Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:50][CH:51]1[CH2:54][NH:53][CH2:52]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:53]3[CH2:54][CH:51]([OH:50])[CH2:52]3)[CH:32]=[CH:31][CH:30]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2nc(-c3ccc(C(C)(C)C(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Product: Cc1cc(-c2nc(-c3ccc(C(C)(C)C(F)(F)F)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1

Procedure:
Analogously to the process described in Example 1, 150 mg (0.297 mmol) of the compound from Example 3A and 139 mg (0.445 mmol) of the compound from Example 8A were used to obtain 68 mg (46% of theory) of the title compound. The reaction time in the first component step of the process here was 1 h. The crude product was purified by means of preparative HPLC (method 13). The free base was obtained from the resulting formate salt of the title compound by percolation of a methanolic solution of the salt through a hydrogencarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol). The final purification was effected by extractive stirring in a mixture of 3 ml of pentane and a few drops of diisopropyl ether.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1F>CS(C)=O.C(OCC)C>[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1[O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OC2CCCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cylcohexanol (2.9 g) in dimethylsulfoxide (20 mL) is added slowly to a flask containing potassium hydride (0.90 g, pre-washed three times with hexanes) under an atmosphere of argon and the solution is stirred for about 1 hour at room temperature. A solution of 3-chloro-4-fluoro-nitrobenzene (1 g) in dimethylsulfoxide (10 mL) is added and the resulting dark red colored solution is then heated for three hours to approximately 100 degrees. The reaction mixture is then cooled, diluted with diethyl ether (300 mL), and washed successively with saturated aqueous anmmonium chloride, three times with water, then with saturated aqueous sodium chloride. The organic layer is then dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an orange solid.
Reaction SMILES: [CH:1]([C:13]([O:15]CC)=O)([C:8]([O:10][CH2:11]C)=[O:9])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C[O-].[Na+].[CH3:21][C:22]([OH:41])([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])/[CH:23]=[CH:24]/[CH:25]1[CH2:27][C:26]1(C(OC)=O)[C:28]([O:30][CH3:31])=[O:29]>CO>[C:3]([CH2:2][C:1]1([C:8]([O:10][CH3:11])=[O:9])[C@@H:25]([CH:24]=[CH:23][C:22]([OH:41])([CH3:21])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:27][C@H:26]([C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:15])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCCCC(C)(O)/C=C/C1CC1(C(=O)OC)C(=O)OC
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(C)(O)C=C[C@H]1C[C@H](C(=O)OC)C(=O)C1(CC(=O)OCC)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a solution of triethyl 1,1,2-ethanetricarboxylate (1.36 g) in 3 ml of methanol, a freshly prepared solution of sodium methoxide (from 0.126 g of sodium and 6 ml of absolute methanol) is added. The mixture is heated to 80°. A solution of dimethyl trans-(3-methyl-3-hydroxy-1-octenyl)cyclopropane-1-1-dicarboxylate (1.7 g) is gradually added and the resulting mixture stirred for an additional 15 min. The methanol is removed by distillation at reduced pressure. The residue is then heated at 100° for 45 min. Thereafter the mixture is cooled in an ice bath and rendered neutral with acetic acid. The mixture is extracted with ether. The extract is dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel using ethyl acetate/benzene (1:4) as eluant gives the title compound, νmaxfilm 3350, 1727 cm-1.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[C:46]([NH2:47])=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:47][C:46]1[CH:45]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[N:42][C:41]=1[O:40][CH3:39]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1N
Yield: 58.1 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (101 mg, 0.4 mmol), sodium carbonate (43 mg, 0.41 mmols) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 63 mg (59% yield) of the title compound. Purity 100%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[NH:7][CH2:6][CH2:5]2.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=1)[N:7]([C:39]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:40])[CH2:6][CH2:5]2
Reactant: Fc1ccc2c(c1)CCNC2c1ccc(C(F)(F)F)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)N1CCc2cc(F)ccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
A solution of 6-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.3 g, 1.0 mmol) and diisopropylethylamine (0.2 mL, 0.919 mmol) in anhydrous dichloromethane (6 mL) was treated with 4-fluorophenyl isocyanate (0.14 g, 1.0 mmol) and stirred at RT for 16 h. Formation of a white precipitate was observed which was collected by filtration. The solid was dried under high vacuum to give 6-fluoro-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (0.35 g, 80%). MS (ESI pos. ion) m/z: 433 (M+H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].C(O)C.[CH3:13][C:14]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:15]=1[CH2:16]Cl>O>[CH3:13][C:14]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:15]=1[CH2:16][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Reactant: Cc1ccc(C)c(CCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C)c(CSc2ccccn2)c1
Temperature: 40 °C

