Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 95 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 95%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 2.50 (s, 3H), 3.18-3.29 (m, 4H), 3.73-3.80 (m, 4H), 4.12 (s, 3H), 6.58 (s, 3H), 7.31 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.55 (s, 1H), 7.72 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]([OH:18])[C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:3].COC.[C:24]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:27])[CH2:25]O.O1CCCC1>CS(O)(=O)=O.CCCCCC>[CH3:17][N:15]([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([CH:8]([C:7]2[CH:19]=[CH:20][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)[O:18][CH2:25][C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Reactant: O=C(CO)OCc1ccccc1
Agent: COC
Agent: CS(=O)(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(OCC(=O)OCc2ccccc2)c2ccc(N(C)C)cc2)cc1

Procedure:
A solution of 4,4'-bis(N,N-dimethylamino)benzhydrol, methyl ether (11.0 g, 0.039 mole), benzyl glycolate (6.6 g, 0.039 mole), 90 ml of tetrahydrofuran, 200 ml of hexane, and 10 drops of methanesulfonic acid was refluxed for 6 hours, replacing solvent as distillate was removed; then, 10 drops of tetramethylguanidine was added to discharge the color and the reaction mixture was filtered hot and cooled. A white solid formed which was filtered, washed with petroleum ether and then recrystallized from 4/1 hexane/acetone. The resulting white crystalline product had a mp 101.8°-103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([NH:17][CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=4)[CH2:20]3)=[O:16])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>N1C=CC=CC=1>[NH:1]([C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([NH:17][CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=4)[CH2:20]3)=[O:16])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1)[C:34]([CH3:35])=[O:36]
Reactant: Nc1cccc(-c2csc(SCC(=O)NC[C@H]3CN(Cc4ccc(Cl)c(Cl)c4)CCO3)n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2csc(SCC(=O)NC[C@H]3CN(Cc4ccc(Cl)c(Cl)c4)CCO3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the resultant product (262 mg) of Example 9 in pyridine (2 mL) was added dropwise acetic anhydride (57 μL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (279 mg) as a white amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[NH:14]([CH2:16]C(O)=O)[CH3:15]>>[Br:1][C:2]1[C:7]2[C:8](=[O:9])[N:14]([CH3:16])[CH2:15][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2cccc(Br)c2c(=O)o1
Product: CN1CC(=O)Nc2cccc(Br)c2C1=O

Procedure:
4.84 g (0.02 mol) of 6-bromoisatoic acid anhydride and 1.78 g (0.02 mol) of sarcosine are finely rubbed together and subsequently heated to 260° under a protective gas for 6 minutes. After cooling, the crude product is chromatographed on silica gel using chloroform/methanol (20:1) for the elution. After recrystallization from chloforom/hexane, there is obtained 6-bromo-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 232°-233°.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH2:26][CH2:27]OC)=[C:17](OCCOC)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].[OH-:30].[Na+]>C(O)C1C=CC=CC=1>[CH2:8]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH2:26][C:27]4[CH:7]=[CH:8][CH:3]=[CH:1][CH:2]=4)=[C:17]([O:30][CH2:15][CH2:16][O:25][CH3:26])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:2][CH:1]=1)[CH3:7]
Reactant: CCc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: OCc1ccccc1
Product: CCc1cccc(Nc2ncnc3cc(OCc4ccccc4)c(OCCOC)cc23)c1
Temperature: 151 °C

