Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6](=[O:31])[C:7]([CH3:30])([CH3:29])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH3:28])[CH:19]=2)=[CH:12][CH:11]=1)=[O:9])[CH3:4]>CO>[CH2:3]([O:5][C:6](=[O:31])[C:7]([CH3:30])([CH3:29])[CH:8]([OH:9])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH3:28])[CH:19]=2)=[CH:12][CH:11]=1)[CH3:4]
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(C)(C)C(O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reaction time: 2 h
Yield: 49.9 %

Procedure:
Sodium borohydride (0.021 g, 0.56 mmol) was added to a solution of 2,2-dimethyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-3-oxo-propionic acid ethyl ester (0.22 g, 0.56 mmol) in methanol (10 mL) under nitrogen at room temperature. The reaction was stirred for 2 h then was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by FCC on silica gel eluting hexane:ethyl acetate (50:50, v:v) to give 3-hydroxy-2,2-dimethyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionic acid ethyl ester (0.11 g, 50%) as an oil. MS found: (M+H)+=394.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:10][C:9]([CH2:33][C:34]#[N:35])([N:11]3[CH:15]=[C:14]([C:16]4[C:17]5[CH:24]=[CH:23][N:22](COCC[Si](C)(C)C)[C:18]=5[N:19]=[CH:20][N:21]=4)[CH:13]=[N:12]3)[CH2:8]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[N:45]([CH:48]([CH3:50])[CH3:49])=[C:46]=[O:47].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:34]([CH2:33][C:9]1([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH:13]=[N:12]2)[CH2:10][N:7]([CH:4]2[CH2:3][CH2:2][N:1]([C:46]([NH:45][CH:48]([CH3:50])[CH3:49])=[O:47])[CH2:6][CH2:5]2)[CH2:8]1)#[N:35]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: CC(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)N1CCC(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)CC1
Reaction time: 2 h

Procedure:
To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (0.075 g, 0.15 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) in methylene chloride (2 mL) was added N,N-diisopropylethylamine (0.026 mL, 0.15 mmol) followed by 2-isocyanatopropane (20 μL, 0.2 mmol, Aldrich). The reaction was continued for 2 hours. The crude product was deprotected by the addition of 1 mL TFA to the solution, which was stirred for 1 hour and evaporated. The deprotection was completed by stirring with ethylenediamine (0.2 mL) in methanol for 30 minutes. The product was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Fractions containing desired product were frozen and lyophilized. Yield: 0.025 g (37%); LC-MS: 448.2 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 10.21 (br s, 1H), 8.85 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 7.41 (dd, 1H), 6.79 (dd, 1H), 4.22 (d, 1H), 4.04-3.87 (m, 1H), 3.81-3.69 (m, 4H), 3.61 (d, 2H), 3.40 (s, 2H), 3.00-2.86 (dq, 2H), 2.44-2.31 (m, 1H), 1.76-1.64 (m, 2H), 1.40-1.22 (m, 2H), 1.15 (d, 6H).
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][C:6]([CH3:10])=[N:5]1)[CH:2]=[CH2:3].[OH-].[Ca+2].[OH-].[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(O)(C)C>[CH2:1]([N:4]1[C:8]([OH:9])=[C:7]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:15]=2[Cl:14])[C:6]([CH3:10])=[N:5]1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: C=CCN1N=C(C)CC1=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(C)O
Product: C=CCn1nc(C)c(C(=O)c2ccc(Cl)cc2Cl)c1O
Reaction time: 1.5 h
Yield: 40.7 %

Procedure:
A suspension of 1.4 g. of 1-allyl-3-methyl-2-pyrazolin-5-one and 0.74 g. of calcium hydroxide in 20 ml. of isopropanol is heated under reflux with stirring for 1.5 hours. After cooling, to the resulting mixture is added dropwise 2.3 g. of 2,4-dichlorobenzoyl chloride. After completion of the dropwise addition, the resulting mixture is heated under reflux for 5.5 hours. After completion of the reaction, the solvent is distilled off from the reaction mixture and to the residue is added 3 ml. of 2N hydrochloric acid to adjust pH to 3.0. Then, the mixture is extracted with chloroform and the extract solvent is distilled off from the extract. The residue is dissolved in a small amount of benzene and the solution is washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off. The resulting residue is recrystallized from isopropyl ether containing a small amount of methylene chloride to give 1.18 g. of the desired product as white crystals melting at 161°-163° C. Yield 40.7%.
Reaction SMILES: [C-:1]#[N:2].[Na+].CC1C=CC(S(O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([NH2:33])=[O:32])[CH:26]=2)(=O)=O)=CC=1>O.CCO>[C:1]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]([C:31]([NH2:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCCOc2cccc(C(N)=O)c2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCCCCCCCCCOc1cccc(C(N)=O)c1
Temperature: 75 °C
Reaction time: 48 h
Yield: 21 %

