Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]([C:18](OC)=[O:19])[CH:11]=[C:12]([CH:17]=2)[C:13](OC)=[O:14])[C:4]([CH3:7])=[CH:5][CH:6]=1.CC(C[Al]CC(C)C)C>C1COCC1>[CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:12]([CH2:13][OH:14])[CH:11]=[C:10]([CH2:18][OH:19])[CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(-n2c(C)ccc2C)c1
Agent: CC(C)C[Al]CC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(CO)cc(CO)c1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a solution of 9 (2.87 g, 10 mmol) in THF (60 mL) at −78° C. was added Dibal-H (1 M solution in toluene, 60 mL, 60 mmol) drop wise. The reaction mixture was slowly warmed to room temperature over a period of 6 h, and then quenched by sodium potassium tartrate (1 M, 40 mL). The THF was removed by rotary evaporation, and the resulting aqueous solution was extracted by ether (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (EtOAc/hexanes, 2:1-4:1) to yield 10 (2.24 g, 97%) as a white solid (Caution: the product is not stable as solution forms, while stable in solid form for weeks at room temperature): 1H NMR (500 MHz, CDCl3) δ 2.01 (s, 6H), 2.45 (s, 2H), 4.69-4.70 (d, J=5.5 Hz, 4H), 5.89 (s, 2H), 7.10 (s, 2H), 7.39 (s, 1H); 13C NMR (125 MHz, CDCl3) δ13.1, 64.5, 105.8, 124.3, 125.6, 128.7, 139.3, 142.4; LC-MS (M+H+) calcd for C14H18NO2 232, found 232.
Reaction SMILES: [Se](=O)=O.O.[CH2:5]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:23]/[C:24](/[C:29]#[N:30])=[C:25](\[NH2:28])/[C:26]#[N:27]>O1CCOCC1.C(O)(=O)C>[CH2:5]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:23]=[C:24]([C:29]#[N:30])[C:25]([C:26]#[N:27])=[N:28][CH:21]=2)=[CH:16][CH:15]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CCCCCCCCOc1ccc(C(C)=O)cc1
Agent: O=[Se]=O
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCCCCCCCOc1ccc(-c2cnc(C#N)c(C#N)n2)cc1
Reaction time: 2 h
Yield: 81.3 %

Procedure:
Selenium dioxide in an amount of 11.4 g (0.1 mol) was mixed with 100 ml of dioxide and 2 ml of water. The mixture was stirred for 2 hours at 70°-75° C., and a solution of 24.8 g (0.1 mol) of p-octyloxyacetophenone in 60 ml of dioxane was added thereto. After 2 hours of refluxing, the mixture was cooled to precipitate metal selenium, which was then removed by filtration. Into the filtrate were added 10.8 g (0.1 mol) of diaminomaleonitrile and 3.0 ml of acetic acid, and the mixture was refluxed for 2 hours at 90°-93° C. After the reaction, the mixture was subjected to cooling and filtration, and the filtrate was condensed to obtain a crude product. The crude product was subjected to recrystallization from hexane to obtain 27.2 g (82% yield) of the product. The meling point: 79° C., IR (νcm-1): 2245 (C≡N).
