Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
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: C1COCCO1
Product: C[C@@H](Oc1nc(-c2ccncc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 150 °C
Yield: 52.3 %

Procedure:
Into a microwave reaction vial, a mixture of (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (100.0 mg, 0.27 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (168.4 mg, 0.82 mmol), sodium carbonate (116.0 mg, 1.10 mmol) and Pd(PPh3)4 (31.6 mg, 0.027 mmol) were placed in dioxane (4 mL) and water (1 mL). The reaction mixture was placed in the microwave reactor and heated at 150° C. for 30 min. Then, it was filtered through a pad of Celite and partitioned between EtOAc (2×30 mL) and brine (2×10 mL). The combined organic layers were washed with water (2×5 mL), concentrated, and purified by flash chromatography (100% EtOAc to 20% MeOH in EtOAc) to give 52.0 mg (52.3%) of (R)-4-((R)-1-((3-cyclopropyl-6-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (dd, J=1.8, 1.2 Hz, 2H), 8.162 (s, 1H), 7.896-7.863 (m, 3H), 7.383 (s, 1H), 5.438-5.398 (m, 1H), 3.551-3.492 (m, 1H), 3.22 (t, J=9.5 Hz, 1H), 3.03 (dd, J=6.6, 6.6 Hz, 1H), 2.701-2.633 (m, 1H), 2.15 (dd, J=2.3, 1.7 Hz, 2H), 1.24 (d, J=6.5 Hz, 3H), 1.0-0.828 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd C20H21N5O2: 363.17; found 364.14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21]Cl.[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[C:29]([OH:33])=[CH:30][CH:31]=[CH:32][C:26]=2[CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:23][C:24]1([CH3:34])[O:28][C:27]2[C:29]([O:33][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:3]3[C:4]([Cl:16])=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:7][C:2]=3[Cl:1])=[CH:30][CH:31]=[CH:32][C:26]=2[CH2:25]1
Reactant: ClCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: CC1(C)Cc2cccc(O)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)c2O1
Yield: 63.7 %

Procedure:
A stirred solution of 1.0 gram (0.0028 mole) of 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene, 0.6 gram (0.0034 mole) of 2,2-dimethyl-2,3-dihydrobenzo[b]furan-7-ol (known compound), and 0.6 gram (0.0043 mole) of potassium carbonate in 25 mL of DMF was heated at 80° C. for about 18 hours. After this time, the reaction mixture was cooled and 50 mL of water was added. The mixture was then extracted with three 25 mL portions of diethyl ether. The combined extracts were washed with 25 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using mixtures of 1:3 methylene chloride:hexane and 1:1 methylene chloride:hexane as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.87 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][O:17][C:16](=[O:19])[NH:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH2:8][CH2:9]Cl)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:27][C:28]1[C:36]2[C:31](=[N:32][CH:33]=[N:34][C:35]=2[NH2:37])[NH:30][N:29]=1>CN(C)C=O.O>[NH2:37][C:35]1[N:34]=[CH:33][N:32]=[C:31]2[N:30]([CH:8]([C:6]3[C:5]([O:11][CH2:12][CH3:13])=[C:4]([CH:14]4[CH2:18][O:17][C:16](=[O:19])[NH:15]4)[C:3]([F:20])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:29]=[C:28]([CH3:27])[C:36]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: CCOc1c(CCCl)cc(Cl)c(F)c1C1COC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1COC(=O)N1
Temperature: 80 °C

