Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.Cl.[NH2:26][C@H:27]([C:35]([N:37]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:38])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[C@@H:2]([C:15]([NH:26][C@H:27]([C:35]([N:37]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:38])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1cn(C=O)c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Boc-D-Trp(CHO)-OH (3.26 g), HCl.H-Phe-NMeBzl (2.99 g) and HOBT (1.32 g) were dissolved in DMF (40 ml). To this solution was added WSC under ice cooling. The reaction mixture was stirred for an hour at this temperature and for additional an hour at room temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with diluted sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid, and sodium chloride solution and dried over magnesium sulfate. The evaporated residue was crystallized from a mixed solvent of ethyl acetate and diisopropyl ether (3:4) (35 ml) with seeding. The crystals were collected by filtration after addition of diisopropyl ether (55 ml) and dried to give Boc-D-Trp(CHO)-Phe-NMeBzl (4.96 g).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[F-:16].[K+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[F:16][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: [F-]
Reactant: O=C(OCC(F)(F)F)c1ccccc1Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: O=C(OCC(F)(F)F)c1ccccc1F
Yield: 60.5 %

Procedure:
Into a 1 l glass reactor equipped with a condenser, 238.5 g (1 mol) of 2,2,2-trifluoroethyl 2-chlorobenzoate, 87 g (1.5 mol) of spray dried potassium fluoride, 23.9 g of tetrabutyl phosphonium bromide and 480 g of sulforane were charged and reacted at 180° C. for 20 hours under vigorous stirring. After cooling, the inorganic salt was removed by filtration, and the filtrate was distilled under reduced pressure to obtain 134.3 g (yield: 60.5%) of 2,2,2-trifluoroethyl 2-fluorobenzoate.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(O[CH:16]([C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[F:31])[C:17]1[N:18]([CH3:23])[C:19]([Cl:22])=[CH:20][N:21]=1)=O)(C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([SH:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39][CH:16]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:17]2[N:18]([CH3:23])[C:19]([Cl:22])=[CH:20][N:21]=2)=[CH:35][CH:34]=1
Reactant: Cn1c(Cl)cnc1C(OC(=O)OC(C)(C)C)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(Cl)cnc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
Trifluoroacetic acid (10 ml) was added to the 2-[(t-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole (404 mg, 1.13 mmol) obtained in Referential Example 14. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in thionyl chloride (2.0 ml) and to the resulting solution was added a drop of dimethylformamide. The mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in dimethylformamide (5.0 ml). To the resulting solution were added 4-chlorobenzenethiol (244 mg, 1.69 mmol) and potassium carbonate (936 mg, 6.78 mmol). The resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was allowed to stand until it became room temperature. Ethyl ether (60 ml) was added. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 5:1) to give the title compound (195 mg, 89%) as a colorless oil.
Reaction SMILES: C(O[C:4](=[O:17])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][CH:14]1[CH2:16][CH2:15]1)C.ClS[N:20]=[C:21]=[O:22]>ClCCl>[CH:14]1([N:13]2[C:6]3[C:5](=[CH:10][C:9]([F:11])=[C:8]([F:12])[CH:7]=3)[C:4](=[O:17])[NH:20][C:21]2=[O:22])[CH2:15][CH2:16]1
Reactant: O=C=NSCl
Reactant: CCOC(=O)c1cc(F)c(F)cc1NC1CC1
Solvent: ClCCl
Product: O=c1[nH]c(=O)n(C2CC2)c2cc(F)c(F)cc12
Temperature: -20 °C
Yield: 38.2 %