Reaction SMILES: Br[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C1COCC1>[Cl:8][C:3]1[C:2]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Clc1ncccc1Br
Reactant: O=C1CCOCC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2cccnc2Cl)CCOCC1
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-2-chloropyridine (0.33 g, 1.715 mmol) in THF (2 mL) at room temperature was added isopropylmagnesium chloride (0.857 mL, 1.715 mmol, 2M solution). Reaction mixture was stirred for 1 hr at room temperature before addition of dihydro-2H-pyran-4(3H)-one (0.158 mL, 1.715 mmol). After overnight stirring, reaction mixture was quenched with saturated NH4Cl solution followed by aqueous workup. Purification by Prep-plate TLC (10% MeOH/DCM) produced product that was advanced to the next step.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:23]1[NH:27][N:26]=[N:25][N:24]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:12][CH:11]=1)(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[CH3:22][C:18]1[CH:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][C@H:8]([NH2:7])[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)c3nnn[nH]3)cc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccc(C[C@H](N)c3nnn[nH]3)cc2)c1

Procedure:
[(S)-2-(3′-Methyl-biphenyl-4-yl)-1-(1H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (560 mg, 1.48 mmol) was treated with 4M HCl in dioxane (10 mL) at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give (S)-2-(3′-methyl-biphenyl-4-yl)-1-(1H-tetrazol-5-yl)-ethylamine hydrochloride; MS: m/z (MH+) 280; Retention time=1.14 min. (condition A).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[O:26]>>[CH3:31][O:30][CH2:29][CH2:28][O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: COCCOC(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OCCOC)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid 2-methoxy-ethyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2-methoxyethyl chloroformate (103 μl, 0.89 mmol). The title compound was obtained as yellow powder (196 mg, 59%).
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([S:1][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(S)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Sc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
Combine 4-mercapto-benzaldehyde (0.45 g, 3.3 mmol), 6-chloro-nicotinamide (0.52 g, 3.3 mmol), potassium carbonate (0.7 g, 5.1 mmol), and dimethylformamide (15 mL) then heat at 70° C. overnight. Cool to room temperature, pour into water, and then extract with dichloromethane (3×75 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (1 g). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 6-(4-formyl-phenylsulfanyl)-nicotinamide (120 mg). 1H NMR (DMSO-D6, 300.00 MHz): 10.08 (s, 1H), 8.91 (dd, 1H, J=2.3, 0.7 Hz), 8.18-8.12 (m, 2H), 8.03-7.98 (m, 2H), 7.83-7.78 (m, 2H), 7.61 (s, 1H), 7.34 (dd, 1H, J=8.4, 0.8 Hz).
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH:16]=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C)[Na].[BH4-].[Na+].Cl>C(O)C.CO.CCOC(C)=O>[ClH:1].[CH3:8][C:2]1[CH:7]=[CH:6][C:5]([CH:16]([CH:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)[OH:17])=[CH:4][CH:3]=1
Reactant: O=CC1CCN(CCc2ccccc2)CC1
Agent: CO[Na]
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C(O)C2CCN(CCc3ccccc3)CC2)cc1

Procedure:
A solution of (4-methylphenyl)[1-(2-phenylethyl)-4-piperidinyl -methanone hydrochloride (9.5 g, 0.028 mol in absolute ethanol (350 ml) was treated first by the addition of NaOCH3 (1.62 g, 0.03 mol) and then, portionwise, with sodium borohydride (2.27 g, 0.06 mol) and stirred at room temperature for 18 h. The reaction mixutre was concentrated to a solid and stirred with 10% aqueous NaOH. The mixture was extracted with CH2Cl2 (3×50 ml). The CH2Cl2 solution was washed with water and then saturated NaCl solution, and dried over Na2SO4. After filtering off the Na2SO4, the filtrate was concentrated to a solid. This material was dissolved in EtOAc/Et2O (1:1, 200 ml) and treated with a solution of HCl 0.023 mol in CH3OH/EtOAc (3:10, 13 ml). The resulting precipitate was twice recrystallized from butanone containing a small amount of CH3OH to give alpha(4-methylphenyl)- 1-(2-phenylethyl)-4-piperidinemethanol hydrochloride, mp 181°-183° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[CH2:9]([Mg]Br)[CH3:10].B(F)(F)F.CCOCC>CCOCC.O.Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2([NH2:8])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: N#CC1CCOCC1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: NC1(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
