Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=CC=1.C(C(=O)C(=NO)C)C.[F:29][C:30]([F:40])([F:39])C1C=CC=CC=1C=O>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:30]([F:40])([F:39])[F:29])[O:6][C:7]=1[CH2:8][CH3:13]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: CCC(=O)C(C)=NO
Product: CCc1oc(-c2ccccc2C(F)(F)F)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, 1-ethyl-1,2-propanedione-2-oxime and 2-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-ethyl-2-(2-trifluoromethylphenyl)oxazole.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([NH:15][C:16](=[O:22])[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][NH:7][C:8](=[O:14])[O:9][CH2:10][CH:11]([CH3:13])[CH3:12].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:30][S:31]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([NH:15][C:16]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:22])[CH2:6][NH:7][C:8]([O:9][CH2:10][CH:11]([CH3:12])[CH3:13])=[O:14])(=[O:33])=[O:32]
Reactant: CC(C)COC(=O)NC[C@H](CCCO)NC(=O)OCC(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)NC[C@H](CCCOS(C)(=O)=O)NC(=O)OCC(C)C
Temperature: -78 °C

Procedure:
A round bottom flask was charged with (S)-diisobutyl (5-hydroxypentane-1,2-diyl)dicarbamate (5.0 g, 15.7 mmol), CH2Cl2 (80 mL), and triethylamine (5.3 mL, 38 mmol), and cooled to −78° C. Methanesulfonyl chloride (2.3 mL, 30 mmol) was added dropwise with stirring and the cold bath was allowed to warm to 0° C. over the course of 5 h. Aqueous citric acid (20%, 140 mL) and CH2Cl2 (150 mL) were added and the phases were separated. The organic phase was washed with saturated NaHCO3 solution, and then dried on anhydrous Na2SO4. The solvent was removed by rotary evaporation and dried in oil pump vacuum. The product (S)-4,5-bis((isobutoxycarbonyl)amino)pentyl methanesulfonate was obtained as a yellowish white solid. The crude product was used without further purification in the next procedure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[Br:16]Br>C(Cl)(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>[Br:16][C:5]1[S:1][C:2]([C:6]2([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)C1(c2nccs2)CC1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1(c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.9 %

Procedure:
The product from Step 2 (860 mg, 3.82 mmol) was taken up in CHCl3 (19 mL) and placed in a cool water bath. NaHCO3 (353 mg, 4.20 mmol) was added, followed by bromine (1.22 g, 7.63 mmol). After stirring for 90 min at room temperature, the reaction was diluted with 10% Na2S2O3 and saturated NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-10% ether in hexanes) afforded tert-butyl 1-(5-bromo-1,3-thiazol-2-yl)cyclopropane-carboxylate (545 mg, 47%) as a colorless oil. MS ESI: [M-t-Bu]+ m/z 247.9/249.9.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][NH2:31])=[N:28][CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(#N)C>[CH3:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][NH:31][C:13]([C:10]2[CH:11]=[C:12]3[C:7]([CH:6]=[N:5][N:4]3[CH:1]([CH3:2])[CH3:3])=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH:9]=2)=[O:15])=[N:28][CH:29]=1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc3c2cnn3C(C)C)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc3c2cnn3C(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a solution of 1-isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (0.24 g, 0.814 mmol) in acetonitril was added C-(5-methyl-pyrazin-2-yl)-methylamine (0.12 g, 0.976 mmol), EDCI (0.23 g, 1.22 mmol), HOBt (0.16 g, 1.22 mmol), and NMM (0.45 mL, 4.07 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography gave 0.144 g (44%) of 1-isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide MS (M+H)=401.
Reaction SMILES: Cl.[C:2]([O:6][C@H:7]([CH3:19])[C@@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(N(CC)CC)C>ClCCl>[CH2:24]([O:23][C:21]([NH:9][C@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[C@@H:7]([CH3:19])[O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](OC(C)(C)C)[C@H](N)C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C#N
Yield: 100 %

