Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[C:17]([CH2:18]O)=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1)=[O:10].P(Br)(Br)[Br:23]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[C:17]([CH2:18][Br:23])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1)=[O:10]
Reactant: CSc1ncc(CO)c(NC(=O)Nc2ccccc2Cl)n1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: CSc1ncc(CBr)c(NC(=O)Nc2ccccc2Cl)n1
Reaction time: 4 h
Yield: 71 %

Procedure:
[(2—Chlorophenyl)amino]-N-[5-(hydroxymethyl)-2-methylthiopyrimidin-4-yl]carboxamide (1363 g) was mixed with 8L of tetrahydrofuran and mechanical stirring begun under nitrogen. Then phosphorus tribromide (135 mL) in 800 mL tetrahydrofuran were added to the mixture over 15 minutes. Stirring was continued for 4 hours, at which time the reaction was stopped and filtered. The filter cake was washed once with tetrahydrofuran and dried overnight at 55° C. in vacuum oven to give 1360 g (71%) of [(2-chlorophenyl)amino]-N-[5-(bromomethyl)-2-methylthiopyrimidin-4-yl]carboxamide (M+1 377).
Reaction SMILES: C([N:4]1[CH2:26][CH2:25][C:7]2[N:8]([CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[OH:18])[C:9]3[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.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:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[OH:18])[C:7]3[CH2:25][CH2:26][NH:4][CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: C=CCN1CCc2c(c3cc(Cl)ccc3n2CC(O)c2ccncc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: OC(Cn1c2c(c3cc(Cl)ccc31)CNCC2)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
2-(2-Allyl-8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (4.0 g, 10.87 mmol) was dissolved in DCM (350 mL) and nitrogen was purged for 10 min into the reaction mixture. 1,3-Dimethyl barbituric acid (5.08 g, 32.62 mmol) and Pd(PPh3)4 (251 mg, 0.217 mmol) was added and stirred for 2 h at RT. After consumption of starting material, the reaction mixture was diluted with saturated potassium carbonate (200 mL) and extracted with DCM (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude mixture crystallized in MeOH (5 mL) and ether (50 mL) to obtain 2.2 g of 2-(8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.58 (d, 2H), 7.37 (s, 1H), 7.25 (d, 2H), 7.23 (d, 1H), 7.13 (d, 1H), 5.0 (t, 1H), 4.15 (d, 2H), 3.99 (s, 2H), 3.19 (m, 2H), 2.81 (m, 1H), 2.53 (m, 1H). Separation by chiral HPLC provided enantiomers 10a and 10b. Optical rotations: Compound 10a, (−)34.60 (c 0.55, Chloroform, 99.16% HPLC purity); Compound 10b, (+)31.78 (c 0.53, Chloroform, 92.71% HPLC purity).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:12]1(B(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](B(O)O)=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O>O.C1COCC1.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>[CH3:7][O:6][C:4]([C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:14][CH:13]=1)=[O:5]
Reactant: COC(=O)c1ccccc1Br
Reactant: OB(O)c1ccc(B(O)O)c2ccccc12
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-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1-c1ccc(-c2ccccc2C(=O)OC)c2ccccc12

Procedure:
1.55 g (0.1 mmol) of Pd(PPh3)4 are added to a vigorously stirred, degassed suspension of 21.6 g (7.1 mmol) of methyl 2-bromobenzoate, 10.1 g (28 mmol) of 1,4-naphthalenediboronic acid and 18.9 g (6.6 mmol) of trispotassium phosphate in a mixture of 350 ml of water and 350 ml of THF, and the mixture is refluxed for 60 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated sodium chloride solution and subsequently dried over magnesium sulfate. The organic phase is evaporated to dryness under reduced pressure in a rotary evaporator. The grey residue obtained in this way is recrystallised from dioxane. The deposited crystals are filtered off with suction, washed with 50 ml of ethanol and subsequently dried under reduced pressure. Yield: 13 g, 82% of theory.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[Cl:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:30](O)[CH2:31][OH:32]>C1C=CC=CC=1>[Cl:12][C:3]1[CH:4]=[C:5]([C:9]2([CH3:10])[O:32][CH2:31][CH2:30][O:11]2)[CH:6]=[C:7]([Cl:8])[C:2]=1[NH2:1]
Reactant: CC(=O)c1cc(Cl)c(N)c(Cl)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CC1(c2cc(Cl)c(N)c(Cl)c2)OCCO1

