Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1/[CH:17]=[CH:18]/[CH:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][CH2:18][CH:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: COC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COCCCCN1C(=O)CCC[C@@H]1CCC(O)Cc1ccccc1
Reaction time: 4 h
Yield: 87.3 %

Procedure:
Palladium on carbon (10 wt. %, 3 mg) was added to a solution of {4-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-butoxy}-acetic acid methyl ester (9.5 mg, 0.024 mmol) in MeOH (2.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 4 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 8.2 mg (86%) of the title compound.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([OH:13])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].[ClH:14]>O.S>[Cl:14][C:6]1[C:7]([OH:13])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccnc(O)c1N
Reactant: Cl
Agent: O=N[O-]
Agent: S
Agent: [Na+]
Solvent: O
Product: Cc1ccnc(O)c1Cl

Procedure:
A solution sodium nitrite (2.38 g) in water (10 ml) was added dropwise to a stirred mixture of 3-amino-2-hydroxy-methylpyridine (4.8 g) in aqueous hydrochloric acid (48% 10 ml) and water (5 ml) at 0°-5° C. This solution of the diazonium salt was added to a hot solution of cuprous chloride (2.5 g) in conc. hydrochloric acid and following cessation of nitrogen evolution the mixture was heated on the steam bath for 0.5 hours, diluted with water and saturated with hydrogen sulphide. Filtration, concentration to low bulk and extraction with chloroform yielded 3-chloro-2-hydroxy-methyl-pyridine (3.7 g), m.p. 42°-44° (from n-pentane). This was dissolved in aqueous hydrobromic acid (48%, 50 ml), cysteamine hydrochloride (3.22 g) added and the solution obtained was heated under reflux for 6 hours. Concentration, followed by recrystallisation from aqueous ethanol afforded 2-[(2-aminoethyl)thiomethyl]-3-chloropyridine dihydrobromide (6.0 g), m.p. 250°.
Reaction SMILES: F[B-](F)(F)F.[C:6]([N+:10]1[O:11][C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=12)([CH3:9])([CH3:8])[CH3:7].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[C:6]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C:12]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:11]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)[n+]1oc(-c2ccccc2)c2cc(Cl)ccc21
Reactant: C1COCCN1
Agent: F[B-](F)(F)F
Product: CC(C)(C)N1OC(c2ccccc2)(N2CCOCC2)c2cc(Cl)ccc21
Reaction time: 1 h

Procedure:
To a flask containing 6 g. of 1-tert.-butyl-5-chloro-3-phenyl-2,1-benzisoxazolium tetrafluoroborate is added 9 ml. of morpholine and the mixture heated at 80°C. with stirring for 1 hour. The reaction mixture is washed in diethyl ether and water and the ether layer separated, dried, evaporated in vacuo to dryness and the residue recrystallized from ether to obtain 1-tert.-butyl-5-chloro-3-morpholino-3-phenyl-2,1-benzisoxazoline, m.p. 130°-132°C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[C:16](Cl)[C:15]([F:19])=[CH:14][N:13]=1>CO.O>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:12]2[N:17]=[C:16]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)[C:15]([F:19])=[CH:14][N:13]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)O)cc3)n2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 4-Aminobenzoic acid (410 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) in methanol (10 mL) and water (1 mL) was stirred at 100° C. for 24 h to yield N2,N4-bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine after methanol was removal. This residue was redissolved in DMF (10 mL) and to it was added potassium carbonate (1.65 g, 12 mmol) and iodomethane (0.37 mL, 6 mmol), stirred at room temperature overnight, and then diluted with 1 N HCl (80 mL) and ethyl acetate (80 mL). The ethyl acetate layer was washed with 1N HCl (60 mL) and water (60 mL). The organic layer was separated, dried, evaporated and the resulting residue was recrystallized from ethyl acetate/hexanes to give N2,N4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (150 mg, 63%). 1H NMR (acetone-d6): δ 3.85 (s, 3H), 3.88 (s, 3H), 7.88-7.97 (m, 4H), 7.98-8.05 (m, 4H), 8.18 (d, J=3.0 Hz, 1H), 9.00 (br, 1H, NH), 9.04 (br, 1H, NH); LCMS: ret. time: 27.07 min.; purity: 95.54%; MS (m/e): 397.04 (MH+).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].[F:6][C:7]1[N:8]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=[C:10]([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[N:11]=1>CN(C=O)C>[CH2:1]([S:3][CH2:14][CH2:13][CH2:12][C:10]1[N:11]=[C:7]([F:6])[N:8]([C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:9]=1)[CH3:2]
Reactant: CS(=O)(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethanethiol in DMF was treated with sodium hydride, and then with 2-fluoro-4-(3-methanesulphonyloxypropyl)-1-triphenylmethylimidazole. After stirring at ambient temperature for 16 hours, the mixture was worked up by extraction and chromatography to give 4-(3-ethylthiopropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.2 (t, 3H); 1.85 (quintet, 2H); 2.48 (q, 6H); 6.24 (s, 1H); 7.0-7.4 (m, 15H). This thioether was dissolved in CH2Cl2, cooled to 0°, and treated in portions with one equivalent of 3-chloroperbenzoic acid, having the reaction closely by HPLC. Complete conversion to product occurred 10 minutes after the final addition of peracid. The solution was extracted with aqueous sodium bicarbonate, dried and evaporated to give 4-(3-ethanesulphinylpropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.28 (t, 3H); 2.02 (quintet, 2H); 2.66 (m, 6H); 6.27 (s, 1H); 7.0-7.4 (m, 15H).
Reaction SMILES: Br[C@H:2]([CH2:10][OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[O:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].CCCCCC.C(=O)([O-])[O-].[K+].[K+]>O>[O:11]1[CH2:10][C@@H:2]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[O:12][C:13]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)[C@H](Br)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)C1(C(=O)OCC)OC[C@@H](C(=O)OC(C)(C)C)O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83 %