Combined tetrahydro-2H-pyran-4-carbonitrile (1.000 g, 9.00 mmol) and titanium (IV)isopropoxide (2.90 mL, 9.90 mmol) in ether (45.0 mL), then ethylmagnesium bromide (6.60 mL, 19.79 mmol) was added and the reaction was allowed to warm to room temperature for 1 hour. The reaction was stirred for an additional 30 minutes and boron trifluoride etherate (2.280 mL, 18.0 mmol) was added and the reaction was stirred for 2 hours. The reaction was then diluted with 10 mL water and 20 mL 1 N HCl and extracted twice with 200 mL EtOAc. The organic layers were combined and concentrated to afford the title compound (850 mg, 53.5%) as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(Cl)Cl.[CH3:68][O:69][C:70]1[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=1[NH2:72]>C(N(CC)CC)C.O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:72][C:71]5[CH:73]=[CH:74][CH:75]=[CH:76][C:70]=5[O:69][CH3:68])[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: COc1ccccc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1Nc1cccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1
Temperature: 150 °C

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide (72 mg, 0.2 mmol), XANTPHOS (7.00 mg, 0.008 mmol), KtBuO (31 mg, 0.28 mmol), (DPPF)2PdCl2.CH2Cl2 (33.00 mg, 0.24 mmol), and 2-methoxyaniline (30 mg, 0.24 mmol), 1,4-dioxane (0.400 mL) and triethylamine (0.200 mL) were added. The reaction mixture was heated to 150° C. in a microwave reactor for 10 minutes. The resulting material was cooled to room temperature. The solvent was evaporated under reduced pressure. The resulting mixture was dissolved in dichloromethane and washed with H2O. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxyphenylamino)pyridin-2-yl)cyclopropanecarboxamide which was then treated with HCl in MeOH to form the HCl salt (2.4 mg, 0.0055 mmol, 2.7%). ESI-MS m/z calc. 403.1. found 404.5 (M+1)+; retention time 3.01 minutes.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:21]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: Oc1ccccc1O
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccccc1O
Temperature: 60 °C
Yield: 40.9 %

Procedure:
A mixture of catechol (11 g, 100 mmole), bromododecane (32.4 g, 130 mmoles) and potassium carbonate (18.2 g, 130 mmole) in dry DMF (100 ml) was stirred and heated at 60° C. for 48 h. The mixture was poured into water (500 ml) and extracted with diethyl ether (3×100 ml). The combined ether extracts were washed with saturated sodium chloride solution (2×100 ml) and dried with anhydrous magnesium sulphate. The ether was removed to give a solid. Distillation at reduced pressure gave 2-dodecyloxyphenol (11.4 g, 41%), b.p. 175° C./0.5 mmHg, (Found C, 77.80; H, 10.80; C18H30O2 requires C,77.65; H, 10.86; MS (CI) m/e 296 (M+ +NH4+), δH (200 MHz, CDCl3) 0.90(t, 3H), 1.28(br s, 18H), 1.82(q, 2H), 4.04(t, 2H), 5.70(s, 1H) and 6.85(m, 4H) and Catechol bis-decyl ether (11.2 g, 25%), b.p. 225° C./0.5 mmHg, m.p. 46° C. (Lit. 46° C.)5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([Cl:24])[N:15]=2)[CH2:10][C@@H:9]1[CH3:25])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:24][C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][C@@H:9]([CH3:25])[CH2:10]2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:21])[F:22]
