Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].Cl.C(N(CC)CC)C.[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][C:24](O)=[O:25].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:24](=[O:25])[CH2:23][N:19]1[CH2:20][CH2:21][CH2:22][C:18]1=[O:17])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CN1CCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOC(=O)CNC(=O)CN1CCCC1=O
Temperature: 0 °C
Yield: 64.8 %

Procedure:
167.4 g (1.2 mole) of glycine ethyl ester hydrochloride are suspended in 4 liters of methylene chloride, the hydrochloric acid being neutralized by adding 168 ml (1.2 mole) of triethylamine. The reaction mixture is cooled to about 0° C. and a suspension of 171.6 g (1.2 mole) of 2-oxo-1-pyrrolidineacetic acid in 1500 ml methylene chloride is added. Without allowing the temperature to rise above 5° C., a solution of 272 g (1.4 mole) of DCC in 300 ml of methylene chloride is added dropwise to this mixture. Stirring is maintained for 2 hours at the same temperature and the reaction mixture is then allowed to return to ambient temperature, while stirring for 16 hours. 80 ml of acetic acid are then added, the reaction mixture is cooled to 0° C. and the precipitate is filtered off. The filtrate is evaporated to dryness and the residue redissolved in ethyl acetate, followed by filtering to remove insoluble matter. The filtrate is treated with highly absorbing active charcoal (Norite), again filtered and the filtrate is distilled at 190° C. at a pressure of 0.01 mm Hg. There are thus obtained 256 g of a syrup which is stirred with 1500 ml of anhydrous diethyl ether and which is crystallized by cooling in an ice bath. 177.5 g of N-(2-oxo-1-pyrrolidineacetyl)-glycine ethyl ester are thus obtained (yield: 64% of theory); M.P. 63°-64° C. The melting point of a sample recrystallized from a 1:2 v/v mixture of ethyl acetate and anhydrous diethyl ether is 64°-65° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23]Br>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:6]=2[N:5]=[C:4]1[CH:1]1[CH2:3][CH2:2]1
Reactant: Fc1cccc(F)c1CBr
Reactant: COc1cccc2nc(C3CC3)[nH]c12
Product: COc1cccc2c1nc(C1CC1)n2Cc1c(F)cccc1F
Yield: 92.1 %

Procedure:
2-(Cyclopropyl)-4-methoxylbenzimidazole (1.00 g, 5.32 mmol) (5014) was reacted with 2,6-difluoro-a-bromo-toluene (1.30 g, 6.28 mmol, 130 M%). The crude product was purified by flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-(2,6-Difluorobenzyl)-2-(cyclopropyl)-4-methoxylbenzimidazole (5016) (1.54 g, 4.90 mmol, 92% yield). M.p. 136-139° C. 1H-NMR (200 MHz, CD2Cl2) δ7.31 (m, 1H, H4′), 7.07 (dd, J=8.0, 7.8 Hz, 1H, H6), 6.94 (m, 3H, H3′,5′,5), 6.61 (dd, J=7.8, 1.0 Hz, H7), 5.46 (s, 2H, CH2PhF2), 3.95 (s, 3H, OCH3), 2.20-2.03 (m, 1H), 1.18-0.97 (m, 4H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[F:20])[CH:3]=1.[CH3:21][O-:22].[Na+].O>CN(C=O)C>[F:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[O:11][C:4]1[CH:3]=[C:2]([O:22][CH3:21])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C[O-]
Reactant: COc1cccc(F)c1Oc1cc(F)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(Oc2c(F)cccc2OC)c1
Temperature: 80 °C
Yield: 69.6 %