Procedure:
6.90 g of tert-butyl (2R)-2-bromo-3-hydroxypropionate and 5.3 g of diethyl ketomalonate were mixed, and after the heat-generated reaction solution returned to room temperature, 15 ml of hexane and 6.4 g of potassium carbonate were sequentially added, followed by stirring at room temperature for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl ether. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1) to obtain 8.0 g (yield: 83%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[CH:4]=[N:3]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(C(=O)O)cn1
Reaction time: 18 h
Yield: 86 %

Procedure:
A solution of ethyl 1-methyl-1H-pyrazole-4-carboxylate (20.2 g, 131 mmol) and NaOH (6.3 g, 158 mmol) in 200 mL absolute ethanol was refluxed for 2 h and stirring was continued at RT for 18 h. After that, the solvent was removed in vacuo. The residue was dissolved in water. The aq solution was washed with ether and acidified with concentrated HCl. The solid was filtered, washed with water and air-dried to give 14.2 g of 1-methyl-1H-pyrazole-4-carboxylic acid in 86% yield.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Nc1nc(Nc2ccccc2)nc2c1ncn2Cc1ccccc1
Yield: 88.7 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (100 mg, 0.385 mmol) and aniline (359 mg, 3.85 mmol) in 1-butanol (10 ml) were refluxed on heating for 20 hours. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (108 mg, yield 89%).
Reaction SMILES: [Cl:1][C:2]([F:14])([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>O1CCCC1>[Cl:1][C:2]([F:14])([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([NH:31][CH2:30][CH2:29][O:28][CH3:27])=[O:12])=[CH:5][CH:4]=1
Reactant: COCCN
Reactant: O=C(O)c1ccc(C(F)(F)Cl)[nH]c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCNC(=O)c1ccc(C(F)(F)Cl)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg (2.2 mmol) of 6-[chloro(difluoro)methyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid were dissolved in 10 ml of tetrahydrofuran, 508 mg (3.1 mmol) of N,N-carbonyldiimidazole were added and the mixture was then stirred initially at room temperature for 30 min and then under reflux for min. A solution of 202 mg (2.7 mmol) of 2-methoxyethylamine in 2 ml of tetrahydrofuran was then added dropwise, and the mixture was heated under reflux for a further 2 h. The solution was evaporated to dryness, the residue was taken up in ethyl acetate and the solution was washed with 1N hydrochloric acid and water, dried and concentrated. This gave 360 mg (54% of theory) of a light-brown powder.
Reaction SMILES: [Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[C:16]1([S:22]([CH2:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:23])[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2c(Br)cc(O)cc21
Reactant: O=S(CCCCBr)c1ccccc1
Product: CC1(C)OC(=O)Nc2c(Br)cc(OCCCCS(=O)c3ccccc3)cc21