Reactant: C[C@H]1CN(c2ccc(C(F)(F)F)c(Cl)n2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(c2ccc(C(F)(F)F)c(Cl)n2)CCN1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A solution of 4-(6-chloro-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine-1-carboxylic acid tert-butyl ester (7.80 g, 26.4 mmol) was dissolved in CH2Cl2/TFA (50:50; 30 mL) and stirred at room temperature over night. The solvent was removed at reduced pressure and the resulting oil was taken up between alkaline water (NaOH) and CHCl3. The aqueous phase was extracted once with CHCl3, the combined organic phases were dried (MgSO4) and the solvent was evaporated at reduced pressure to yield 5.79 g (78%) of a light yellow oil. A NOE between the methylene protons at C-2 in the piperazine ring and the C3-hydrogen in the pyridine ring was observed. Purity 100% (HPLC). Fragmenting MS analysis supports the stated structure. HRMS m/z calcd for C11H13ClF3N3 (M)+ 279.0750. found 279.0751
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][CH2:9][C@@H:10]([C:27]([OH:29])=[O:28])[NH:11][C:12](=[O:26])[C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)([CH3:15])[CH3:14])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:34]I.O>CN(C)C=O>[CH3:34][O:28][C:27](=[O:29])[C@H:10]([CH2:9][S:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=1)[NH:11][C:12](=[O:26])[C:13]([S:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH3:15])[CH3:14]
Reactant: COc1ccc(CSC[C@H](NC(=O)C(C)(C)SCc2ccc(OC)cc2)C(=O)O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CSCc1ccc(OC)cc1)NC(=O)C(C)(C)SCc1ccc(OC)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred solution of S-p-methoxybenzyl-N-(2-p-methoxybenzylthio-2-methylpropionyl)-L-cysteine (3.0 g) in dimethylformamide(20 ml), sodium hydride(0.3 g) was added under nitrogen atomosphere at room temperature and the mixture was stirred for 1 hour. Methyl iodide(0.5 ml) was added to the mixture. The reaction mixture was stirred for 4 hours at room temperature. Water(300 ml) was added to the reaction mixture and extracted with ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 2.8 g(90%) of the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]3)[C:11]([C:28]([F:31])([F:30])[F:29])=[CH:10][N:9]=2)[CH:4]=[N:3]1>CN(C=O)C.CCOC(C)=O.CCN(CC)CC.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]3)[C:11]([C:28]([F:29])([F:31])[F:30])=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cn1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1cc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Reaction time: 16 h
Yield: 74 %

Procedure:
A mixture of 1-(2-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)cyclopropanecarboxamide A75 (0.120 g, 0.281 mmol) and 10% Pd/C (0.135 g) in DMF (3 mL), EtOAc (5 mL) and Et3N (0.5 mL) was stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered through Celite and concentrated under reduced pressure before purification by silica gel column chromatography (0-15% MeOH in EtOAc). The product was triturated with Et2O and the resulting precipitate was collected to give the title compound 65 (0.090 g, 74%). LCMS-D: rt 3.316 min; m/z 431.2 [M+H]+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(N(C)C)=C(C)C.[CH2:27]([O:34][C:35]([C@:37]1([O:48][C@@H:47]([C@@H:49]([C@@H:51]([CH2:53]O)[OH:52])[OH:50])[C@H:42]([NH:43][C:44](=[O:46])[CH3:45])[C@@H:40]([OH:41])[CH2:39]1)[OH:38])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.N1C=CC=CC=1>[CH2:27]([O:34][C:35]([C:37]1([OH:38])[CH2:39][CH:40]([OH:41])[CH:42]([NH:43][C:44](=[O:46])[CH3:45])[CH:47]([CH:49]([OH:50])[CH:51]([OH:52])[CH2:53][O:17][C:16](=[O:18])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH:13]([CH3:14])[CH3:15])[O:48]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@](O)(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC1C(O)CC(O)(C(=O)OCc2ccccc2)OC1C(O)C(O)COC(=O)C(NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a solution of Carbobenzyloxy-L-Valine (1.35 g, 5.37 mmol) in anhydrous dichloromethane (12 mL) at 0° C. under argon is added 1-Chloro-N,N,-2-trimethyl-1-propenylamine (848 μL, 6.34 mmol) by dropwise addition via a syringe. The resulting solution is then stirred at 0° C. for 10 minutes resulting in a clear colorless solution. To this solution is then added the N-Acetyl-β-neuraminic Acid Benzyl ester (1-2), previously