Procedure:
To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid ethyl ester (Example 22) (5.0 g, 22.0 mmol) in dry dichloromethane (120 mL) under a N2 atmosphere is added chlorosulfanyl isocyanate (3.11 g, 22 mmol). The solution is reacted at room temperature for 4 hours, and the solvent is removed under reduced pressure. The residue is cooled to −20° C., and a cold brine solution (100 mL) buffered with NaHCO3 is added. The solution is warmed to room temperature for 1 hour. The volume is reduced by half with a stream of air, and the solid is collected by filtration. The dry solid is added to a solution of triethylamine (5 mL) in THF (250 mL) and refluxed overnight. The reaction is cooled, the solvent removed under reduced pressure, dissolved in water (100 mL), and acidified to pH 1–2 with 1.0 M hydrochloric acid. The resulting precipitate is collected via filtration to afford 2.0 g of the title compound. MS CI: m/z 239 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1.[Br:12]N1C(=O)CCC1=O>CN(C=O)C.C(Cl)Cl>[Br:12][C:10]1[CH:9]=[CH:8][C:7]2[N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCOc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCOc2cc(Br)ccc21
Temperature: 80 °C
Yield: 77.5 %

Procedure:
A mixture of the 104B (0.225 g, 1.51 mmol) and N-bromosuccinimide (0.269 g, 1.51 mmol) in DMF (10 mL) was heated at 80° C. overnight. The reaction mixture was dissolved in DCM and washed with water several times. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 0.267 g (78%) of 104C. HPLC retention time=3.32 min. (Condition B) and LC/MS M+1=230.03 (d). 1H-NMR (500 MHz, CDCl3) δ 2.83 (s, 3H), 3.22 (t, 2H), 4.26 (t, 2H), 6.49 (d, 1H, J=8.8 Hz), 6.87 (s, 1H), and 6.90 (d, 1H, J=8.8 Hz).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:59][C:60]1[CH:61]=[C:62]([CH2:68][NH2:69])[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]>ClCCl.CCOC(C)=O>[Br:59][C:60]1[CH:61]=[C:62]([CH2:68][NH:69][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Reactant: COc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (0.931 g, 2 mmol) was partially dissolved in the dichloromethane (DCM) (50 mL), and then HBTU (0.758 g, 2.000 mmol) was added followed sequentially by {[3-bromo-4-(methyloxy)phenyl]methyl}amine (0.432 g, 2.000 mmol) and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap to give the crude product. The residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL), 1× with brine, dried over anhydrous Na2SO4 filtered and the solvent concentrated. The residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by CombiFlash on an 80 g silica column eluted with 0-10% DCM/MeOH to give the title compound as a white solid. LC-MS m/z 663.0 (M+H)+, 0.91 min (ret time); mp 123-126° C.; analytical HPLC shows 97.6% purity, (ret time 13.411 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>CN(C)C=O>[Cl:16][C:17]1[N:22]=[C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.6 %

Procedure:
2-Amino-N,N-dimethyl-benzenesulfonamide (10.00 g, 49.94 mmol) in N,N-dimethylformamide (200 mL) was treated with sodium hydride 60% dispersion in mineral oil (3.99 g) at 0° C., then 2,4,5-trichloropyrimidine (8.587 mL, 74.90 mmol) was added and the reaction was stirred for 5 minutes at 0° C., then for 3 hours at room temperature. The reaction was quenched with aqueous saturated ammonium chloride, then water. The precipitate was collected by filtration and recrystallized from methanol to give 2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide as a light grey solid (9.3 g, 52%). LC/MS (ESI+): 346.93 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:9]([CH3:20])[C:10]([C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH3:20])[CH:10]([C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]1)[OH:11])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(C(=O)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C1(C(O)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.5 %

Procedure:
A solution of ethyl 1-[2-(dibenzylamino)propanoyl]cyclopropanecarboxylate (1.31 g) in methanol (60 mL) was cooled to 0° C., 90% sodium borohydride (350 mg) was added, and the mixture was stirred at room temperature for 17 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue s was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→1/1) to give the title compound as a colorless oil (yield: 1.31 g, 99%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:10]1(Br)[CH2:12][CH2:11]1.N12CCCN=C1CCCCC2>O>[CH:10]1([O:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH2:12][CH2:11]1
Reactant: N#Cc1cccc(O)c1
Reactant: BrC1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: N#Cc1cccc(OC2CC2)c1
Yield: 35.8 %