Procedure:
Prepared analogously to Example 4 from 8-bromo-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-phenylsulfinyl-butylbromide.
Reaction SMILES: Cl.C(OC([N:9]1[C@H:14]([CH2:15][NH:16][C:17]2[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=2)[CH2:13][C@H:12]2[C@@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1>[C@H:10]12[CH2:11][C@H:12]1[CH2:13][C@@H:14]([CH2:15][NH:16][C:17]1[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1)[NH:9]2
Reactant: CC(C)(C)OC(=O)N1[C@H](CNc2ncc(Br)cn2)C[C@@H]2C[C@@H]21
Agent: Cl
Solvent: C1COCCO1
Product: Brc1cnc(NC[C@@H]2C[C@@H]3C[C@@H]3N2)nc1

Procedure:
A solution of HCl in dioxane (4.0 M, 30 mL) is added to a solution of (1S,3S,5S)-3-[(5-bromo-pyrimidin-2-ylamino)-methyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (5.40 mmol) in dioxane (30 mL). After 2 h the solvents are removed in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.63 min; [M+H]+=269.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[OH:34][C:35]([CH3:50])([CH3:49])[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:37][CH2:36][C:35]([OH:34])([CH3:50])[CH3:49])=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(O)cc4)ccc(F)c32)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(OCCC(C)(C)O)cc4)ccc(F)c32)cc1
Reaction time: 8 h

Procedure:
(1S,2S)-2-{4-[(R)-7-Fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid ethyl ester (Intermediate 7, 47 mg, 0.10 mmol), toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester (Intermediate 10, 54 mg, 0.21 mmol), and cesium carbonate (107 mg, 0.21 mmol) are suspended in dry N,N-dimethylformamide (2 mL) and stirred overnight. The mixture is diluted with ethyl acetate, washed with water, dried and the solvent removed. The residue is purified by flash chromatography (gradient of ethyl acetate in cyclohexane) to give the title compound. (Yield 60 mg). LC (METHOD 6): tR=0.75 min; Mass spectrum (ES+): m/z=535 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([CH2:36][C:37]([O:39]C)=O)[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[NH3:41].C(O)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([CH2:36][C:37]([NH2:41])=[O:39])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: N
Reactant: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1NC1CCN(c2ccnc(C)c2)CC1
Solvent: CCO
Product: Cc1cc(N2CCC(NN3C(=O)CN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3CC(N)=O)CC2)ccn1

Procedure:
Methyl 4-[(6-chloro-2-naphthyl)sulfonyl]-1-[[1-(2-methyl-4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazineacetate (100 mg) obtained in Example 138 and a 13% ammonia/ethanol solution (6.0 ml) were heated in a sealed tube at 90° C. for 6 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue obtained was purified by a column chromatography on a silica gel (dichloromethane: 10% aqueous ammonia-containing methanol=15:1) and crystallized from a mixture of ethyl acetate and diethyl ether to obtain the title compound (12 mg) as colorless crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[C@@H:11]([O:23]CC1C=CC(OC)=CC=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:34])[C@@H:11]([OH:23])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6]
Reactant: CCOC(=O)OCCOC(=O)[C@H](OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)OCCOC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCCl
Yield: 19 %

Procedure:
Following the general procedure for the oxidative cleavage of (4-methoxy)benzyl ethers of Description 19, (ethoxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (36a) (0.77 g max.) dissolved in a mixture of dichloromethane (DCM) and water (10:1) (10 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.68 g, 3.0 mmol). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.2 g (19% yield over two steps) of the title compound (36b) as a colorless oil. Rf=0.57 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=0.99-1.01 (2s, 3H), 1.12-1.14 (2s, 3H), 1.32-1.37 (m, 3H), 1.59-1.62 (m, 3H), 2.31-2.38 (m, 2H), 2.89-2.94 (2d, J=6.0, 6.8 Hz, 1H), 3.31-3.35 (m, 2H), 3.69-3.72 (m, 2H), 3.97-4.02 (m, 1H), 4.06-4.08 (m, 1H), 4.10-4.22 (m, 1H), 4.21-4.28 (m, 2H), 6.83-6.89 (m, 1H) ppm. MS (ESI) m/z: 426.94 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[CH:12][C:13]=1[C:14]#[N:15].C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29].O>CN(C)C=O>[NH2:29][C:28]1[N:30]=[C:16]([C:11]2[NH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:13]([C:14]#[N:15])[CH:12]=2)[CH:17]=[CH:18][N:27]=1
Reactant: CN(C)/C=C/C(=O)c1cc(C#N)c(-c2ccc(Cl)cc2Cl)[nH]1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(-c2ccnc(N)n2)[nH]c1-c1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 22 h
Yield: 83 %

