Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9].[OH-].[K+].Cl>CO.O>[OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cccc(OC)c1C#CCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(C(=O)O)c1C#CCCO
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Methyl 2-(4-hydroxybut-1-yn-1-yl)-3-(methyloxy)benzoate (0.056 g, 0.24 mmol) was dissolved in methanol (2 ml), and a solution of potassium hydroxide (0.027 g, 0.48 mmol) in water (0.5 ml) was added. The reaction mixture was stirred at 60° C. for 1 h, cooled to room temperature, and 1.5M hydrochloric acid was added to pH 4. The aqueous mixture was extracted with ethyl acetate, and the organic layer was washed with brine then dried over sodium sulfate. The mixture was then filtered and concentrated to give 2-(4-hydroxybut-1-yn-1-yl)-3-(methyloxy)benzoic acid (0.052 g, 99% yield). MS (EI) for C12H12O4: 219 (M−H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([I:15])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: II
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
6-chloropyridin-3-ol (5.0 g, 38.6 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2CO3 (8.2 g, 77.4 mmol) was added followed by iodine (9.8 g, 38.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M Na2S2O3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the product of 6-chloro-2-iodopyridin-3-ol (7.0 g, yield: 70.9%). 1H-NMR (CDCl3, 400 MHz) δ 7.17 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H). MS (M+H)+: 256/258.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][CH:4]=[O:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O.CC(C)=CCO.[N+]([O-])(O)=O>O>[CH3:6][C:2]([CH3:1])=[CH:3][CH2:4][O:5][CH2:10][CH:9]=[C:8]([CH3:12])[CH3:7]
Reactant: C=C(C)CC=O
Reactant: CC(C)=CC=O
Agent: CC(C)=CCO
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(C)=CCOCC=C(C)C
Reaction time: 16 h

Procedure:
700 g of a mixture containing 90.2% by weight of 3-methyl-but-3-en-1-al and 5.3% by weight of 3-methyl-but-2-en-1-al, 2,780 g of 3-methyl-but-2-en-1-ol and 6 g of 51% strength aqueous nitric acid are boiled under 100 mm Hg in a 4 liter flask surmounted by a packed column (filled with 5 mm Raschig rings). The bottom temperature assumes a value of from 86 to 93° C. The column has a diameter of 45 mm and has 30 theoretical plates. The water formed in the reaction is taken off at the top of the column and the organic materials which separates from the water is returned continuously into the column. With a reflux of 600 g/hour, quantitative conversion of the aldehyde is achieved in 16 hours. After distilling off the excess alcohol, a mixture consisting of 74.5% by weight of 1,1-bis-(3-methyl-but-2-en-1-yloxy)-3-methyl-but- 3-ene and 10.6% by weight of 1,1-bis-(3-methyl-but-2-en-1-yloxy)-3-methyl-but-2-ene, together with the by-products 3-methyl-butadien-1-yl-3-methyl-but-2-en-1-yl-ether (5.9% by weight) and di-(3-methyl-but-2-en-1-yl)-ether is obtained. The selectivity of the acetals obtained is 86.5% based on the sum of the aldehydes employed and 72.5% based on 3-methyl-but-2-en-1-ol.
Reaction SMILES: [CH2:1]([C:3]1(O)[CH2:11][CH:10]2[CH2:12][CH:4]1[CH:5]1[CH:9]2[CH2:8][CH2:7][CH2:6]1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1](=[C:3]1[CH2:11][CH:10]2[CH2:12][CH:4]1[CH:5]1[CH:9]2[CH2:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: CCC1(O)CC2CC1C1CCCC21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC=C1CC2CC1C1CCCC21
Yield: 75.3 %

Procedure:
In 600 ml of benzene was dissolved 155.0 g of 8-ethyltricyclo[5.2.1.02,6 ]decan-8-ol in endo-form. To the solution was added 8.2 g of p-toluenesulfonic acid monohydrate. This reaction mixture was heated, agitated under reflux for 6 hours while removing water, and subjected to conventional post-treatment. The resulting oily substance was purified by silica gel column chromatography, obtaining 105.0 g of 8-ethylidenetricyclo[5.2.1.02,6]decane. The yield was 75.3%.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:24]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH2:41])[CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:24]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH:41][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:3][CH2:2]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: NCCC1CCN(C(=O)OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCC4CCN(C(=O)OCc5ccccc5)C4)ncc3Cl)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
A mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.10 g, 0.27 mmol), racemic 3-(2-aminoethyl)-pyrrolidine-1-carboxylic acid benzyl ester (0.14 g, 0.55 mmol) and triethylamine (0.11 mL, 0.81 mmol) in 1,4-dioxane (1.5 mL) in a sealed reaction vessel is stirred at 90° C. overnight. The reaction is cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer is separated, dried over Na2SO4, filtered and concentrated. The crude solid is washed with ethyl acetate, dried under vacuum to provide 3-{2-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-pyrrolidine-1-carboxylic acid benzyl ester as a white solid (90 mg, 56% yield). A stirred solution of this intermediate (16 mg, 0.028 mmol) in TFA (0.5 mL) and water (0.1 mL) is heated in a sealed tube at 100° C. for 20 minutes. At room temperature the mixture is concentrated and the residue is dissolved in methanol, passed through a SCX column, washed with methanol and 2 M NH3/methanol to give the crude product. It is further passed through a short pad of silica gel to afford the title compound as a solid (11 mg, 90% yield). ES+(m/z) 442 (35Cl) and 444 (37Cl) [M+H].