Procedure:
N-(3-ethylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, prepared as described above (4.0 g, 10 mmol), solid anhydrous sodium hydroxide (104 mg, 2.6 mmol) and benzyl alcohol (20 mL) was heated at 150-152° C. for 23 hours. The reaction mixture was allowed to cool to room temperature and purified by column chromatography on silica gel using a gradient system with ethyl acetate/hexane as eluent to give a white solid which was dried under vacuum at 45-50° C. to give the title product. (2.52 g, 58%), mp 156-157° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[C:21]([F:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>CS(C)=O>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:31][C:18]2[CH:17]=[C:16]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([NH:8][CH2:9][CH:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[N:4]=3)[C:21]([F:22])=[CH:20][N:19]=2)[CH2:25][CH2:26]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(F)cn1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(F)cn2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
3-chloro-2′,5′-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (0.0509 g, 0.150 mmol) was dissolved in anhydrous DMSO (3.0 ml) and charged to a microwave vial. This was treated with trans-cyclohexane-1,4-diamine (0.171 g, 1.498 mmol). The reaction mixture was then heated at 100° C. for 18 hr. More trans-cyclohexane-1,4-diamine (0.171 g, 1.498 mmol) was added and the reaction mixture was stirred at 120° C. for 18 hr. The reaction mixture was allowed to cool to ambient temperature. The material was purified by preparative reverse-phase HPLC to give 0.2410 g (30%) of N2′-(trans-4-aminocyclohexyl)-3-chloro-5′-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine as the TFA salt. LCMS (m/z): 434.2 (MH+), retention time=0.55 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[N+:12]([CH:15](C(OC)=O)[C:16]([O:18][CH3:19])=[O:17])([O-])=[O:13].F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>C1(C)C=CC=CC=1>[CH:2]([C:3]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:12][O:13][C:4]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:11])[CH3:1]
Reactant: CC(C)C#Cc1ccccn1
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1noc(-c2ccccn2)c1C(C)C
Yield: 2.8 %

Procedure:
A solution of (3-methylbut-1-ynyl)pyridine (170 mg, 1.17 mmol), dimethyl nitromalonate (0.395 mL, 2.93 mmol), and 1-butyl-3-methylimidazolium hexafluorophosphate (0.024 mL, 0.117 mmol) in toluene (7 mL) was heated to 170° C. for 120 minutes under microwave. The reaction mixture was concentrated and purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to afford methyl 4-isopropyl-5-(pyridin-2-yl)isoxazole-3-carboxylate (11 mg, 0.033 mmol, 2.8% yield). The compound had an HPLC retention time=2.96 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=247.15. 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (s, 3H), 1.38 (s, 3H), 4.02 (s, 3H), 4.03-4.10 (m, 1H), 7.33-7.38 (m, 1H), 7.80-7.90 (m, 2H), and 8.72-8.76 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:21]=[N:22][C:23](Cl)=[C:24]([Br:26])[CH:25]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[H-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1.Cl>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:21]=[N:22][C:23]([O:38][C:35]4[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=4)=[C:24]([Br:26])[CH:25]=3)(=[O:18])=[O:19])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(Br)c1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
The mixture of {(R)-4-[(5-Bromo-6-chloro-pyridine-3-sulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (80 mg, 0.16 mmol), sodium hydride (60% dispersed in mineral oil, 40 mg) and 4-chlorophenol (315 mg, 2.45 mmol) in N,N-dimethylformamide (2 mL) was heated in a microwave oven at 100° C. for 15 minutes, and then acidified with 0.1N hydrochloric acid to pH 5. The precipitate was filtered through a glass funnel and purified by preparative HPLC to afford ((R)-4-{[5-bromo-6-(4-chloro-phenoxy)-pyridine-3-sulfonyl]-methyl-amino}-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (70 mg, 75%) as a white powder. MS cald. for C23H24BrClN4O5S 582, obsd. (ESI+) [(M+H)+]: 583.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15]O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:15][CH2:14][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([F:13])[F:12])=[C:4]([O:3][CH:2]([F:17])[F:1])[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccc(OC(F)F)c(OC(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)Oc1ccc(CCBr)cc1OC(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-[3,4-Bis(difluoromethoxy)phenyl]ethanol (6 g, 0.024 mol; see step (iv) above) and triphenylphosphine (12.6 g, 0.048 mol) were taken up in dichloromethane (100 mL) and cooled to 0° C. CBr4 (15.9 g, 0.048 mol) in dichloromethane was added dropwise, and the mixture stirred at RT overnight under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate concentrated under reduced pressure and the residue purified by column chromatography over silica gel (using 20% ethyl acetate in petroleum ether as eluent) to give the title compound as a yellow liquid. Yield 5.2 g.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-:21][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[CH2:28]([O:30][C:31]([C:33]1[CH:37]=[CH:36][N:35]([CH:38]([CH3:40])[CH3:39])[C:34]=1[CH3:41])=[O:32])[CH3:29]>CC#N.O>[CH2:28]([O:30][C:31]([C:33]1[CH:37]=[CH:36][N:35]([CH:38]([CH3:40])[CH3:39])[C:34]=1[CH:41]=[O:21])=[O:32])[CH3:29]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccn(C(C)C)c1C=O
Reaction time: 0.17 h