Procedure:
4-[3-chloro-5-(chloroethyl)-6-ethoxy-2-fluorophenyl]-1,3-oxazolidin-2-one (160 mg, 0.50 mmol) (from Step 11) was stirred in N,N-dimethylformamide (21 mL) with cesium carbonate (324 mg, 0.99 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (89 mg, 0.60 mmol) was added. The mixture was heated to 80° C. for 1.5 hours and cooled to rt. The mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by preparative LCMS (pH 10) using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) separated the two diastereomers (peak 1 [compound 353] Rt=4.9 min. and peak 2 [compound 354] Rt=5.6 min.); providing compound 354 as the desired single enantiomer, 28 mg, 13%. peak 2: LCMS calculated for C19H21ClFN6O3 (M+H)+: m/z=435.1; found: 435.1. 1H NMR (300 MHz, CD3OD): δ 8.15 (s, 1 H), 7.62 (m, 1 H), 6.31 (m, 1 H), 5.39 (m, 1 H), 4.79 (m, 1 H), 4.40 (m, 1 H), 3.95 (m, 1 H), 3.80 (m, 1 H), 2.60 (s, 3 H), 1.80 (m, 3 H), 1.40 (m, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[NH:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>ClCCl.O>[CH2:34]([O:33][C:31]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[NH:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:4][CH:3]=1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
To a solution of (3aR*,10aS*)-9-(4-aminobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (3.64 g, 12 mmol) in dichloromethane (15 mL) was added a solution of sodium carbonate (1.88 g, 18 mmol) in water (15 mL) at 0° C. To this mixture was added benzyl chloroformate (2.0 mL, 14 mmol) at the same temperature and the mixture was stirred at 0° C. for 15 minutes. Upon phase separation, the aqueous layer was extracted with dichloromethane and the pooled organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to provide 4.18 g (yield 79%) of the title compound. m.p. 161.7°-162.5° C.
Reaction SMILES: ClC1C=[C:4](C=CC=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8].[C:27]([O:31][C:32](=[O:44])[N:33](CCN)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:44])[N:33]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:4][CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(NCc1cccc(Cl)c1)c1occc1Nc1ncnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N(CCN)Cc1ccccc1
Product: CC(C)(C)OC(=O)N(CCNC(=O)c1occc1Nc1ncnc2[nH]ccc12)Cc1ccccc1
Yield: 8 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-furan-2-carboxylic acid 3-chloro-benzylamide using (2-aminoethyl)-benzyl carbamic acid tert-butyl ester instead of 3-chlorobenzylamine and obtained in 8% yield (HPLC: 90%, RT: 6.60 min). 1H NMR (DMSO-d6) 11.99 (br s, 1H), 9.80 (br s, 1H), 8.44 (br s, 1H), 8.38 (s, 1H), 7.80 (br s, 1H), 7.71 (br s, 1H), 7.37 (dd, J=3.3, 2.6 Hz, 1H), 7.33 (d, J=7.3 Hz, 2H), 7.28-7.21 (m, 3H), 6.42 (br s, 1H), 4.44 (s, 2H), 3.40 (br s, 2H), 1.34 (s, 9H); MS (m/z) 477 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])(=[O:7])=[O:6].[OH-:26].[K+]>O1CCOCC1.O>[F:16][C:11]1[C:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[C:9]([NH:8][S:5]([CH2:4][CH2:3][CH2:2][OH:26])(=[O:7])=[O:6])[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: O=S(=O)(CCCCl)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: [OH-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(CCCO)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
To a solution of 3-chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-propane-1-sulfonamide (69.4 mg, 0.138 mmol) in a mixture of 8 ml 1,4-dioxane and 2 ml H2O was added KOH powder (0.674 g, 12.0 mmol) and the mixture was heated to the reflux temperature for 3 days. It was extracted using EtOAc/brine, the organic fraction was dried with Na2SO4 and the volatiles were removed. The residue was purified using flash-column chromatography (Si, DCM/MeOH 5:1, Rf=0.3). Yield: 41 mg (62%). 1H-NMR (500 MHz, MeOH [d4]): δ=7.38-7.21 (d, 1H), 7.23-7.21 (d, 1H), 7.06-7.00 (q, 1H), 6.52-6.50 (m, 1H), 6.17-6.13 (t, 1H), 3.30-3.27 (t, 2H), 2.86-2.83 (t, 2H), 2.05-2.00 (m, 2H); m/z=485 [M−1]−.
Reaction SMILES: OC1C=CC(C2OCCN=2)=CC=1.[Cl:13][C:14]1[S:15][C:16]([C:19](=O)[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[O:32][CH2:33][CH2:34][N:35]=3)=[CH:27][CH:26]=2)=[CH:17][CH:18]=1>>[Cl:13][C:14]1[S:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[O:32][CH2:33][CH2:34][N:35]=3)=[CH:27][CH:26]=2)=[CH:17][CH:18]=1
Reactant: O=C(CCCCOc1ccc(C2=NCCO2)cc1)c1ccc(Cl)s1
Agent: Oc1ccc(C2=NCCO2)cc1
Product: Clc1ccc(CCCCCOc2ccc(C3=NCCO3)cc2)s1