Procedure:
Sodium cyanide (60 mg, 1.22 mmol, 1.3 equiv.) was added to a solution of 9-[3-(aminocarbonyl)phenoxy]nonyl 4-methylbenzenesulfonate (407 mg, 0.94 mmol, 1 equiv.) in water (10 ml) and 95% EtOH (8 ml), and the reaction mixture was stirred at 75° C. for 2 days. After cooling at r.t., the mixture was diluted with water (10 ml) and extracted with CH2Cl2 (3×10 ml). The combined organic extracts were dried (MgSO4) and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography on silica eluting with EtOAc/hexane (50%), to give the desired compound as white solid (57 mg, 21%), mp 96-97° C. HPLC-MS (method 1): m/z 289 [M+H]+, Rt=4.16 min.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([CH3:11])[C:8]([OH:10])=O)=[CH:4][CH:3]=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:6][CH:7]([CH3:11])[C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: CC(Cc1ccc(F)cc1)C(=O)O
Solvent: O
Product: CC1Cc2ccc(F)cc2C1=O
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To 932 g polyphosphoric acid at 70° C. (steam bath) is added p-fluoro-α-methylhydrocinnamic acid (93.2 g, 0.5 mol) slowly with stirring. The temperature is gradually raised to 95° C., and the mixture is kept at this temperature for 1 hour. The mixture is allowed to cool and is added to 2 l. of water. The aqueous suspension is extracted with ether. The extract is washed twice with saturated sodium chloride solution, 5% Na2CO3 solution, and water, and is dried, and is concentrated on 200 g silica-gel; the slurry is added to a five pound silica-gel column packed with 5% ether-petroleum ether. The column is eluted with 5-10% ether-petroleum ether, to give 6-fluoro-2-methylindanone. Elution is followed by TLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([CH:16]3[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[O:19][C:18]([CH3:26])([CH3:25])[C:17]3=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)(Cl)Cl>[CH3:39][O:38][C:36](=[O:37])[O:27][C:17]1[C:18]([CH3:26])([CH3:25])[O:19][C:20]([CH3:24])([CH3:23])[C:21](=[O:22])[C:16]=1[C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:15]
Reactant: COC(=O)Cl
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1=C(OC(=O)OC)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.141 g, 0.366 mmol) in dry chloroform (3 ml) is added triethylamine (0.152 ml, 1.09 mmol), and methyl chloroformate (0.084 ml, 1.09 mmol) and the mixture is stirred at room temperature for 2 hours. Solvents are removed, and the residue is purified directly by column chromatography (hexane/ethyl acetate 5:1 ratio) to afford carbonic acid 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethyl-5-oxo-5,6-dihydro-2H-pyran-3-yl ester methyl ester (0.150 g) as a white solid.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]([F:32])([F:31])[CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>CO>[OH:18][CH2:19][CH2:20][C:21]([F:32])([F:31])[CH2:22][P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29]
Reactant: CCOP(=O)(CC(F)(F)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Agent: Cl
Solvent: CO
Product: CCOP(=O)(CC(F)(F)CCO)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of diethyl 4-(tert-butyldiphenylsilyloxy)-2,2-difluorobutylphosphonate (1 mmole) in methanol (1 mL) was treated with hydrochloric acid (4 N, 4 mmole) at 0° C., and the resulting reaction was stirred at room temperature for 2 h. Evaporation and chromatography gave diethyl 4-hydroxy-2,2-difluorobutylphosphonate as a clear oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+].C([O-])([O-])=O.[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>C1(C)C=CC=CC=1.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OCc1ccccc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1
Reaction time: 0.33 h
Yield: 69.1 %

Procedure:
To a mixture of 2-chloro-5-nitropyridine (3.28 g, 20.0 mmol), benzyl alcohol (3.09 mL, 30.0 mmol), KOH (4.49 g, 80.0 mmol), and K2CO3 (2.76 g, 20.0 mmol) in toluene (100 mL) at rt was added tris[2-(2-methoxyethoxy)ethyl]amine (0.646 g, 2.00 mmol). The mixture was stirred for 20 min, poured into water, and the layers were separated. The aqueous layer was adjusted to pH 7 by addition of solid KHSO4, and extracted with EtOAc (×3). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOH/H2O, affording 3.18 g of the title compound as tan needles: 1H NMR (400 MHz, CDCl3) δ 9.10 (dd, J=2.9, 0.6 Hz, 1H), 8.37 (dd, J=9.1, 2.9 Hz, 1H), 7.48-7.44 (m, 2H), 7.42-7.33 (m, 3H), 6.88 (dd, J=9.1, 0.6 Hz, 1H), 5.49 (s, 2H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[C:2]=[S:3].[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1cccc(N=C=S)c1
Reactant: Nc1ccc(I)cc1F
Product: NS(=O)(=O)c1cccc(NC(=S)Nc2ccc(I)cc2F)c1