Procedure:
A solution of (2S)-1-(O′-tert-butylthreoninyl)pyrrolidine-2-carbonitrile hydrochloride (35 mg, 0.12 mmol; prepared according to Jenkins et al., WO95/15309), benzyl chloroformate (32 mg, 0.13 mmol) and triethylamine (24 mg, 0.24 mmol) in dichloromethane (25 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant: chloroform:methanol; 98:2) yielding a white solid identified as the title compound (47 mg, 0.12 mmol, 100%).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])/[CH:20]=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:24])[CH:20]=[CH:21][CH2:22][OH:23])=[CH:25][CH:26]=1)[CH:11]=[N:10]2
Reactant: CC(/C=C/CO)Oc1ccc(O)cc1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C=CCO)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.99 g (10 mmol) of 2,6-dichloroquinoxaline, 2.13 g (11 mmol) of (E)-4-(4-hydroxyphenoxy)-2-penten-1-ol, 1.73 g (12.5 mmol) of powdered, anhydrous potassium carbonate and 50 ml of dry acetonitrile was warmed at reflux under nitrogen for a period of 3 hours. The mixture was cooled to room temperature, and the solid filtered off and washed well with ether. The filtrates were combined and evaporated to dryness, and the residue partitioned between ether and 2 percent aqueous sodium hydroxide. The aqueous layer was separated and extracted again with ether. The combined organic layers were washed with water, dried over MgSO4 and evaporated to dryness. The residual solid was purified by preparative scale HPLC, eluting with 7:3 hexane:ethyl acetate, to give a solid which was recrystallized from toluene. This gave 2.60 g (73%) of the desired pentenol as pale yellow crystals, having a melting point (m.p.) of 124°-126° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:10]1[C:15]([CH3:16])=[N:14][CH:13]=[C:12]([CH3:17])[N:11]=1>CC(O)C>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:10]2[C:15]([CH3:16])=[N:14][CH:13]=[C:12]([CH3:17])[N:11]=2)[N:8]=[CH:7]1
Reactant: NCCc1c[nH]cn1
Reactant: Cc1cnc(C)c(Cl)n1
Solvent: CC(C)O
Product: Cc1cnc(C)c(NCCc2c[nH]cn2)n1

Procedure:
1 g (8.9 mmol) of histamine and 1.28 g (8.9 mmol) of 2-chloro-3,6-dimethylpyrazine in 10 ml of 2-propanol are brought to reflux for 3 days, evaporated and the residue is chromatographed on a column of silica gel, using mixtures of chloroform and methanol (1, 10 and 20% respectively) to give the title compound in the form of an oil. The latter is converted to a monohydrated dioxalate salt which is crystallized from an isopropanol/ether (1/1) mixture. M.p.: 164°-165° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C1Cc2cc(-c3cccc(Cl)c3)ccc2N1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of the 5-bromoxindole (0.5 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol) in dimethoxyethane (10 cm3) was stirred under N2 for 20 min. To this mixture was then added 3-chlorophenylboronic acid (0.44 g, 2.83 mmol) and sodium carbonate (0.75 g, 7.1 mmol) in water (4 cm3). The solution was brought to reflux for 6 h then cooled to RT, poured into water and extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane 1:3) to afford the title compound (0.49 g, 2.0 mmol, 86%) as a tan solid: m.p. 169-171° C., 1H NMR (THF-d8) δ 3.45 (s, 2H), 6.85 (d, 1H J=8.1 Hz), 7.25 (d, J=8.0 Hz, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.50 (s, 1H), 7.59 (dd, J=1.78, 1.78 Hz, 1H), 9.5 (br s, 1H); 13C NMR (THF-d8) δ 36.39 (t), 109.80, 123.97, 125.55, 127.19 (d), 127.68 (s), 130.89 (d), 133.73, 135.29, 144.23, 145.09, 176.45 (s); MS (EI) m/z 243, 245 (M)+; Anal. (C14H10ClNO) C, H, N.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([CH:15]([CH2:18][CH3:19])[CH2:16][NH2:17])[CH3:14]>>[CH2:13]([CH:15]([CH2:18][CH3:19])[CH2:16][NH:17][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:14]
Reactant: CCC(CC)CN
Reactant: CCOC(=O)c1cccnc1Cl
Product: CCOC(=O)c1cccnc1NCC(CC)CC
Yield: 76.3 %