Procedure:
A solution of 2-chloro-5-(5-chloropentanoyl)thiophene (3c) (1.18 g, 0.005 mol) and aluminum trichloride (0.66 g, 0.005 mol) in anhydrous ethyl ether (40 ml) and tetrahydrofuran (30 ml) was slowly added to a mixture, cooled to 0°-5° C., consisting of lithium and aluminium hydride (1.33 g, 0.01 mol) in anhydrous ethyl ether (40 ml). The reaction mixture was magnetically stirred for 6 hrs. at 30°-40° C., cooled to 0°-5° C., and cautiously diluted with water (20 ml) and 6N hydrogen sulphate (20 ml). The organic phase was separated, washed with water, and dried on anhydrous sodium sulphate. Solvent removal gave a chromatographically pure liquid residue (TCL: silicon dioxide-cyclohexane) consisting of 7 (0.99 g; 89%), which was directly used in the subsequent reaction with 2-(4-hydroxyphenyl)-4,5-dihydro-oxazole, as described for the preparation of 4c, to give 9 (0.81 g; 52%) (after crystallization via cycloexane). M.p. 99°-100° C. Anal. (C18H20ClNO2S).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH:14]=[N:15]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]#[N:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C=NO)o2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COc1ccc(-c2ccc(C#N)o2)cc1
Temperature: 25 °C

Procedure:
A 500 ml three-necked flask equipped with stirrer, thermometer and reflux condenser was charged with 5-(p-methoxyphenyl)-2-furaldehyde oxime (28 g, 0.129 mole) and acetic anhydride (317 ml). This mixture was refluxed (138°) for 3 hours. After cooling to room temperature overnight, the green solution was poured into ice water (ca. 2l. ) with stirring. When the ice melted, the solid was collected by filtration, washed with water, and dried to give 26 g.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:34])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:15]3[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].C(O)(C(F)(F)F)=O.C(O)(C)C.C(=O)([O-])[O-]>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[C:15]3[CH2:20][NH:19][CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)=[O:34])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)OC(C)(C)C)C3)cc1
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step 3—Synthesis of d: tert-butyl 2-(4-(3-ethylureido)phenyl)-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (c, 1.74 mmol) was dissolved in dichloromethane (5 mL), then TFA (3 mL) was added. The mixture was stirred at room temperature for 2 hours. Isopropanol and toluene were added and the resulting mixture was concentrated in vacuo. The resulting residue was azeotroped with toluene two more times. Methanol and methylene chloride (4 mL each) were added to the resulting residue, then PS-carbonate (2.5-3.5 mmol N/gram resin, 1.45 g) was added. The mixture was stirred at room temperature until the pH reached >7 (˜1 hr). The mixture was filtered, the resin was washed with methanol and dichloromethane. The filtrate was concentrated to provide 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea as a free amine, which was used in the next step. An aliquot was purified by reverse-phase HPLC to give the pure desired product: 1H NMR (400 MHz, DMSO) δ 9.57 (s, 1H), 8.75 (s, 1H), 8.19 (d, J=8.9, 2H), 7.50 (d, J=8.9, 2H), 6.38-6.08 (m, 1H), 4.71 (s, 2H), 4.38 (s, 2H), 3.72 (s, 8H), 3.24-3.03 (m, 2H), 1.06 (t, J=7.2, 3H); LC-MS: m/z=+369 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.N([O-])=O.[Na+].[CH3:13][N:14]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]1=[O:20].C(=O)(O)[O-].[Na+].N1C(C)=CC=CC=1C>Cl.O.CC(C)=O.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:16]2[C:15]([N:14]([CH3:13])[C:18](=[O:19])[CH:17]=2)=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: CN1C(=O)C=CC1=O
Reactant: Nc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CN1C(=O)C=C(c2cccc(Br)c2)C1=O
Reaction time: 72 h