Procedure:
A mixture of 5.6 g (0.05 mole) of 2-mercaptopyridine, 3.3 g (0.05 mole) of potassium hydroxide (85% pellets), 35 ml of ethanol and 5 ml of water was prepared. To this mixture was added 7.8 g (0.05 mole) of 2,5-dimethyl-benzylchloride, while maintaining good stirring. The mixture was stirred and heated to 40° C. for 45 minutes, cooled to room temperature, and then added to 150 ml of water. The aqueous mixture was extracted with 150 ml of diethyl ether; the ether phase washed with 150 ml of water. Finally, the ether phase was dried with anhydrous sodium sulfate. Removal of the ether left a green oil. An infrared spectrum was consistent with the structure of 2-((2,5-dimethylphenyl)methylthio) pyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)([CH3:30])[CH3:29]
Reactant: CC(C)Oc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc(OC(C)C)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-isopropoxyphenyl borate (0.48 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (25/2.5/2.5 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 13 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:2) to give colorless crystals of methyl 7-(4-isopropoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (606.5 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[C:4](=[O:7])[CH2:5]O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C>ClCCl>[Br:29][CH2:5][C:4]([N:3]([CH2:8][CH3:9])[CH2:1][CH3:2])=[O:7]
Reactant: CCN(CC)C(=O)CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)CBr
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Under a nitrogen atmosphere, N,N-diethyl-2-hydroxy-acetamide (42 mg, 0.320 mmol) was dissolved in dichloromethane (1.5 mL) and the mixture was cooled to 0° C. Triphenylphosphine (125.9 mg, 0.480 mmol) and N-bromosuccinimide (85.4 mg, 0.480 mmol) were added in order and the mixture was stirred at room temperature for 3.5 hours. The mixture was warmed to room temperature and 2-bromo-N,N-diethylacetamide was prepared in situ. To the mixture, solution of No. 5447725 (Compound G; 56 mg, 0.080 mmol) in dichloromethane (1.0 mL) was added dropwise under a nitrogen atmosphere. N,N-Diisopropylethylamine (69.7 μL, 0.40 mmol) was then added at room temperature, and the mixture was stirred under feflux for 14 hours. After completing the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated brine and dried over anhydrous sodium sulfate. After the organic layer was filtered and the solvent was distilled off, the residue was then purified by HPLC (water with 0.05% TFA-acetonitrile with 0.05% TFA) to obtain 31.2 mg (42% yield) of the triester form.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.I[CH2:11][C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].P(=O)(O)(O)O>C(OCC)(=O)C.O>[C:12]([CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([OH:14])=[O:13]
Reactant: O=C(O)CI
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(OCC(=O)O)cc1
Temperature: 60 °C