Procedure:
Irradiate (200 C, ˜6 W [150 W max.], ˜25 psi) a solution of 3-cyanophenol (9.5 g, 80 mmol), cyclopropyl bromide (8.0 mL; 100 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (18 mL, 120 mmol) divided equally into five 10-mL tubes for 15 min. with stirring and cooling. After cooling, take the dark reaction mixtures together in water (200 mL) and extracted with ether (200 mL). Wash the organic layer with 0.2 M aq NaOH (40 mL, salted), 0.2 M aq HCl (100 mL, salted), and water (100 mL, salted). Dry the organic layer (Na2SO4) and rotary evaporate (30° C.) yielding 3-cyclopropoxybenzonitrile (4.56 g, 28.65 mmol, 36% yield) as a dark brown liquid. GCMS: 4.20 min.; EIMS m/z 159.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([C:25](Cl)=[O:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C(=O)Cl)cccc4c3)ccc21
Reactant: C1COCCN1
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C(=O)N5CCOCC5)cccc4c3)ccc21
Yield: 70.6 %

Procedure:
Utilizing a procedure analogous to that of Example 16(b), 593 mg (1.5 mmol) of 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)naphthoyl chloride were reacted with 320 μl (3.6 mmol) of morpholine to provide 470 mg (70%) of the expected amide, having a melting point of 118°-20° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH:14](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:14]=[N:8][N:7]=2)[CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12]
Reactant: NNC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: CCOC(OCC)OCC
Product: Oc1c(Cl)cc(-c2nnco2)cc1Cl

Procedure:
A mixture of 8.9 g 3,5-dichloro-4-hydroxybenzoic acid hydrazide and 500 ml triethyl orthoformate was stirred and heated at reflux for 4 hrs. The solvent was removed in vacuo to afford the product (9.9 g) as a yellow solid, used directly in the next reaction.
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].C([CH:10]([CH2:15][CH2:16][CH2:17]C)[CH2:11][C:12]([OH:14])=[O:13])C.[N+]([O-])([O-])=O.[Co+2:23].[N+]([O-])([O-])=O>C1CCCCC1>[CH3:17][CH2:16][CH2:15][CH2:10][CH:11]([C:12]([O-:14])=[O:13])[CH2:1][CH3:2].[CH3:17][CH2:16][CH2:15][CH2:10][CH:11]([C:12]([O-:14])=[O:13])[CH2:1][CH3:2].[Co+2:23]
Reactant: CCCCC(CC)CC(=O)O
Reactant: CCN(CC)CC
Agent: [Co+2]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCCCC1
Product: CCCCC(CC)C(=O)[O-]
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
Using a 1 liter flask, 0.40 mol triethylamine is added with stirring at room temperature to 0.40 mol 2-ethyl hexane carboxylic acid. After the exothermic reaction has abated, the reaction mixture is diluted with 65 ml cyclohexane and 0.20 mol cobalt nitrate is added. After stirring for 30 minutes, the reaction solution is filtered, leaving a 55.5% blue cobalt octoate solution in cyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]Cl)=[O:4].[CH3:13][C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[S:18][C:14]=1[CH3:13]
Reactant: COC(=O)c1ccccc1SCl
Reactant: Cc1cc2ccccc2s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)c1ccccc1Sc1c(C)sc2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-(Methoxycarbonyl)phenyl sulfenyl chloride (10 mL 0.29 M solution in 1,2-dichloro-ethane, 2.9 mmol) is added to a solution of 2-methyl-benzo[b]thiophene (445 mg, 3mmol) in 5 mL 1,2-dichloro-ethane. The reaction mixture is cooled to 0° C. Aluminium chloride (400 mg, 3 mmol) is added and the reaction mixture is stirred for 4 hours at room temperature. The reaction is quenched with water. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography on silica gel using ethyl acetate-heptane as eluent. This furnishes 651 mg (69%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH2:16]([O:23][CH2:24][C@H:25]([C:27]([OH:29])=[O:28])[NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][CH2:24][C@@H:25]([NH:26][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:27]([OH:29])=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@H](COCc1ccccc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@H](COCc1ccccc1)C(=O)O
Yield: 34 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with O-benzyl-D-serine to provide the title compound in 34% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:5][N:4]=1.[CH2:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:14]([O:20][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:5][N:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCO
Reactant: Clc1nonc1-c1cccnc1
Agent: [Na]
Product: CCCCCCOc1nonc1-c1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of sodium (100 mg, 4.3 mmol) in 1-hexanol(10 ml) was added 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine (180 mg, 1 mmol). The mixture was stirred at 25° C. for 18 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:30][CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:30][CH2:31][CH2:32][CH2:33][S:34]([NH:29][C@H:26]1[CH2:27][CH2:28][C@@H:24]([C:21]2[N:20]3[C:15]4[CH:14]=[CH:13][N:12]([S:2]([C:5]5[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=5)(=[O:4])=[O:3])[C:16]=4[N:17]=[CH:18][C:19]3=[N:23][N:22]=2)[CH2:25]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](N)C4)n23)cc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](NS(=O)(=O)CCCCl)C4)n23)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a suspension of (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.05 g, 0.11 mmol, prepared using E from Preparation #B.1 and HCl) and TEA (0.03 mL, 0.21 mmol) in DCM (5 mL) at about 0° C. was added 3-chloropropane-1-sulfonyl chloride (0.02 g, 0.11 mmol) dropwise. The reaction mixture was stirred at about 0° C. for about 1.5 h. The reaction mixture was diluted with 5% aqueous citric acid (10 mL), and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give 3-chloro-N-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)propane-1-sulfonamide (0.052 g, 91%) as a brown residue: LC/MS (Table 1, Method a) Rt=2.18 min; MS m/z: 537 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12].[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3]2)=[O:21]
Reactant: CS(=O)(=O)NC1Cc2ccccc2C1
Reactant: O=C(Cl)CCCCCl
Product: CS(=O)(=O)NC1Cc2ccc(C(=O)CCCCCl)cc2C1