Procedure:
An 86 g portion of m-bromoaniline was dissolved in a mixture of 150 ml of 12N hydrochloric acid and 100 ml of water, cooled in an ice-salt bath. A 100 g portion of ice was added, followed by a solution of 34.5 g of sodium nitrite in 80 ml of water, added dropwise over 45 minutes. A solution of 55.5 g of N-methylmaleimide and 12.5 g of cupric chloride dihydrate in 700 ml of acetone was then added slowly over 40 minutes, while maintaining the temperature between 10° C. and 15° C. A 56 g portion of sodium bicarbonate was added to achieve pH 2.6. The mixture was allowed to stand for 72 hours, and the resultant oil was extracted with 300 ml of chloroform. This solution was filtered through magnesium silicate. The filtrate was evaporated in vacuo and gave a crude crystalline product. The crude product was combined with 58 ml of 2,6-lutidine and 600 ml of isopropyl alcohol and heated on a steam bath for 1/2 hour. The reaction mixture was poured into 1.25 liters of water and allowed to stand at room temperature for 18 hours. The crystalline product was collected, washed with water, air dried, and then recrystallized from 500 ml of acetonitrile to give 62.5 g of 2-(m-bromophenyl)-N-methylmaleimide.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:18][C:19]#[N:20]>CN(C=O)C>[O:6]=[C:2]1[NH:3][CH2:4][CH2:5][N:1]1[CH2:18][C:19]#[N:20]
Reactant: O=C1NCCN1
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#CCN1CCNC1=O
Temperature: 45 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
A solution of imidazolidin-2-one (0.75 g, 8.71 mmol) in DMF (17 mL) was treated drop-wise with LiHMDS (1M THF, 10.45 mL, 10.45 mmol), stirred for 2 h, treated with bromoacetonitrile (0.607 mL, 8.71 mmol) and heated at 45° C. overnight. The mixture was cooled to RT, treated with satd. NH4Cl, extracted with EtOAc (4×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 2-(2-oxoimidazolidin-1-yl)acetonitrile (65 mg, 6%). 1H NMR (400 MHz, DMSO-d6): δ 6.38 (s, 1 H), 4.66 (s, 2 H), 3.98-3.93 (m, 2H), 3.91-3.86 (m, 2H); MS (ESI) m/z: 126.1 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[C:29]([CH3:33])=[N:28]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:32][C:30]3[C:29]([CH3:33])=[N:28][N:27]([CH3:26])[CH:31]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cc1nn(C)cc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nn(C)cc1Nc1cnc2c(n1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Temperature: 150 °C
Yield: 55.3 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol), 1,3-dimethyl-1H-pyrazol-4-amine (58.5 mg, 526 μmol), xantphos (60.9 mg, 105 μmol), Pd2(dba)3 (32.1 mg, 35.1 μmol) and cesium carbonate (229 mg, 702 μmol) in dioxane (2 mL) was heated in a microwave at 150° C. for 20 min. The mixture was cooled then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, 25-100% ethyl acetate in hexanes) lo give N-tert-butyl-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (89 mg, 194 μmol, 55%) as a yellow gum. (EI/CI) m/z: 458.3 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.ClC1C=C(SC2N(CC(F)(F)F)C(CO)=[N:36]C=2C(C)C)C=C(Cl)C=1>>[NH2:36][CH2:2][C:3]1[N:4]([CH2:20][C:21]([F:22])([F:24])[F:23])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1
Reactant: CC(C)c1nc(CCl)n(CC(F)(F)F)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1nc(CO)n(CC(F)(F)F)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CN)n(CC(F)(F)F)c1Sc1cc(Cl)cc(Cl)c1

Procedure:
2-Chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(2,2,2-trifluoroethyl)-1H-imidazole (28k)was synthesized from [5-(3,5-dichlorophenylthio)-4-isopropyl-1-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl]methanol (Compound I-33)by the same synthetic process as that for (28a)in Example 66, and without purification of this compound, 2-azidomethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(2,2,2-trifluoroethyl)-1H-imidazole (29k)was obtained by the same synthetic process as that for (29a)in Example 66. Oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=O)=[CH:15][CH:14]=1)([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+]>>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]2[NH:9][C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[CH:7][C:6]=3[N:8]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(N)c(N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1
Temperature: 180 °C
Yield: 42.3 %