Procedure:
The subject compound was prepared utilizing the procedure described above from 3-isothiocyanatobenzenesulfonamide and 2-fluoro-4-iodoaniline. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.67 (s, 1H), 7.96 (m, 1H), 7.70 (m, 2H), 7.58-7.49 (m, 3H), 7.38 (bs, 3H); (M+H)+ (452).
Reaction SMILES: [ClH:1].C(OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N)C.[CH3:18][O:19][P:20](CC(CC(C)C)C(O)=O)([CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])=[O:21].OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[ClH:1].[CH3:18][O:19][PH:20]([CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])=[O:21]
Reactant: COP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)c2ccccc2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)[C@H](C)NC(=O)[C@@H](N)CC(C)C
Solvent: CN(C)C=O
Product: CO[PH](=O)CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.06 g of L-leucyl-L-alanine ethyl ester hydrochloride and 1.46 g of 2(RS)-[[(RS)-(methoxy)(phthalimidomethyl)-phosphinyl]methyl]-4-methylvaleric acid, prepared as described in Example 1(A)(iii), were dissolved in 12 ml of dimethylformamide. The solution was cooled to 0° C. Thereafter, 1.08 g of hydroxybenzotriazole and 0.46 g of N-ethylmorpholine were added and, after all of the solids had dissolved, 0.88 g of N,N'-dicyclohexylcarbodiimide was added. The mixture was stirred at room temperature for 18 hours. The solvent was then removed by evaporation. The residue was triturated with 50 ml of ethyl acetate and the mixture was filtered in order to remove dicyclohexylurea. The filtrate was washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time, dried over anhydrous sodium sulfate and evaporated to give a yellow gum. This gum was purified by flash chromatography using ethyl acetate for the elution. There were obtained 1.06 g of [(R or S)-2-[[(S)-1-[[(S)-1-(ethoxycarbonyl)ethyl]carbamoyl]-3-methyl-butyl]carbamoyl]-4-methylpentyl](phthalimidomethyl)phosphinic acid methyl ester hydrochloride in the form of a white foam.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[C:14]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10]>CO.O>[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[C:14]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 73.3 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 1.0 ml) was added to a mixture of methyl 2,4-bis-(methoxymethyloxy)-5-isopropylbenzoate (560 mg, 1.88 mmol) in methanol (12 ml) and water (4 ml) and the mixture was stirred and held at reflux for 3 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue diluted with water (20 ml) and acidified by the addition of 2M hydrochloric acid (10 ml). The organic material was extracted with dichloromethane (2×20 ml) and the combined organic extracts were evaporated in vacuo. The residue was triturated with a mixture of petroleum ether and diethyl ether to afford 2,4-bis-(methoxymethyloxy)-5-isopropylbenzoic acid (392 mg, 73%) as a colourless solid. 1H NMR (DMSO-d6) 12.38 (1H, br s), 7.59 (1H, s), 6.84 (1H, s), 5.31 (2H, s), 5.20 (2H, s), 3.41 (6H, s), 3.21 (1H, m), 1.18 (6H, d). MS: [M+Na]+ 307.
Reaction SMILES: [OH:1][C@@:2]1([CH3:23])[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[F:24][C:25]([F:37])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH2:35])=[CH:32][N:31]=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:37][C:25]([F:24])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH:35][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@@:2]([OH:1])([CH3:23])[C:3]([CH3:22])([CH3:21])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:32][N:31]=[CH:30][N:29]=1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@]1(C)O
Reactant: CC(F)(F)COc1ncncc1CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@@H]2CC[C@](C)(O)C(C)(C)C2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 4-(((1R,4S)-4-hydroxy-3,3,4-trimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, crude) in THF (2.8 mL) was added (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (50 mg, 0.246 mmol) and DIEA (100 mg, 0.738 mmol). The resulting mixture was stirred at 100° C. in a microwave reactor for 2 h. The solvent was evaporated and the residue was purified by standard methods to afford the title compound (38.7 mg, 0.084 mmol, 34% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.90 (s, 1H), 8.57-8.54 (s, 1H), 8.34 (s, 1H), 4.92 (t, J=12.0 Hz, 1H), 4.81-4.78 (m, 2H), 4.34-4.28 (m, 1H), 2.04-1.95 (m, 3H), 1.92-1.68 (m, 6H), 1.47-1.45 (m, 3H), 1.09-1.01 (m, 6H). MS (ESI) m/z 462.2 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:28]=[C:29]([NH:33][C:34](=O)[C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH:30]=[CH:31][CH:32]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:28]=[C:29]([NH:33][C:34](=[S:51])[C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH:30]=[CH:31][CH:32]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: S=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of N-(3-{3-[2-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-pyrimidin-4-yl]-pyrazolo[1,5-a]pyridin-2-yl}-phenyl)-benzamide (43 mg, 0.08 mmol) and excess of Lawesson's Reagent in 1,4-dioxane (1 mL) was heated at 100° C. in a sealed tube. When LC/MS showed the starting material to be consumed, the mixture was cooled to ambient temperature and diluted with DCM. The organic phase was washed with water, dried over MgSO4 and concentrated. The crude material was purified through silica gel to give the title compound as a yellow solid. 