dissolved in anhydrous pyridine (8.0 mL) via dropwise addition. The solution immediately turns yellow and is kept at 0° C. and under an argon atmosphere for 3 hours. The cooling bath is then removed and the solution kept at rt for overnight resulting in a cloudy suspension. The solvents are removed under high vacuum being careful that the temperature bath does not exceed 50° C. to give a light yellow oil. In order to remove traces of pyridine, the oil is triturated with toluene and again evaporated under high vacuum. The remaining oil is dissolved in minimum amount of dichloromethane (DCM) and loaded directly unto a silica gel column (Silicycle-FLH-R10030B-ISO80, 80 g Cartridge) and purified by flash chromatography (Mobile Phase: DCM/Methanol=96/4 to 88/12 over 24 minutes). Combination of the purest fractions yields 996 mg (32% yield) of pure (1-5) as a white solid. LC/MS: (+) ESI: m/z=633.2 [M+1]; 655.2 [M+Na, major signal); retention time=3.69 min. 1H NMR (400 MHz, d4-MeOD) δ 7.12-7.37 (m, 11H), 5.08-5.17 (m, 2H), 4.95-5.03 (m, 2H), 4.28 (dd, J=11.6, 2.0 Hz, 1H, C-9), 4.18 (dd, J=11.6, 6.0 Hz, 1H, C-9′) 4.05-4.06 (m, 1H), 3.91-3.98 (m, 1H), 3.89 (dd, J=10.5, 1.2 Hz, 1H), 3.80-3.86 (m, 11H), 3.70 (t, 1H), 3.41-3.43 (m, 1H), 2.14 (dd, J=12.8, 4.8 Hz, 1H), 1.98-2.08 (m, 1H), 1.91 (s, 3H), 1.79-1.89 (m, 1H), 0.80-0.84 (m, 6H); 13C NMR (400 mHz, d4-MeOD) δ 173.7, 170.9, 158.9, 136.2, 137.1, 129.6, 129.5, 129.4, 129.1, 129.0, 128.8, 96.7, 72.0, 70.3, 69.3, 68.3, 68.0, 67.8, 61.1, 54.4, 40.7, 32.1, 22.7, 19.6, 18.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH3:14])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:37]([NH2:46])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:39])[CH3:38]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH3:14])[C:5]([NH:46][C:37]([CH3:39])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:38])=[O:7]
Reactant: CC(C)(N)c1ccccc1
Reactant: COCOc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Yield: 77.1 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-chloro-4-methoxymethoxybenzoic acid (2.39 g, 11.0 mmol) was dissolved in DMF (47 mL), and the solution was treated with EDCI (4.23 g, 22.1 mmol), HOBT monohydrate (1.69 g, 11.0 mmol) and cumylamine (3.20 mL, 22.0 mmol). The reaction mixture was added with water. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 3-chloro-4-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (2.83 g, yield 77%).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(N(CC)CC)C>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCO)cc1)C(=O)OCC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCC(Cc1ccc(OCCOS(C)(=O)=O)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 2-butyl-3-[4-(2-hydroxyethoxy)phenyl]propionate (1.44 g), which is the product of Reference example 6(e), triethylamine (2.04 ml) and methanesulfonyl chloride (0.76 ml) and the reaction mixture was treated to afford the desired compound (1.65 g) as a syrup.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC#N>[I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Ic1n[nH]c2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1nc(I)c2ccncc21
Temperature: 25 °C

Procedure:
To a suspension of 3-iodo-1H-pyrazolo[3,4-c]pyridine (6.24 g, 22.9 mmol) and potassium carbonate (7.29 g, 52.7 mmol) in CH3CN (50 mL) was added tert-butyl bromoacetate (4.06 mL, 27.5 mmol) dropwise at RT and the resulting mixture was heated to reflux for 2 h. The mixture was cooled to RT and filtered, the solid was washed with CH3CN and the filtrate was concentrated under vacuum. The residual oil was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:4, to 1:2, to 1:1) to give the title compound. MS (LC/MS): 360.0 [M+H]+; tR (HPLC conditions d): 2.93 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C:37]1([O:40]C(=O)C)[CH2:39][CH2:38]1)=[O:36]>>[OH:40][C:37]1([C:35]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:36])[CH2:39][CH2:38]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: O=C(N[C@H]1CC[C@@H](NC(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.