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:9][N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:4][CH:3]=1.[CH2:26]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][N:34]=[C:33]2I)[CH3:27].C([Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.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:22]([NH:21][C:19]([C:8]1[C:6]2=[N:7][C:2]([C:33]3[C:32]4[C:36](=[C:28]([CH2:26][CH3:27])[CH:29]=[CH:30][CH:31]=4)[NH:35][N:34]=3)=[CH:3][N:4]=[C:5]2[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCc1cccc2c(I)n[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCc1cccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)n[nH]c12
Temperature: 115 °C
Yield: 12.2 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (320 mg, 749 μmol) and 7-ethyl-3-iodo-1H-indazole (244 mg, 898 μmol) in DMF (2.5 mL) was added 1,1,1,2,2,2-hexabutyldistannane (651 mg, 412 μL, 1.12 mmol) under N2. After 10 min tetrakis(triphenylphosphine)palladium (0) (43.3 mg, 37.4 mmol) was added and the reaction mixture heated to 115° C. After 16 h the reaction was cooled and concentrated. The residue was diluted with 10% methanol/dichloromethane and filtered through a pad of celite. Purification of the filtrate by chromatography (silica, 5-45% ethyl acetate/hexane) gave N-tert-butyl-2-(7-ethyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (45 mg, 91.3 μmol, 12%) as an off-white solid. MS (M+H)+=493.4; 1H NMR (CDCl3) δ: 10.57 (s, 1H), 9.34 (s, 1H), 8.49 (d, J=7.5, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 7.35 (d, J=7.1 Hz, 1H), 7.29 (t, J=7.1 Hz, 1H), 5.77 (s, 2H), 3.62 (t, J=8.3, 2H), 3.07 (q, J=7.5 Hz, 2H), 1.68 (s, 9H), 1.50 (t, J=7.5 Hz, 3H), 0.98 (t, J=8.3, 2H), 0.0 (s, 9H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH:2]=C.[BH4-].[Na+].C(Cl)Cl.C[OH:36]>C(=O)=O.CC(C)=O>[OH:36][CH2:2][CH2:1][O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CO
Reactant: C=CCOCc1cccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)c1
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(-c2cccc(COCCO)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
3-(3′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (260 mg, 0.664 mmol) was dissolved in DCM/methanol (4:1, 7.5 mL) and was cooled to −78° C. in dry ice-acetone bath. O3 was bubbled through the solution for 15 min. Thin layer chromatography (TLC) confirmed the completion of the reaction at this stage. The DCM was evaporated in vacuo; ethanol (5 mL) was added and the solution was cooled in ice-water bath to 0° C. NaBH4 (175 mg, 7 eq.) was added and the reaction was stirred at the temperature of 0˜5° C. for one hour then at room temperature for 1.5 hour. The reaction mixture was quenched with saturated NaHCO3 aqueous solution. The aqueous phase was extracted with DCM (3×8 mL), the combined organic phases were washed with brine (5 mL), dried over sodium sulfate and concentrated. The crude residue was purified on silica gel eluting with 20˜50% ethyl acetate in hexane to give the product (134 mg, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.59 (d, 3H), 7.52 (d, 1H), 7.41 (t, 1H), 7.32 (d, 3H), 4.85 (s, 2H), 4.45 (s, 2H), 3.77 (br, 2H), 3.62 (t, 2H), 3.12 (s, 2H), 2.48 (br, 1H), 1.72 (m, 4H), 1.5 (m, 6H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:21]([O:28][C:29](=[O:38])[CH:30]([NH2:37])[CH2:31][S:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:38])[CH:30]([NH:37][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:31][S:32][C:33]([CH3:35])([CH3:34])[CH3:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)SCC(N)C(=O)OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)SCC(NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Yield: 65 %

Procedure:
With General procedure D, starting from 21 (4.2 g, 30.2 mmol) and 15 (9.43 g, 21.45 mmol), 5.18 g (65%) of the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, 2H), 7.50 (m, 8H), 6.98 (br d, 1H), 5.27 (m, 2H), 5.12 (m, 1H), 3.15 (m, 2H), 1.27 (s, 9H). MS m/z 372 (M+1). HPLC: 96.80% (ACQ_PA95_C_BLS; Column: BEH_C18—2−1×50 mm—1-7 μm).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1)#[N:24].N12CCCN=C1CCCCC2>C(#N)C>[C:23]([CH2:25][C:26]1([N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=34)[CH:3]=[N:2]2)[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1)#[N:24]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 50 °C