Procedure:
Ethyl 2-chloronicotinate (0.646 g, 3.48 mmol) and 2-ethylbutylamine (0.74 g, 7.31 mmol) were reacted in a sealed tube at 130° C. for 2 hours. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×50 mL). The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (19:1) to provide the title compound (0.665 g, 76%). MS (ESI+) m/z 251.1 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 0.93 (t, J=7.54 Hz, 6H), 1.41 (m, 7H), 1.55 (m, 1H), 3.46 (m, 2H), 4.32 (q, J=6.99 Hz, 2H), 6.48 (dd, J=7.72, 4.78 Hz, 1H), 7.99 (s, 1H), 8.11 (dd, J=7.72, 2.21 Hz, 1H), 8.27 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:22]([N:24]=C=O)=[O:23].[OH-].[Na+]>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:16][C:22]([NH2:24])=[O:23])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cccc(N)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)aniline (5.16 g) in dry DCM (50 ml) was treated dropwise with a solution of trichloroacetyl isocyanate (2.36 ml) in dry DCM (6 ml) over 10 min. The reaction mixture was stirred at room temperature for 10 min prior to addition of 2M NaOH (50 ml). The reaction mixture was stirred at 70° C. for 5 h and room temperature for 16 h. The aqueous phase was extracted with DCM and the combined organic layers washed with water and concentrated in vacuo. The residue was purified by chromatography (biotage, EtOAc-Petrol 2:1) to give the title compound. LCMS RT=3.78 min.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[O:12][CH2:13][CH2:14][O:15][C:5]=3[C:4]=2[N:3]1[CH2:16][CH:17]=O.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.CO>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[O:12][CH2:13][CH2:14][O:15][C:5]=3[C:4]=2[N:3]1[CH2:16][CH2:17][N:19]1[CH2:20][CH2:21][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2ccc3c(c21)OCCO3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc4c(c32)OCCO4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
(9-oxo-2,3-dihydro[1,4]dioxino[2,3-h]quinolin-10(9H)-yl)acetaldehyde (1.5 g; 6.12 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (1.84 g; 9.18 mmol) were dissolved in a 1:1 mixture of chloroform and MeOH (50 ml:50 ml) and stirred at rt for 30 mins. NaBH(OAc)3 (5.81 g; 27.54 mmol) was added and the reaction left overnight. The solvents were then removed and the residues purified by column chromatography on silica gel using a 0-12% MeOH/DCM gradient to give the desired product (1 g; 38%).
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].[F:13][C:14]([F:30])([F:29])[C:15]1[N:20]=[C:19]([N:21]2[CH2:28][CH2:27][C:24]3([O:26][CH2:25]3)[CH2:23][CH2:22]2)[CH:18]=[CH:17][N:16]=1>CN(C=O)C>[OH:26][C:24]1([CH2:25][N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:27][CH2:28][N:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:14]([F:30])([F:29])[F:13])[N:20]=2)[CH2:22][CH2:23]1
Reactant: O=C1CCCN1
Reactant: FC(F)(F)c1nccc(N2CCC3(CC2)CO3)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCN1CC1(O)CCN(c2ccnc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 15.1 %

Procedure:
Potassium tert-butoxide (1.03 g, 9 mmol) was added to a solution of 2-pyrrolidinone (0.7 g, 7.7 mmol) in anhydrous DMF (25 mL). The mixture was stirred for 45 min at room temperature to produce a milky white precipitate. A solution of XXIX (2.0 g, 7.7 mmol) in dry DMF (6 mL) was then added and the mixture slowly turned clear as it was stirred for 18 hr. The mixture was concentrated in vacuo and the residue chromatographed on neutral alumina using ethyl acetate as the eluent to give the white solid product (0.40 g, 35%, mp: 170°-172° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([Cl:20])[C:17]([S:21][CH3:22])=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:15]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[Na+].C1COCC1>O>[Cl:20][C:18]1[C:17]([S:21][CH3:22])=[C:16]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([N:7]3[CH2:2][CH2:3][NH:4][C:5]3=[O:6])=[CH:9][CH:10]=2)[N:19]=1
Reactant: CSc1c(Cl)nc(-c2ccc(NC(=O)NCCCl)cc2)nc1N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1c(Cl)nc(-c2ccc(N3CCNC3=O)cc2)nc1N1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2-chloro-ethyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea (20 mg, 0.045 mmol.), 10% NaOH (0.5 ml), THF (2.0 ml), and H2O (1.0 ml) was added to a vessel. The reaction mixture was stirred at 80° C. for 8 hr and then dried, and the solvent was evaporated. The reaction mixture was partitioned between EA and 0.1N HCl, the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 3:1) to give a gray solid of 11.4 mg (62.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:28]([O-:30])=[O:29].[Na+].C(OC(=O)C)(=O)C.N>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[C:23]([N+:28]([O-:30])=[O:29])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reactant: O=N[O-]
Agent: N
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3c([N+](=O)[O-])nccc23)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of the isoquinoline from step A (1.17 g, 3.0 mmol) in anhydrous DMSO (12 mL) was added sodium nitrite (1.24 g, 18 mmol). To the mixture was added slowly over 30 min a solution of acetic anhydride (1.84 g, 18 mmol) in anhydrous DMSO (12 mL). The mixture was stirred overnight and TLC showed most starting material remained. More sodium nitrite (1.24 g, 18 mmol) and acetic anhydride (1.84 g, 18 mmol) in anhydrous DMSO (12 mL) was added and stirring was continued for about 1 h. During this period yellow solid precipitated and TLC showed a new product at Rf 0.5 (hexane/EtOAc 1:1). The mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with EtOAc (100 mL×2). Chromatography on silica eluting with 20% EtOAc/Hexane gave an oil. (0.81 g, 62%). LCMS (+APCI) m/z 454 (M+H+NH3).
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([CH:20]([NH2:22])[CH3:21])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[CH:35]=[C:34]([CH:36]3[CH2:38][CH2:37]3)[NH:33][N:32]=2)[CH:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC(C(O)C(C)C)C>[CH:36]1([C:34]2[NH:33][N:32]=[C:31]([NH:30][C:28]3[CH:27]=[CH:26][N:25]=[C:24]([NH:22][CH:20]([C:15]4[C:14]5[CH:13]=[CH:12][N:11]([S:1]([C:4]6[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=6)(=[O:3])=[O:2])[C:19]=5[CH:18]=[CH:17][N:16]=4)[CH3:21])[N:29]=3)[CH:35]=2)[CH2:38][CH2:37]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)N)nccc32)cc1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: CC(C)C(O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)nccc32)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 51.6 %