Procedure:
A mixture of 4-fluoro-2-(2-fluoro-6-methoxyphenoxy)-1-nitrobenzene (1.33 g, 5 mmol) and sodium methoxide (035 g, 6 mmol) in DMF (10 ml) was heated at 80° C. for 2 h. The mixture was poured into water and was extracted with ethyl acetate (3×20 ml). The combined organic layer was washed with water, brine and dried (Na2SO4). The solution was concentrated under reduced pressure to obtain 2-(2-fluoro-6-methoxyphenoxy)-4-methoxy-1-nitrobenzene (1.02 g, 70%). This compound was reduced to 2-(2-fluoro-6-methoxyphenoxy)-4-methoxyaniline (0.62 g, 73%) following the general procedure C. N-[2-(2-Fluoro-6-methoxyphenoxy)-4-methoxyphenyl]-N′-(thiazol-2-yl)urea (136 mg, 70%) was prepared from 2-(2-methoxy-6-fluorophenoxy)-4-methoxyaniline (132 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure D.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>CCOCC.C1COCC1>[CH2:9]([N:16]1[CH:17]2[CH2:23][CH2:22][CH:21]1[CH2:20][C:19]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:24])[CH2:18]2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccccc2)CC2CCC(C1)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of phenylmagnesium bromide in ether (3 M, 2.3 mL) was added dropwise to a solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (1.0 g, 4.6 mmol) in THF (20 mL) that had been cooled to 0° C. The mixture was stirred for 3 hours and a solution of saturated aqueous ammonium chloride was added and the products extracted into diethyl ether, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 10-30% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.5 g) as an oil. LCMS m/z 294.4 [M+H]+. R.T.=2.59 min (Analytical Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:23])[CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:11]1[CH:10]=[C:9]([C:24]#[N:25])[CH:8]=[CH:7][C:6]=1[S:5]2.C(N(CC)CC)C.[SH2:33]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:23])[CH2:17][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1)[C:11]1[CH:10]=[C:9]([C:24](=[S:33])[NH2:25])[CH:8]=[CH:7][C:6]=1[S:5]2
Reactant: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C(N)=S)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 7-chloro-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonitrile (31.07 g) and triethylamine (11.8 cc) in anhydrous pyridine (300 cc) is saturated with hydrogen sulphide for 4 hours at 25° C. The clear solution obtained is kept stirred for 12 hours at 25° C. The mixture is outgassed by bubbling nitrogen through for 2 hours, then diluted with ethyl acetate (250 cc) and washed with distilled water (5×200 cc). The organic phase is dried over magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The residue is purified by chromatography on a column (height: 38 cm; diameter: 6.5 cm) of silica gel (0.06-0.2 mm), eluting with a mixture of cyclohexane and ethyl acetate in proportions (by volume) of 70:30 (6 liters), 50:50 (4 liters) and 30:70 (4 liters), then with pure ethyl acetate (2 liters) and finally with a 90:10 mixture (6 liters) of ethyl acetate and methanol, collecting 50-cc fractions. The first 13.3 liters are discarded and fractions 6 to 94 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 7-chloro-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinethiocarboxamide (21.43 g).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:37])[C:12]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:19]([CH3:21])[CH:20]=1)=[CH2:13])[CH3:9].C(OCC)(=O)C.[C:44]([OH:47])(=[S:46])[CH3:45]>>[CH2:8]([O:10][C:11](=[O:37])[CH:12]([CH2:13][S:46][C:44](=[O:47])[CH3:45])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:19]([CH3:21])[CH:20]=1)[CH3:9]
Reactant: C=C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)OCC
Reactant: CC(O)=S
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Triethylamine (0.234 mL, 1.68 mmol) was added to a solution of 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.68 g, 1.61 mmol) in thioacetic acid (3 mL) at 0° C. The mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic phase was washed with water, saturated NaHCO3 and brine and dried. The crude product was purified by flash chromatography (toluene/ethyl acetate, 3:1→1:2) to give pure 2-acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (489 mg, 61%) and slightly impure 2-acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (0.34 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH2:11]O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P(Br)(Br)[Br:14]>C(Cl)Cl>[Br:14][CH2:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10]
Reactant: BrP(Br)Br
Reactant: Cc1c(CO)ccc(C#N)c1Cl
Solvent: ClCCl
Product: Cc1c(CBr)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 3 h
Yield: 28.3 %

Procedure:
To a solution of compound 7B (700 mg, 3.9 mmol) in CH2Cl2 (15 mL) was added PBr3 (5.8 mL, 5.8 mmol, 1N in CH2Cl2) at −15° C., and stirred at −15° C. for 3 hr. The reaction was slowly quenched with saturated NaHCO3 solution at −15° C. The organic layer was separated, dried over MgSO4, and concentrated. Purification by silica gel chromatography (0-10% EtOAc in hexanes) provide the title compound (270 mg) as a white powder.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])C(C)C.C[C:21]([CH3:24])([O-:23])[CH3:22].[Li+].C([O:30]C[C@H]1CO1)(C)(C)C>CN(C)C=O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][N:7]1[CH2:22][C@H:21]([CH2:24][OH:30])[O:23][C:6]1=[O:5]
Reactant: COc1ccccc1OCCNC(=O)OCC(C)C
Reactant: CC(C)(C)OC[C@H]1CO1
Reactant: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccccc1OCCN1C[C@H](CO)OC1=O

Procedure:
Using N,N-dimethylformamide solution of isobutyl-2-(2-methoxyphenoxy)ethylcarbamate 53.46 g (0.2 mol), lithium-t-butoxide 3.2 g (0.04 mol) and (R)-2-t-butoxymethyl-oxiran 28.6 g (0.22 mol), the procedures as described in Example 1 were carried out to obtain the targeted product.
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1.CS(C)=[O:33]>>[CH2:29]1[O:33][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)=[CH:23][C:24]=2[O:28]1
Reactant: CS(C)=O
Reactant: COc1ccc(N2C[C@H](CN3CCC(Oc4cccc(OC)c4)CC3)OC2=O)cc1
Product: c1cc2c(cc1OC1CCNCC1)OCO2