Procedure:
1-(4-Amino-3,5-dichlorophenyl)ethanone (15 g, 73.5 mmol), pyridinium p-toluene sulfonic acid (5.5 g, 22 mmol), and ethylene glycol (6.2 mL, 110 mmol) were heated together in benzene (250 mL) with a Dean Stark trap at 100° C. overnight. The benzene was distilled off until ˜75 mL remained and the reaction mixture was extracted with EtOAc and saturated NaHCO3. The organic layer was separated, dried with MgSO4, filtered, and concentrated under rotary evaporation to afford a oily residue. The crude mixture was purified on silica gel chromatography (100% Hex to 100% EtOAc) to afford the desired product.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:13][CH2:14][CH2:15]Br.[OH-].[Na+]>C(O)C>[Br:13][CH2:14][CH2:15][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: BrCCBr
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: BrCCOc1ccc(-n2ccnc2)cc1
Yield: 42.8 %

Procedure:
4-(Imidazol-1-yl)phenol (5 g, 31.3 mmol), 1,2-dibromoethane (8.09 g, 93.9 mmol) and sodium hydroxide (1.25 g, 31.3 mmol) were refluxed in ethanol for 24 h. Thereafter, the solvent was evaporated and the residue was diluted with a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extracted organic layer was washed twice with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate, followed by evaporation of the solvent. The residue was purified by column chromatography on silica gel using, as an eluent, methylene chloride containing 30% ethyl acetate. The fractions containing the product were subjected to evaporation to yield the end compound 1-bromo-2-[4-(imidazol-1-yl)phenoxy]ethane (3.58 g) in a solid form.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>CO.O1CCCC1.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]([O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=2)=[CH:26][CH:27]=1
Reactant: COCCOCOC(C(=O)OC)c1ccc(OCc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOCOC(C(=O)O)c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
Methyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-[(2-methoxyethoxy)methoxy]acetate (0.421 g, 1.11 mmol) was dissolved in a mixture of methanol (6 ml) and tetrahydrofuran (6 ml), and 1N sodium hydroxide (3 ml) was added thereto. After being stirred for 1 hour at room temperature, the reaction mixture was neutralized and then extracted with ethyl acetate. The organic layer dried over MgSO4, and then the solvent was evaporated out. The obtained residue was purified by silica gel column chromatography (50% ethyl acetate/hexane), to give 2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-[(2-methoxyethoxy)methoxy]acetic acid (0.156 g, 39%).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:24])[C:9]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]#[N:35]>CC(C)=O>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:33][C:34]#[N:35])=[CH:21][CH:22]=3)[CH:15]=2)[N:10]([CH3:24])[C:9]=1[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Cc1c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc2n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc2n1C

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(3-benzyl-1,2-dimethyl-1H-indol-5-yl)-phenol (0.159 g, 0.486 mmol) was reacted with K2CO3 (0.087 g, 0.631 mmol) and bromoacetonitrile (0.076 g, 0.631 mmol) in acetone (5 ml) to give the product (0.161 g, 0.439 mmol, 90%) as a white solid, mp 135-138° C. 1H NMR (DMSO-d6) δ 2.40 (s, 3H), 3.68 (s, 3H), 4.07 (s, 2H), 5.18 (s, 2H), 7.08-7.12 (m, 3H), 7.20-7.25 (m, 4H), 7.32 (dd, J=1.8, 8.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.57-7.60 (m, 3H); [ESI(+)], m/z 367 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([OH:33])[CH:14]([N:19]3[CH2:24][CH2:23][C:22]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([OH:25])[CH2:21][CH2:20]3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[Pd].C(O)(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2([OH:25])[CH2:23][CH2:24][N:19]([CH:14]3[CH:13]([OH:33])[C:12]4[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=4)[O:16][CH2:15]3)[CH2:20][CH2:21]2)=[CH:27][CH:28]=1
Reactant: OC1c2ccc(OCc3ccccc3)cc2OCC1N1CCC(O)(c2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)OCC(N1CCC(O)(c3ccc(F)cc3)CC1)C2O
Reaction time: 8 h
Yield: 54.7 %