Procedure:
A mixture of (±)-1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanamine (referential example 11) (800 mg, 2.54 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-pyrimidin-4-amine (500 mg, 2.12 mmol), and DIPEA (820 mg, 6.36 mmol) in 2,4-dimethylpentan-3-ol (10 mL) in a sealed tube under nitrogen was stirred at 140° C. for 18 h. The crude product was purified by preparative HPLC to afford 563 mg (51.7%) of (±)—N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethyl)pyrimidine-2,4-diamine as a yellow solid (563 mg, 51.7%): MS (ESI) m/z: 515.2 [M+1]+
Reaction SMILES: C([C:3]1[C:8]([C:9]([NH2:11])=[O:10])=[C:7](CC)[C:6]([OH:14])=[CH:5][C:4]=1[OH:15])C.[H-].[Na+].[N+:18]([C:21]1[CH:26]=[C:25]([S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1Cl)([O-:20])=[O:19]>C1COCC1>[N+:18]([C:21]1[CH:26]=[C:25]([S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[O:14][C:6]1[CH:7]=[C:8]([CH:3]=[C:4]([O:15][C:22]2[CH:23]=[CH:24][C:25]([S:27]([C:30]([F:32])([F:33])[F:31])(=[O:29])=[O:28])=[CH:26][C:21]=2[N+:18]([O-:20])=[O:19])[CH:5]=1)[C:9]([NH2:11])=[O:10])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: CCc1c(O)cc(O)c(CC)c1C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl 3,5-dihydroxybenzamide (100 mg, 0.6553 mmol) in THF was added sodium hydride (60 mg of 60% dispersion in mineral oil) followed by 2-nitro-4-(trifluoromethylsulfonyl) chlorobenzene (378 mg, 1.306 mmol). The mixture was stirred at room temperature for overnight. The reaction was extracted with ethyl acetate, the organic layer was washed with water and brine, dried, concentrated and purified to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.32 (br s, 1H, NH), 10.58 (br s, 1H, NH), 8.78 (d, J=2.2 Hz, 1H), 8.57 (br s, 1H), 8.47 (br d, 1H), 8.33 (dd, J=2.2 & 8.8 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.35 (m, 2H), 7.01 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:3]1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:47])([F:46])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:34][CH:33]=1.CN(P(N(C)C)(N(C)C)=O)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:11]([O:10][C:8]([N:6]1[C@@H:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:3][C:2](=[O:1])[C@H:7]1[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([F:46])([F:47])[C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])=[CH:36][CH:37]=1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)C(F)(F)c1ccc(CBr)cc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(F)(F)c1ccc(C[C@@H]2C(=O)O[C@H](c3ccccc3)[C@H](c3ccccc3)N2C(=O)OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution at −78° C. of benzyl (2R, 3S)-(−)-6 oxo-2,3 diphenyl-4 morpholine carboxylate (10.5 g) and tert butyl 2-{4-(bromomethyl)phenyl}-2,2-difluoroacetate (6.2 g) and HMPA 55 mL in THF 550 ml. was added LiHMDS (28 mL, 1 M in THF) over a period of 1 hour 20 minutes. The reaction mixture was stirred further at −78° C. for 1 hour.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH2:11]([N:13]([CH2:16][C:17]1[S:21][C:20]2=[N:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:24][N:19]2[N:18]=1)[CH2:14][CH3:15])[CH3:12].[OH-].[Na+]>O>[CH2:11]([N:13]([CH2:16][C:17]1[S:21][C:20]2=[N:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:24]([CH:8]=[O:9])[N:19]2[N:18]=1)[CH2:14][CH3:15])[CH3:12]
Reactant: CCN(CC)Cc1nn2cc(-c3ccccc3)nc2s1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCN(CC)Cc1nn2c(C=O)c(-c3ccccc3)nc2s1
Temperature: 100 °C

Procedure:
2.3 ml (0.025 mol) of phosphorus oxychloride are added dropwise to 20 ml of dimethylformamide at 0°-5° C. 5.7 g (0.02 mol) of 2-diethylaminomethyl-6-phenyl-imidazo-[2,1-b]-1,3,4-thiadiazole are then added and the mixture is warmed at 100° C. for 2 hours. After cooling, 50 ml of water are added and the mixture is neutralised with 20% strength sodium hydroxide solution and extracted with ether.