Procedure:
To a suspension of 2-(2,4-dichloro-phenyl)-5-((E)-3-dimethylamino-acryloyl)-1H-pyrrole-3-carbonitrile (6.80 g, 20.35 mmol) in 82 mL of N,N-dimethylformamide was added guanidine carbonate (9.17 g, 101.75 mmol). The mixture was heated to 110° C. for 18 hours under efficient stirring. Then, a further amount of guanidine carbonate (1.83 g; 20.35 mmol) was added to the mixture and heating to 115° C. was prolonged for additional 22 hours. The resulting mixture was diluted by dropwise addition of 325 mL of water over 30 minutes. The solid was isolated by filtration, washed with 100 mL of water, dried in the air and, finally, in a vacuum oven at 60° C. affording 5.58 g of product as a light brown powder. Yield=83%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:27][C:22]([F:28])([C:23]([F:26])([F:25])[F:24])[CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)C(F)(F)CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)F)Cc1ccc(C(F)(F)F)cc1
Yield: 60.6 %

Procedure:
Using 0.30 g of (4-(trifluoromethyl)benzyl)malononitrile, 6 ml of N,N-dimethylformamide, 0.60 g of sodium hydride (60% in oil), and 0.38 g of 4-iodo-1,1,1,2,2-pentafluorobutane, and according to the process described in the Production Example 1, there was obtained 0.30 g of 2-(3,3,4,4,4-pentafluorobutyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (8)).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[NH:10][CH2:9][C@H:8]2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Cl:24][CH2:25][C:26]([N:10]1[CH2:9][C@H:8]([CH3:14])[N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][C@H:11]1[CH3:13])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of (2R, 5S)-1-(4-fluoro-benzyl)-2,5-dimethyl-piperazine (2.5 g, 11.25 mmol) in dry dichloromethane (11 ml) at 0° C. was added triethylamine (1.57 ml, 11.2 mmol) followed by chloroacetyl chloride (0.858 ml, 11.2 mmol). The resulting reaction mixture was stirred for 30 minutes. The reaction was then filtered through a pad of celite, washed with dichloromethane and the resulting filtrate was concentrated to give a yellow oil Chromatography on silica get gave the title compound (2.84 g, 86% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]3[C:20]([NH:42][CH3:43])=[N:21][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:16]=3[CH:15]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]3[C:20]([NH:42][CH3:43])=[N:21][NH:22][C:16]=3[CH:15]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccc(F)cc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CNc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccc(F)cc3)ncc12

Procedure:
(R)-1-(1-(4-Fluorophenyl)ethyl)-3-(3-(methylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (404 mg, 0.708 mmol) and triethylsilane (0.170 mL, 1.062 mmol) were stirred in TFA (5 mL) at room temperature for 30 min. The solvent was removed in vacuo, saturated NaHCO3 was added, and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered through Celite, and concentrated in vacuo. Purification of the residue by flash chromatography (0-15% MeOH-EtOAc) gave 1-[(1R)-1-(4-fluorophenyl)ethyl]-3-[3-(methylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl]urea. MS ESI calc'd. For C16H17FN6O [M+1]+ 329. found 329. 1H NMR (500 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.86 (s, 1H), 8.54 (s, 1H), 8.05 (br s, 1H), 7.36 (dd, J=8.5, 5.5 Hz, 2H), 7.24 (s, 1H), 7.14 (t, J=9.0 Hz, 2H), 6.25 (q, J=5.0 Hz, 1H), 4.88-4.83 (m, 1H), 2.81 (d, J=5.0 Hz, 3H), 1.38 (d, J=6.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[N:10]=2)[N:7]=1.CO.[CH3:21][NH2:22]>>[CH3:21][NH:22][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[N:10]=2)[N:7]=1
Reactant: CN
Reactant: N#Cc1cccc(-c2cn3nc(Cl)ccc3n2)c1
Solvent: CO
Product: CNc1ccc2nc(-c3cccc(C#N)c3)cn2n1
Temperature: 125 °C

Procedure:
A mixture of 3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)benzonitrile (0.25 mmol) and 10 mL methylamine methanol solution was heated at 125° C. in microwave synthesizer for 30 min. After purification to provide 3-(6-(methylamino)imidazo[1,2-b]pyridazin-2-yl)benzonitrile.