Procedure:
2,4,5 Triaminopyridine (6, 0.660 g, 5.32 mmol), p-nitro benzoic acid (7, 0.888 mg 5.32 mmol) was taken in PPA (30 g) and heated at 180° C. for 7 h. The reaction mixture was cooled to room temperature and poured on to crushed ice. The excess PPA was neutralized carefully by addition of solid K2CO3 portion wise (caution) till effervescence ceased. The brownish green precipitate was filtered and washed with water and dried. The solid was taken in (CH2Cl2: MeOH:THF:NH4OH 50:30:17:3) mixture and filtered (repeated the process 3-4 times). The solvents were removed and the nitro amine precipitated with EtOAc to give 8 (0.575 g, 56%). 1H NMR (DMSO-d6; 500 MHz): δ11.10 (1H, brs), 8.77 (1H, s), 8.45-8.25 (4H m), 6.50 (1H, s), 5.67 (2H, brs); EIMS m/z: 256.4 (M+1) and 290 (M+Cl−);
Reaction SMILES: C[C:2]1[C:3](=[O:20])N[C:5]2[C:10]([N:11]=1)=[CH:9][C:8](OCCCCC(O)=O)=[CH:7][CH:6]=2.[CH2:21]([C:23]1[C:24](=[O:41])[NH:25][C:26]2[C:31]([N:32]=1)=[CH:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=O)=[CH:28][CH:27]=2)[CH3:22]>>[CH2:21]([C:23]1[C:24](=[O:41])[NH:25][C:26]2[C:31]([N:32]=1)=[CH:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:11]([CH:10]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH2:2][CH2:3][OH:20])=[O:40])=[CH:28][CH:27]=2)[CH3:22]
Reactant: Cc1nc2cc(OCCCCC(=O)O)ccc2[nH]c1=O
Reactant: CCc1nc2cc(OCCCCC(=O)O)ccc2[nH]c1=O
Product: CCc1nc2cc(OCCCCC(=O)N(CCO)C3CCCCC3)ccc2[nH]c1=O
Yield: 47.2 %

Procedure:
In Example 70 the compound 1037 was replaced by compound 1013 to obtain the compound 1015.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12](=[O:17])[CH:11]=[C:10]2[OH:18])[CH3:6]>C(Cl)(Cl)Cl>[CH2:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12](=[O:17])[C:11]([N+:1]([O-:4])=[O:2])=[C:10]2[OH:18])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc2oc(=O)cc(O)c2c1
Solvent: ClC(Cl)Cl
Product: CCc1ccc2oc(=O)c([N+](=O)[O-])c(O)c2c1

Procedure:
Fuming nitric acid (33 ml) was added to a stirred suspension of 6-ethyl-4-hydroxycoumarin (m.p. 216°-8°; 5.52g) in chloroform (500 ml) at room temperature over 1 hour. After standing for a further hour, the solvent was removed in vacuo at room temperature and 6N hydrochloric acid (100 ml) added to the residue. Filtration gave the product m.p. 114°-5°, (C11H9NO5 requires C, 56.17; H, 3.86 N, 5.96. Found: C, 55.86; H, 3.80; N, 5.86). Recrystallisation from benzene-petroleum ether (b.p. 40°-60°) raised the melting point to 117°-9°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.CN(C)C=O.[CH2:27]([OH:30])[C:28]#[CH:29]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]#[C:28][CH2:27][OH:30]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#CCO
Temperature: 70 °C

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (200 mg, the compound of Example A1) in triethylamine (2 ml) and dimethylformamide (1 ml) at room temperature was added propargyl alcohol (0.2 ml), cuprous iodide (10 mg) and bis(triphenylphosphine)palladium(II) chloride (20 mg). The reaction mixture was heated at 70° C. for two hours. The reaction mixture was partitioned between ether (10 ml) and water (10 ml). The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with ether:dichloromethane (10:1) to provide the title compound as a pale yellow solid m.p. 237-9° C.