1H NMR (400 MHz, d6-DMSO): δ 11.85 (s, 1H), 9.34 (s, 1H), 8.82 (d, J=6.8 Hz, 1H), 8.49 (d, J=8.4 Hz, 1H), 8.20 (d, J=5.6 Hz, 1H), 8.14 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.80 (d, J=7.2 Hz, 1H), 7.57-7.42 (m, 6H), 7.35 (m, 1H), 7.13-7.10 (m, 2H), 6.73 (d, J=8.8 Hz, 1H), 6.49 (d, J=5.2 Hz, 1H), 4.19 (m, 4H). MS (ESI) m/z=557 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)[C:2]#[CH:3]>FC(F)(F)C(O)=O.O>[CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[C:2]#[CH:3]
Reactant: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
tert-Butyl 4-propargylpiperazine-1-carboxylate of step 2(ii) above (570 mg, 2.545 mmol) was dissolved in trifluoroacetic acid (10 ml) and water (2.5 ml). The mixture was then stirred at room temperature overnight. The solution was evaporated to dryness in vacuum. The residue was dissolved in water (10 ml) and then basified with Na2CO3 (pH 11), and extracted with Et2OAc (3×50 ml). The organic layer was washed with brine (2×50 ml) and dried over Na2SO4 overnight. Evaporation in vacuum gave N-propargylpiperazine (D7) as white solid. (crude, 193 mg, 62% yield). H1 NMR (250 MHz, CDCl3) 1.64 (s, 1NH), 2.26 (m, 1H), 2,55 (dd, J=4.73, 4.50 Hz, 4H), 2.93 (dd, J=4.96, 4.84 Hz, 4H), 3.29 (d, J=2.44 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22]([C:24]#[C:25][CH2:26][O:27][CH3:28])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].O1CCCC1.N1C2C(=CC=CC=2)C=CC=1>C(#N)C.O.FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:23]=[C:22](/[CH:24]=[CH:25]\[CH2:26][O:27][CH3:28])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: COCC#Cc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Solvent: CC#N
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: COC/C=C\c1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To a mixture of 2-amino-6 (3methoxy-1-propynyl)-N-(5-phenoxy-thiophen-2-yl methyl)-nicotinamide described in Example A-91 (11 mg, 0.028 mmol) and tetrahydrofuran (1 mL) were added quinoline (5.4 mg, 0.042 mmol) and Linear catalyst (5.0 mg), and the mixture was stirred under hydrogen atmosphere at room temperature for 15 minutes. The interior of the reaction system was exchanged with nitrogen, then, filtration was carried out through Celite pad, and the solvent was evaporated in vacuo. The residue was filtered by NH silica gel, then, purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound (4.4 mg, 0.0086 mmol, 31%) was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[Br:11][C:12]1[CH:13]=[C:14]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH:15]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Br:11][C:12]1[CH:13]=[C:14]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH:15]=[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][N:9]=[CH:10][C:3]=23)[CH:17]=1
Reactant: Ic1ccnc2[nH]ncc12
Reactant: CC(C)(C#N)c1cc(Br)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C#N)c1cc(Br)cc(-c2ccnc3[nH]ncc23)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
A suspension of 4-iodo-1H-pyrazolo[3,4-b]pyridine (116 mg, 0.47 mmol), 2-(3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropanenitrile (137 mg, 0.39 mmol), 2 M aqueous solution of sodium carbonate (0.79 ml, 1.58 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mol %, 23 mg, 0.02 mmol), in ethylene glycol dimethyl ether (4 ml) was heated under microwave irradiation at 150° C. for 30 minutes. The mixture was cooled down to room temperature, filtered through a path of celite and evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (102.5 mg, 77% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([S:15]([N:18]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)(=[O:17])=[O:16])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:14]=[C:13]([S:15]([N:18]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)(=[O:16])=[O:17])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)OCC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)O)c(C)c1
Yield: 107.7 %

Procedure:
To a solution of ethyl [2-methyl-4-({pentyl[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}sulfonyl)phenoxy]acetate (76 mg, 0.13 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature was added 2M NaOH aq. (1 mL, 2 mmol). The resultant mixture was stirred for 1 h. The solvents were removed in vacuo and the residue was partitioned between CH2Cl2 (2×15 mL) and 2M HCl (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo affording the title compound as a white solid (75 mg).