Procedure:
To a solution of p-hydroxybenzaldehyde (49 g, 0.40 mol) were added iodoacetic acid (75 g, 0.40 mol) and potassium carbonate (anhydrous, 120 g), and the magnetically stirred mixture was warmed at 60° C. for three days. The resulting solid was dispersed mechanically in a mixture of ethyl acetate (400 ml) and water. The mixture was neutralized cautiously with phosphoric acid. After the dissolution of the solid mass, the neutral aqueous layer was withdrawn. The organic layer was extracted repeatedly with a concentrated solution of dibasic sodium phosphate, to remove additional acidic organic material. The aqueous extracts were combined, filtered through glass wool, and acidified to pH 1 using 6N HCl. This solution was placed in the refrigerator overnight, and a product of tan crystals (21.85 g) was collected. Unreacted p-hydroxybenzaldehyde was recovered upon evaporation of the organic layer. Yield based on recovery of starting material was 60%. Mp 191°-193° C. Analysis (C9H8O4): calc. 60.00% C, 4.48% H; found 59.66% C, 4.37% H.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f37) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:14]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=S.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]([CH2:24][CH2:25][CH2:26][OH:27])[C:14]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=[CH:22][C:13]=2[N:12]=1
Reactant: COC(=O)c1cccc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of methyl 3-({[(2,4-dichlorophenyl)amino]carbonothioyl}amino)-2-[(3-hydroxypropyl)amino]benzoate (1.87 g, 4.37 mmol), triethylamine (0.67 mL), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (838 mg, 4.37 mmol) in tetrahydrofuran (15 mL) was stirred at 50° C. for 2 hr. The mixture was diluted with water, concentrated in vacuo, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a pale yellow powder (1.67 g, 4.24 mmol, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[N:11][C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.C(O)(=[O:29])C>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:4]([C:3]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=3[Cl:1])=[N:6][C:7]3[C:12]2=[N:11][CH:10]=[N:9][C:8]=3[OH:29])=[CH:15][CH:16]=1
Reactant: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: CC(=O)O
Product: Oc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A suspension of 2,4-dichloro-N-[4-chloro-6-(4-chlorophenylamino)-pyrimidin-5-yl]-benzamide I-(1A-1)b (48 g, 0.11 mol) in acetic acid (1 l) was heated to reflux for 7 hours. The reaction mixture was cooled to 0° C., the product (colorless needles) was collected by vacuum filtration, and the solid was washed with additional acetic acid, ethyl acetate, and then ether. The product was dried overnight under high vacuum to afford the title compound I-(1A-1)c (32 g, 73%) as a colorless, fluffy solid. The mother liquor was concentrated under reduced pressure and the solid crystallized from methanol to provide additional material (16 g) as a colorless solid: mp 314–315° C.; +ESI MS (M+1) 391.3; 1H NMR: (400 MHz, CD3OD): δ 8.06 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.48–7.41 (m, 3H), 7.31 (d, J=8.7 Hz, 2H).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:31]=[CH:30][C:22]([C:23]([NH:25][NH:26][C:27](=[S:29])[NH2:28])=O)=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>ClCCl.CCOC(C)=O>[NH2:28][C:27]1[S:29][C:23]([C:22]2[CH:30]=[CH:31][C:19]([C:18]3[CH:17]=[N:16][N:13]4[CH:14]=[CH:15][C:10]([N:5]5[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]5=[O:9])=[N:11][C:12]=34)=[CH:20][CH:21]=2)=[N:25][N:26]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)NNC(N)=S)cc3)c2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nnc(N)s4)cc3)c2n1
Temperature: 50 °C
Yield: 7.4 %

Procedure:
To a solution of (S)-2-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoyl)hydrazinecarbothioamide (20.2 mg, 0.029 mmol) in dichloromethane (3 ml) was added PPh3 (22.7 mg, 0.087 mmol), triethylamine (32 μL, 0.231 mmol), and CCl4 (13.3 mg, 0.087 mmol). The reaction mixture was heated to 50° C. for 3 hours. After cooling to ambient temperature the reaction mixture was dissolved in EtOAc, washed with water then brine, dried over MgSO4, and concentrated under reduced pressure. The crude was purified by silica gel flash column chromatography (0-5% 7N NH3-MeOH in dichloromethane). The product was then subjected to preparative plate chromatography (10% MeOH in dichloromethane) to afford 0.9 mg (7%) of (S)-3-(3-(4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, 1H), 8.42 (s, 1H), 8.08 (m, 3H), 7.76 (d, 2H), 4.95 (m, 1H), 4.46 (m, 2H), 2.85 (m, 1H), 1.10 (d, 3H), 0.95 (d, 3H); LCMS (APCI+) m/z 422.5 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COC(OC)C.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>[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(C)OC
Agent: [Ba+2]
Solvent: O
Product: Cc1cc(C)c(-c2ncccc2[N+](=O)[O-])c(C)c1
Yield: 78.5 %