Procedure:
A mixture of 3R*4S*7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4-ol (0.80 g, 1.78 mmol), 10% palladium on carbon (0.16 g), methanol (40 mL), and acetic acid (0.8 mL) was hydrogenated for 8 hours with a starting pressure of 48.5 psi. The reaction was filtered through celite and the filtrate was concentrated. The residue was stirred vigorously with ether and saturated sodium bicarbonate for 1 hour. The solid was washed with water and ether and dried in vacuo. Recrystallization from ethanol yielded 0.35 g (54%) of 3R*4S*3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4,7-diol as a white solid which had mp 159-160° C.; NMR DMSO∂σ δ7.55-7.47 (m, 2H), 7.11 (t, J=9 Hz, 2H), 7.02 (d, J=8.4 Hz, 1H)k, 6.32 (dd, J=2.3, 8.3 Hz, 1H), 6.15 (d, J=2.3 Hz 1H), 5.10-4.50 (br m with s at 4.63, 3H), 4.23 (dd, J=2.8, 10.3 Hz, 1H), 4.04 (t, J=10.5 Hz, 1H), 2.99 (br d, J=10.8 Hz, 1H), 2.86 (br d, J=10.7 Hz, 1H), 2.73-2.50 (m, 3H), 2.08-1.90 (m, 2H), 1.58 (br d, J=13 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]([Cu])#[N:13].O>CN(C)C=O.Cl.[Fe](Cl)(Cl)Cl>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)CCC2=O

Procedure:
9.5 g of 5-bromoindan-1-one and 4.93 g of CuCN are suspended in 10 ml of dimethylformamide and the mixture is refluxed for 4 hours. A solution of 18 g of iron(III) chloride in 5 ml of conc. hydrochloric acid with 30 ml of water is added dropwise with stirring to the cooled, dark-brown, viscous suspension and the mixture is then stirred at 70° C. for 30 minutes. The reaction mixture is extracted three times by shaking with 50 ml of toluene, and the combined organic phases are extracted by shaking with 50 ml of 2N hydrochloric acid and 50 ml of 2N sodium hydroxide solution and then washed with water until neutral. The toluene extract is dried over magnesium sulfate and concentrated in vacuo, and the residue is recrystallized from n-heptane. 1-Oxoindan-5-carbonitrile of melting point 123-125° C. is obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[CH3:27][Si:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][O:23][CH2:22][N:19]1[C:16]2=[N:17][CH:18]=[C:13]([C:12]3[C:7]([NH:6][C@H:3]4[CH2:4][CH2:5][N:1]([C:30](=[O:32])[CH3:31])[CH2:2]4)=[N:8][CH:9]=[CH:10][CH:11]=3)[N:14]=[C:15]2[CH:21]=[CH:20]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@H]3CCNC3)cnc21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CC[C@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-((S)-3-{3-[5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidin-1-yl)-ethanone was prepared from (S)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and acetic anhydride following the general synthetic procedures described in the above Examples.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[CH2:15][C:10]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)([CH2:11]2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.C(OCC)(=O)C>C(OCC)(=O)C.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]23[CH2:15][CH:12]([CH2:11]2)[C:13](=[O:14])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]3=[O:25])=[CH:17][CH:18]=1
Reactant: O=C1C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C(=O)N1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Nc1ccc(C23CC(C2)C(=O)N(Cc2ccccc2)C3=O)cc1

Procedure:
In a manner analogous to that described in Example 1a, 2.46 g of 3-benzyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 50 ml of ethyl acetate, hydrogenated in the presence of 0.3 g of 5% palladium-on-carbon and worked up. Melting point 164°-165.5° (from ether/ethyl acetate).
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33]>CN(C)C(=O)C>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:13]([C:4]3[C:3](=[O:33])[N:2]([N:1]=[CH:3][CH:4]([CH3:13])[CH3:5])[C:11]4[C:6]([C:5]=3[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:14][S:15](=[O:32])(=[O:31])[C:16]=2[CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Solvent: CC(=O)N(C)C
Product: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Temperature: 165 °C
Yield: 169.4 %

Procedure:
The product of Example 304F (0.150 g, 0.32 mmol) and isobutyrlaldehyde (0.44 mL, 4.84 mmol) in N,N-dimethylacetamide (1.5 mL) were reacted at 125° C. for 40 minutes in a microwave reactor in a sealed tube. The reaction was concentrated under a stream of nitrogen warmed through a manifold heated to 165° C. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.140 g, 84%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:15][CH3:16])=[O:8]
Reactant: CCO
Reactant: O=C(O)c1cnccn1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnccn1

Procedure:
To a solution of pyrazine-2-carboxylic acid (100 g) in ethanol (EtOH, 1000 ml) was added conc. sulfuric acid (45 ml) at room temperature. After refluxing for 8 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (AcOEt, 1500 ml) and water (H2O, 1000 ml), and sodium hydrogencarbonate (NaHCO3) was added to adjust the pH of the mixture to 8. The aqueous layer was extracted with AcOEt (1000 ml), and the combined organic layer was washed with brine and dried over magnesium sulfate (MgSO4). The solution was concentrated in vacuo, and the residue was crystallized from hexane (1000 ml) to give 111.2 g of ethyl pyrazine-2 carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([F:27])[CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:28].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[F:27][C:21]1[CH:20]=[C:19]([S:16]([N:6]2[CH:5]([CH3:28])[C:4]3[C:13](=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=3)[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)(=[O:17])=[O:18])[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1F
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(F)c1
Yield: 79.4 %