Procedure:
3-p-methoxyphenyl-5(S)-[(4-m-methoxyphenoxypiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 208°-209°; [α]D =-29.1° (DMSO);
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[C:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[N:6][CH:5]=1.[OH-].[Na+].Cl>O1CCOCC1>[C:14]([O:13][C:11]([NH:10][C:9]1[C:4]([C:3]([OH:18])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cnccc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Temperature: 60 °C

Procedure:
To a solution of 4-tert-butoxycarbonylamino-nicotinic acid methyl ester (6.02 g, 23.86 mmol) in dioxane (100 mL) was added aq. sodium hydroxide (0.970 N solution, 28.05 mL, 27.20 mmol). The solution was heated to 60° C. for 1 hr then cooled. Aqueous hydrochloric acid (1.03 μM solution, 26.99 mL, 27.20 mmol) was added and the mixture was extracted with chloroform (5×100 mL). The extracts were dried (MgSO4), filtered, and evaporated to give 4-tert-Butoxycarbonylamino-nicotinic acid, a cream solid (4.70 g, 83% yield).
Reaction SMILES: [S:1]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]1[CH2:20][C:21]([OH:23])=O)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:57][C:58]([F:74])([F:73])[CH2:59][NH:60][CH2:61][C:62]1[CH:63]=[C:64]2[C:69](=[CH:70][CH:71]=1)[C@H:68]([NH2:72])[CH2:67][CH2:66][CH2:65]2>C1COCC1>[S:1]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]1[CH2:20][C:21]([NH:72][C@H:68]1[C:69]2[C:64](=[CH:63][C:62]([CH2:61][NH:60][CH2:59][C:58]([F:57])([F:73])[F:74])=[CH:71][CH:70]=2)[CH2:65][CH2:66][CH2:67]1)=[O:23])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)O)cc1
Reactant: N[C@@H]1CCCc2cc(CNCC(F)(F)F)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)N[C@@H]2CCCc3cc(CNCC(F)(F)F)ccc32)cc1
Reaction time: 0.25 h
Yield: 22 %

Procedure:
To a solution of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (214 mg, 0.64 mmol, 1.0 eq.) in THF (5 ml) were added DIPEA (340 μl, 1.92 mmol, 3.0 eq.) and HATU (292 mg, 0.77 mmol, 1.2 eq.) at 0° C. and the mixture was stirred for 15 min at the same temperature. A solution of (R)-6-((2,2,2-trifluoroethylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (A53) (0.64 mmol, 1.0 eq.) in THF (5 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was diluted with DCM (50 ml) and washed with sat. NH4Cl solution (20 ml), sat. NaHCO3 solution (20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 0.7% MeOH/DCM) to yield the desired product as an off-white solid. Yield: 22% (80 mg, 0.14 mmol); MS, Rt=3.2 min; m/z=575.0 [MH]+
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9](=[O:45])[CH2:10][CH:11]([NH:19][C:20]([C:22]1([NH:37]C(=O)OC(C)(C)C)[CH2:27][CH2:26][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:24][CH2:23]1)=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>C(Cl)Cl>[NH2:37][C:22]1([C:20]([NH:19][CH:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:10][C:9]([NH2:8])=[O:45])=[O:21])[CH2:27][CH2:26][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CC(N)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)CC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 11.3 %