Procedure:
A solution of 2-chloro-3-nitropyridine (5.0 g, 31.5 mmol), mesitylboric acid (5.65 g, 34.7 mmol), Pd(PPh3)4 (1.82 g, 1.58 mmol) and barium hydroxide octahydrate (14.9 g, 47.3 mmol) in 2,2-dimethoxyethane (150 mL) and water (25 mL) was heated under reflux for one day. The mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatogrpahy (10% ethyl acetate/hexane), to give the title compound (5.99 g) as pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](OCC)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCCN(Cc2ccccc2)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of ethyl 1-benzylpiperidine-3-carboxylate (1.0 g) in tetrahydrofuran (10 mL) at 5° C. under argon was added a 1M solution of lithium aluminium hydride (4.04 mL) dropwise. The mixture was stirred for 1 hour at 5° C. and then quenched by the dropwise addition of ethyl acetate (5 mL). The mixture was warmed to room temperature and dichloromethane (150 mL) was added followed by saturated aqueous sodium potassium tartrate (50 mL). The mixture was stirred vigorously overnight. The layers were separated and the organic layer was dried over magnesium sulfate and evaporated to give the title compound as a colourless oil (0.82 g, 99%).
Reaction SMILES: [H-].[Na+].C([NH:6][C:7]1[N:16]=[C:15](C2N=CNN=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[CH:13]=2)[N:8]=1)(=O)C>C(O)(C)C>[NH2:6][C:7]1[N:16]=[C:15]([O:28][CH:25]([CH3:26])[CH3:24])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[CH:13]=2)[N:8]=1
Reactant: COc1ccc(-c2ccc3nc(NC(C)=O)nc(-c4nc[nH]n4)c3c2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(-c2ccc3nc(N)nc(OC(C)C)c3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 165 %

Procedure:
To isopropanol (10 ml) was added NaH (80 mg of a 60% dispersion in mineral oil, 2.0 mmol). The mixture was stirred at room temperature for 10 minutes. Then, 2-acetamido-6-(3,4-dimethoxyphenyl)-4-(1,2,4-triazolyl)-quinazoline (195 mg, 0.5 mmol) was added. The resulting mixture was stirred at room temperature for another 20 minutes and then heated at 80° C. for 2 hours. The solvents were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of isopropanol/dichloromethane (in a volume ratio of 1:50), yielding the title compound (140 mg, yield: 82%) as a white solid was characterized by its mass spectrum as follows: MS (m/z): 340 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:16](OCC)=[O:17])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C1COCC1.[Li+].[BH4-]>CO>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][OH:17])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CCOC(=O)C(c1ccccc1)n1c(C)cc2c1ccc1nnc(C)n12
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(ccc3nnc(C)n32)n1C(CO)c1ccccc1
Reaction time: 4 h

Procedure:
Ethyl (1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)(phenyl)acetate (0.008 g, 0.02 mmol, from Step 1) was dissolved in MeOH (0.5 mL) and THF (0.5 mL) and LiBH4 (0.0025 g, 0.10 mmol, 90% purity, Aldrich) was added. The reaction was stirred for 4 hours and additional LiBH4 (0.006 g, 0.25 mmol) was added and the reaction continued for a further 3 hours. The reaction was quenched by the addition of water and diluted with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (5 mg, 70%).