Procedure:
The title compound was prepared from 8-fluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.50 g, 1.3 mmol), cyclohexene (2.3 mL, 22 mmol), and 1 M boron tribromide in dichloromethane (7.5 mL, 7.5 mmol) according to the procedure and in the same manner as described in Example 47, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4), followed by trituration from hexane, to yield 2-fluoro-4-[(8-fluoro-6-methylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.40 g, 82%), m.p. 191° C.;
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:26]3[N:27]=[C:28]4[C:34]([C:35](O)=[O:36])=[CH:33][N:32]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:29]4=[N:30][CH:31]=3)=[N:21][N:22]2[CH3:25])=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(#N)C.C(OCC)(=O)C.O>[O:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:35]([C:34]2[C:28]3[C:29](=[N:30][CH:31]=[C:26]([C:20]4[C:19]5[C:23](=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=5)[N:22]([CH3:25])[N:21]=4)[N:27]=3)[N:32]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:33]=2)=[O:36])[CH2:9]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: N[C@H]1CCCOC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CCCOC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
(S)-(Tetrahydro-pyran-3-yl)amine trifluoroacetate (crude from Step 4) was dissolved in acetonitrile (1.8 ml) to which was then added 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.175 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (84 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.15 ml, 0.87 mmol). The reaction was stirred at room temperature for 18 h. Additional O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50 mg, 0.16 mmol) and N,N-diisopropylethylamine (0.11 ml, 0.63 mmol) were added and stirring was continued for 24 h. Water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford 55 mg (58%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (S)—N-(tetrahydro-pyran-3-yl)-amide. (M+Na)+=563.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH:27]([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.Cl.[CH2:39]([C@H:46]([CH2:50][C:51]([N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)=[O:52])C(O)=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[CH2:39]([C@H:46]([CH2:50][C:51]([N:53]1[CH2:54][CH2:55][O:56][CH2:57][CH2:58]1)=[O:52])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH:27]([CH3:28])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:5])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)C
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A mixture of 300 mg (0.56 mmole) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-isopropyl-N-methylhexanamide [prepared as described in Example 1(a)] and 5 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. The solvent was then removed by distillation under reduced pressure. Diethyl ether was added to the residue, and the mixture was concentrated by evaporation under reduced pressure. This operation was repeated three times. After the final residue had been dried under reduced pressure for 8 hours, the dried material was suspended in 10 ml of anhydrous tetrahydrofuran. 170 mg (0.61 mmole) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were then added to the suspension. 0.09 ml (0.59 mmole) of 95% diethyl cyanophosphonate and 0.26 ml (1.86 mmole) of triethylamine were then added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred at room temperature for 8 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative thin layer chromatography on silica gel (using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent), to afford 281 mg (yield 72%) of the title compound as white crystals, melting at 83°-86° C.
Reaction SMILES: [N+]([O-])([O:3][C@H:4]1[O:17][C@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]([O:7][C:8](=[O:10])[CH3:9])[C@H:5]1[N:23]=[N+]=[N-])=O.[N+]([O-])(O[C@@H]1O[C@H](COC(=O)C)[C@H](OC(=O)C)[C@H](OC(=O)C)[C@H]1N=[N+]=[N-])=O>C(O)(=O)C.[Pd]>[C:8]([O:7][C@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[O:17][CH:4]([OH:3])[C@@H:5]1[NH2:23])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@H](O[N+](=O)[O-])[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Agent: CC(=O)OC[C@H]1O[C@@H](O[N+](=O)[O-])[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1OC(O)[C@H](N)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
A solution of the anomeric mixture of the 2-azido-2-deoxy nitrates II and III (1.0 g, 7.68 mmole) was hydrogenated in acetic acid (5 ml) containing 5% palladium on carbon (0.10 g) at one atmosphere and ambient temperature for 5 hours. After removal of the catalyst by filtration and evaporation of the solvent gave 3,4,6-tri-O-acetyl-D-galactosamine (XXXVIII) (0.85 g) as a foam. Treatment of this foam with 2 N aqueous hydrochloric acid (10 ml) at ambient temperature for two to three hours followed by dilution with n-butanol (5 ml) and evaporation gave D-galactosamine hydrochloride XXXVII (0.50 g) which was recrystallized from butanol-ethanol-water.