Procedure:
Using N-(2,3-dihydro-1H-inden-2-yl)methanesulfonamide and 5-chlorovaleryl chloride according to the same method as that of Example 1, the title compound was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[CH3:26][O:27][NH2:28]>>[CH3:26][O:27]/[N:28]=[C:22](/[C:19]1[N:20]=[C:21]2[N:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)[N:14]=[N:15][C:16]2=[N:17][CH:18]=1)\[CH3:23]
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reactant: CON
Agent: Cl
Product: CO/N=C(\C)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 70.2 %

Procedure:
The title compound (22.2 mg, 64%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (30.0 mg, 0.09 mmol) and O-methyl-hydroxylamine hydrochloride (78.0 mg, 0.93 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, CDCl3) δ ppm 9.45 (s, 1H), 8.92 (d, 1H), 8.08 (d, 1H), 7.81 (d, 1H), 7.78 (s, 1H), 7.39 (dd, 1H), 6.16 (s, 2H), 4.13 (s, 3H), 2.33 (s, 3H). LCMS (method E): [MH]+=352, tR=5.43 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.Cl>CO.O>[OH:17][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[N:7]=[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(O)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Temperature: 25 °C

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (0.0167 g, 0.1 mmol) and 3-aminophenol (0.033 g, 0.3 mmol) in MeOH: H2O (1.8:0.2 mL; v/v) was shaken in a sealed tube at 100° C. for 24 h (or 80° C. for 3 days), cooled to room temperature, diluted with water (15 mL), acidified with 2N HCl (pH>2). Upon saturation with sodium chloride it was extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate and solvent was removed. The resulting residue was filtered through a pad of silica gel (200-400 mesh) using CH2Cl2->1>10% MeOH in CH2Cl2 to obtain the desired N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R921218). If the reaction scale is large enough, solid of the resulting product can be isolated by filtration. 1H NMR (CDCl3): δ 7.73 (d, 1H, J=5.1 Hz), 7.12-6.90 (m, 6H), 6.64 (dd, 1H, J=1.8 and 8.1 Hz), 6.53 (dd, 1H, J=1.2 and 5.7 Hz); LCMS: ret. time: 16.12 min.; purity: 100%; MS (m/e): 313 (MH+).