Procedure:
HCl in 1,4-dioxane (4M) (0.228 mL, 0.91 mmol) was added to tert-butyl 4-(3-amino-1-(4-chlorophenyl)-3-oxopropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 108) (99 mg, 0.18 mmol) in DCM (4 mL) at 20° C. The resulting solution was stirred at 20° C. for 3 hours. The reaction mixture was filtered through a PTFE cup and the collected solid was purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(3-amino-1-(4-chlorophenyl)-3-oxopropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (9.00 mg, 11.1%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:40])=[C:4]([S:9]([N:12]([CH2:24][C:25]2[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=2)[CH2:28][NH:29]C(=O)OC(C)(C)C)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][CH2:28][C:27]1[CH:26]=[C:25]([CH:39]=[CH:38][CH:37]=1)[CH2:24][N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=1)[S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:40])(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of tert-butyl 3-((3,5-dichloro-2-hydroxy-N-(4-(trifluoromethyl)benzyl)phenylsulfonamido)methyl)benzylcarbamate (0.4 g, 0.65 mmol) in CH2Cl2 (10 mL) was added TFA (1.49 mL, 19.4 mmol). The resulting mixture was stirred at rt for 16 h. The mixture was concentrated, and the residue was partitioned between saturated NaHCO3 and ethyl acetate. The organic layer was washed with brine twice, dried over MgSO4, and concentrated in vacuo to give a light yellow solid (0.32 g, 86%). 1H NMR (DMF-d7): δ 7.52 (m, 2H), 7.50 (m, 4H), 7.48 (m, 2H), 7.2-7.0 (m, 2H), 4.75 (s, 2H), 4.51 (s, 2H), 4.25 (m, 2H); MS (ESI): (M+H)+=519.11.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([CH3:6])([OH:5])[CH3:4].[C:9](=O)([O:17]C1C=CC=CN=1)[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[F:1][C:2]([F:8])([F:7])[C:3]([O:5][C:9](=[O:17])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:6])[CH3:4]
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: CC(C)(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(OC(=O)Oc1ccccn1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a slurry of KH (1.03 g, 25.8 mmol) in THF (70 mL) was added 1,1,1-trifluoro-2-methylpropan-2-ol (3 g, 23.42 mmol). The reaction was stirred at 0° C. for 20 min. A solution of dipyridin-2-yl carbonate (5.06 g, 23.42 mmol) in THF (30 mL) was then added to the mixture. The mixture was stirred at rt for overnight. A lot of solid came out from the solution. The solid was filtered and washed with EtOAc (30 mL). The combined THF/EtOAc solution was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The obtained white solid (1.24 g, 21%) was directly used for the next step.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[N:16]4[CH:17]=[N:18][CH:19]=[C:15]4[CH:14]=[CH:13][C:12]=3[C:20](O)=[O:21])=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:24]([O:26][CH2:27][CH2:28][O:29][NH:30][C:20]([C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:17]=[N:18][CH:19]=2)[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]=1[F:23])=[O:21])=[CH2:25]
Reactant: C=COCCON
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
To a mixture of 5-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (400 mg, 1.29 mmol), O-(2-vinyloxyethyl)-hydroxylamine (265 mg, 2.57 mmol) and HOBt (225 mg, 1.67 mmol) in DMF (5 mL) was added EDCI hydrochloride (320 mg, 1.67 mmol), and DIPEA (0.290 mL, 1.67 mmol) before the reaction mixture was stirred at room temperature for 18 hours. The products were partitioned between ethyl acetate and saturated aqueous NaHCO3, the organic layer separated and washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0-35% ethyl acetate in cylcohexane) to give the title compound (270 mg, 53%). LCMS (Method B): RT 2.79 [M+H]+397.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[N:7]=1
Reactant: NCC1CC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ccnc(NCC2CC2)n1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
In a microwave reaction vessel, slurry 2,4-dichloropyrimidine (1.0 g, 6.7 mmol), cyclopropylmethylamine (550 μL, 6.0 mmol), and diisopropylethylamine (2.35 mL, 13.4 mmol) in toluene (3 mL). Irradiate in microwave (300 watts) at 120° C. for 30 min. Cool to room temperature and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1 to 3:7 over 30 min; 40 mL/min) to obtain the desired intermediate (157.5 mg, 15%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[C:8]([CH3:32])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH2:11][C:10]2=[O:31])(=O)C.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].Cl>O.C(O)C.CN(C)C=O>[C:38]([O:37][C:35]([CH2:34][O:6][C:7]1[C:8]([CH3:32])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH2:11][C:10]2=[O:31])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Reaction time: 3 h

Procedure:
A mixture of 5.6 g of sodium hydroxide, 150 ml of ethanol and 20 ml of water was added dropwise to a mixture of 25 g of 6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 47), 30 ml of dimethylformamide and 150 ml of ethanol, whilst ice-cooling, and the reaction mixture was stirred for 3 hours. 18.3 g of t-butyl bromoacetate were then added. The reaction mixture was stirred for 1 hour at room temperature and then allowed to stand overnight. After this, the reaction mixture was poured into water, neutralized with a 10% w/v aqueous hydrogen chloride solution and extracted with benzene. This extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography eluted with a 20:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@@H:11]([O:12][CH2:13][CH:14]=[CH2:15])[C@@H:10]1[NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:46](Cl)(=[O:62])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61].CO>C(Cl)(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C:46](=[O:62])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[O:16][C@@H:11]([O:12][CH2:13][CH:14]=[CH2:15])[C@@H:10]1[NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: C=CCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=CCO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Reaction time: 4 h

Procedure:
To 0.38 g. of allyl 3-O-benzyl-2-deoxy-2-palmitamido-β-D-glucopyranoside (Compound 5) in 7 ml. dry pyridine at about 15° C., was added 0.3 ml. of palmitoyl chloride. After warming and holding at room temperature for 4 hours, thin layer chromatography (5% methanol in chloroform) showed the reaction to be complete. Methanol was then added and the solvent evaporated and coevaporated with toluene. Column chromatography of the residue (5% acetone in CHCl3) yielded Compound 6.