[CH:34][CH:33]=1>>[OH:28][C@@H:29]([CH2:42][NH:43][CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:14]=[C:10]3[S:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[N:12][C:11]3=[O:13])=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)[CH2:30][O:31][C:32]1[C:40]2[NH:39][C:38](=[O:41])[NH:37][C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(=O)CC4)cc3)S2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(NC[C@H](O)COc5cccc6[nH]c(=O)[nH]c56)CC4)cc3)S2)CC1

Procedure:
The title compound was prepared from 1-{4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(which was obtained in Intermediate 29) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a yellowish solid; mp>150° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.85-2.00 (m, 2 H), 2.24 (s, 3 H), 2.40-3.00 (m, 11H), 3.50-4.10 (m, 7 H), 6.56 (d, J=8.1Hz, 1 H), 6.62 (d, J=8.1Hz, 1 H), 6.84 (dd, J=8.1, 8.1Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.48 (d, J=9.0 Hz, 2 H), 7.52 (s, 1 H), 10.3-11.0 (brs, 2 H); MS (ES) m/z: 296.5 ((M+2H)2+, 100%); 592.1 (MH+, 20%); HRMS Calcd. for C30H38N7O4S (MH+): 592.2760. Found: 592.2685.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].Cl.[CH3:38][NH:39][CH3:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:29][CH2:30][C@H:31]([C:34]([N:39]([CH3:40])[CH3:38])=[O:35])[CH2:32][CH2:33]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@H](C(=O)O)CC4)c3C)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@H](C(=O)N(C)C)CC4)c3C)cc12
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A mixture of trans-4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanecarboxylic acid (9.00 mg, 0.0176 mmol), dimethylamine hydrochloride (14.4 mg, 0.176 mmol), TBTU (8.48 mg, 0.0264 mmol), DIPEA (0.0153 mL, 0.0881 mmol) and DCM (3 mL, 50 mmol) was stirred at rt for 1 min. The solution was concentrated in vacuo, redissolved in MeOH (1 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.65-1.77 (m, 2H), 1.80 (d, J=7.3 Hz, 3H), 1.89-1.97 (m, 2H), 1.98-2.08 (m, 4H), 2.23 (s, 3H), 2.81 (m, J=11.8, 11.8, 3.4, 3.3 Hz, 1H), 2.95 (s, 3H), 3.16 (s, 3H), 3.65 (br. s., 3H), 4.16-4.30 (m, 1H), 5.06-5.15 (m, 1H), 6.89 (dd, J=9.0, 4.4 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.34 (d, J=1.3 Hz, 1H), 7.40 (s, 1H), 7.48 (s, 1H), 8.11 (s, 1H). MS (ES+): tri/z=538.24/540.24 (100/50) [MH+]. HPLC: tR=1.45 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][S:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>>[C:13]1([S:11]([CH2:10][CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCNCC1
Reactant: O=S(CCCl)c1ccccc1
Product: O=C1CCN(CCS(=O)c2ccccc2)CC1

Procedure:
1-(2-Phenylsulfinylethyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-2-phenylsulfinylethane essentially as described above in Example 38, Scheme C, step a.