Yield: 99.5 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (0.527 g, 1.68 mmol), tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (0.358 g, 1.84 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (135 μL, 0.903 mmol) in acetonitrile (4.0 mL) was heated at 50° C. for 1 hour. After cooling, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, neutralized with 0.5 N HCl aqueous solutions, washed brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (0.85 g, quantitative) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=509.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH:16]2[O:17][CH2:18][CH:19]([OH:20])[CH:15]2[O:14][CH2:13]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:11]([CH3:10])[CH:12]2[CH:16]3[O:17][CH2:18][CH:19]([OH:20])[CH:15]3[O:14][CH2:13]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC1COC2C(O)COC12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(c1nc(Cl)ncc1Cl)C1COC2C(O)COC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (484.9 mg, 2.64 mmol) and 6-(methylamino)hexahydrofuro[3,2-b]furan-3-ol (530.2 mg, 3.33 mmol) in EtOH (30 mL) was added Et3N (566.0 mg, 5.59 mmol). After addition, the reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in a mixture of EtOAc and water (1/1 (v/v), 100 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as a pale yellow solid (760.2 mg, 94.0%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(C1C=CC(C)=C(O)C=1C(C)(C)C)(C)(C)C.[CH2:23]([OH:59])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH3:58].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:59][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH3:58])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCCCCCCCCCO
Agent: Cc1ccc(C(C)(C)C)c(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.87 g (0.018 mol) of methacrylyl chloride and a small amount of di-t-butylhydroxytoluene in methylene chloride are added to a solution of 8 g (0.0148 mol) of 11,14,17,20,23,26,29,32,35-Nonaoxahexatriacontan-1-ol and 1.82 g (0.018 mol) of triethylamine in 40 ml of methylene chloride at a temperature of -20° C. The mixture is stirred at room temperature for 12 hours, without cooling. The solvent is removed at room temperature and the crude product is worked up by flash chromatography over silica gel 60 (0.040-0.063 mm) using acetone/ether 50:50. The mobile phase is distilled off at room temperature and the product is obtained as a colorless liquid. 1HNMR: 1.2-1.8 ppm (m, 16H, (--CH2)8 --), 1.9 ppm (s, 1H, HO--), 3.4 ppm (s, 3H, --OCH3), 3.7 ppm (m, 34H, --(OCH2CH2)8 --O--),--(CH2)8 --CH2 --O--), 4.2 ppm (m, 2H, --COO--CH2 --CH 2 --), 5.5 ppm (s, 1H, H--CH=C(CH3)--COO--), 6.1 ppm (s, 1H, H--CH=C(CH3)--COO--). IR (film): 1700 cm-1 (C=O), 1620 cm-1 (C=C), 1110 cm-l (C--O).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]([NH2:23])=[S:22])=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(N(CC)CC)C.Br[CH2:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1)=O>CCO>[Br:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:37]=[C:38]([CH:40]3[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]3)[N:23]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Reactant: COc1cccc(Sc2cnc(NC(N)=S)c(Oc3ccc(F)cc3Br)c2)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(=O)OC(C)(C)C)CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 70 °C
Yield: 82 %

Procedure:
A 50 mL flask was charged with 1-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)thiourea (1.5 g, 3.12 mmol), triethylamine (0.740 mL, 5.31 mmol), tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (1.15 g, 3.75 mmol), and EtOH (25 mL). The reaction was heated to 70° C. for 2 hours. The reaction was partitioned between EtOAc and water. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica (10% EtOAc in hexanes) to afford tert-butyl 4-(2-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (1.76 g, 82.0% yield).
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=[O:14].[NH2:16][C:17]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH:16][C:17]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: O=C(Cl)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1ccco1
Reaction time: 2 h

Procedure:
0.082 mL of triethylamine, 44 mg of 2-furoyl chloride and 2.0 mL of methylene chloride were added to 1.0 mL of methylene chloride solution containing 50 mg of tert-butyl 2-amino-4-phenethylbenzoate at room temperature and stirred at the same temperature for 2 hours. 380 mg of aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(furan-2-carboxamido)-4-phenethylbenzoate.
Reaction SMILES: C(OC(C)(C)C)(=O)[NH:2][NH2:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:43][C:44]1[CH:45]=[C:46]([C:50]([OH:52])=O)[O:47][C:48]=1[CH3:49]>C(Cl)Cl>[CH3:43][C:44]1[CH:45]=[C:46]([C:50]([NH:2][NH2:3])=[O:52])[O:47][C:48]=1[CH3:49]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cc(C(=O)O)oc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)NN)oc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl carbazate (350 mg, 2.65 mmol), HBTU (1.01 g, 2.66 mmol), and N,N-diisopropylethylamine (923 μL, 5.30 mmol) were added to a methylene chloride (5 mL) solution of commercially available 4,5-dimethylfurancarboxylic acid (248 mg, 1.77 mmol), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated, to the residue, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was subjected to extraction with methylene chloride and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was dissolved in methylene chloride (6 mL). To the solution, trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated to obtain 4,5-dimethylfuran-2-carbohydrazide.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]2[CH:17]=[N:16][N:15]([CH2:18][CH3:19])[C:9]2=[N:10][C:11]=1[O:12][CH2:13][CH3:14])=[O:5])C.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:4]([C:6]1[N:7]=[C:8]2[CH:17]=[N:16][N:15]([CH2:18][CH3:19])[C:9]2=[N:10][C:11]=1[O:12][CH2:13][CH3:14])=[O:5])[CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)c1nc2cnn(CC)c2nc1OCC
Reactant: CCCCN
Product: CCCCNC(=O)c1nc2cnn(CC)c2nc1OCC

Procedure:
18 g. of 6-ethoxy-1-ethyl- 1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid ethyl ester (0.068 mol.), prepared according to Example 1c, are heated with 180 ml. of butylamine in an autoclave at 70° for 5 hours. After vacuum removal of excess butylamine, the residual N-butyl- 6-ethoxy-1-ethyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxamide is recrystallized from acetonitrile, m.p. 115°-117°. The mother liquor contains N-butyl-6-butyl-amino-1-ethyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxamide (m.p. 128°-129°) which is identical with the compound of Example 4.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=[N:16]1.[Cl:29][C:30]1[C:49](I)=[CH:48][C:33]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=2)=[O:35])=[CH:32][N:31]=1>C1(C)C=CC=CC=1.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>[Cl:29][C:30]1[C:49]([C:19]2[N:15]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][O:9]3)[N:16]=[CH:17][CH:18]=2)=[CH:48][C:33]([C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:41][CH:42]=2)=[O:35])=[CH:32][N:31]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
K3PO4 (5.70 g, 26.8 mmol), followed by 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.73 g, 13.42 mmol) and Pd(PPh3)4 (0.517 g, 0.447 mmol) were added to a solution of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.2, 4.0 g, 8.95 mmol) in toluene (45 mL) under an argon atmosphere. The RM was stirred at 80° C. for 5 h, filtered through Hyflo®, washed with EtOAc (100 mL) and the solvent was evaporated off under reduced pressure to give a crude product was purified by flash chromatography (Silica gel column, 80 g, n-hexane/EtOAc from 9:1 to 1:1) and triturated under n-hexane, filtered and dried to afford the title compound as a beige solid. HPLC (Condition 7) tR=7.569 min, UPLC-MS (Condition 3) tR=1.19 min, m/z=466.9 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.67 (m, 3H) 1.81-2.01 (m, 2H) 2.25-2.39 (m, 1H) 3.34-3.46 (m, 1H) 3.74-3.84 (m, 1H) 5.15 (d, J=8.21 Hz, 1H) 6.62 (s, 1H) 7.40 (d, J=8.21 Hz, 2H) 7.69 (s, 1H) 7.88 (d, J=8.99 Hz, 2H) 8.50 (s, 1H) 9.06 (s, 1H) 10.70 (s, 1H).