Procedure:
CAN (979 mmol) was added to a mixture of 1-isopropyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester [224180-70-5] (218 mmol) in CH3CN (1800 mL) and water (360 mL) at 15° C. After 10 min, the reaction mixture was quenched with ice and extracted with MTBE. The organic phase was successively washed with a saturated aqueous solution of NaHCO3 (2×) and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a yellow oil. tR: 4.43 min (HPLC 1); ESI-MS: tR=1.06 min, [M+H]+ 210 (LC-MS 1); TLC: Rf=0.21 (1:9 EtOAc/heptanes).
Reaction SMILES: O=[C:2]([CH3:12])[CH2:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]1=[O:11].[NH2:13][CH2:14][C:15]([OH:17])=[O:16].O>C(O)(=O)C>[CH3:12][C:2]1[N:13]([CH2:14][C:15]([OH:17])=[O:16])[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:11])[C:4]=2[CH:3]=1
Reactant: NCC(=O)O
Reactant: CC(=O)CC1C(=O)CCCC1=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(n1CC(=O)O)CCCC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 2-(2-oxopropyl)cyclohexane-1,3-dione (prepared by evaporation of an ethanolic solution to dryness under vacuum) (20.0 g, 119 mmol) and glycine (17.9 g, 238 mmol) in acetic acid (100 mL) was heated under reflux for 1.5 h then allowed to cool to r.t. Water (100 mL) was then added and the mixture evaporated to a thick oil in vacuo. Acetone (200 mL) and water (40 mL) were added to the residue and the mixture stirred for 30 mins at r.t., after which the solid was collected by filtration and the filtrates retained. The solid was slurried with further acetone (100 mL) and water (20 mL) at r.t. then removed by filtration. The combined filtrates were concentrated in vacuo then dissolved in aqueous sodium hydroxide (1M, 200 mL), adding a small amount of 10M sodium hydroxide to bring the pH to 14. After washing with ethyl acetate (2×100 mL), the mixture was acidified by the addition of aqueous hydrochloric acid (5M, 60 mL) then sodium chloride (50 g) was added. After stiffing for 4 h, the solid product was collected by filtration, washed with acetone (2×25 mL) then dried under vacuum at 40° C. to afford the title compound as an orange-brown solid; 7.45 g (30%); purity 99.1 area % by HPLC; m/z: 208 (MH+); 1H-NMR: 13.2 (1H, br s), 6.02 (1H, s), 4.67 (2H, s), 2.65 (2H, t, J=6.2 Hz), 2.29-2.24 (2H, m), 2.10 (3H, s), 2.02-1.95 (2H, m).
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH2:9][C@H:10]([OH:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[C:28]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[F:42])[N:27]=1.[H-].[Na+]>C1COCC1>[Cl:25][C:26]1[CH:31]=[C:30]([O:12][C@H:10]([CH3:11])[CH2:9][O:8][C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:29]=[C:28]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[F:42])[N:27]=1
Reactant: C[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iii) using (2R)-1-(triphenylmethoxy)-2-propanol (1.35 g) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (ii) (1 g) in THF (15 mL) and 60% sodium hydride (0.18 g) to give the subtitle compound as a pale yellow oil. Yield: 1.8 g.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)NC1C=C(C(O)=O)C(NC2C=CC=C(Cl)C=2)=CC=1C(O)=O>>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=C(O)c1cc(Nc2cccc(Cl)c2)c(C(=O)O)cc1Nc1cccc(Cl)c1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 125 °C

Procedure:
450 parts of polyphosphoric acid containing 85.0% P2O5 are metered into a stirred vessel. Then 135 parts of 2,5dianilinoterephthalic acid and 15 parts of 2,5-di(3-chloroanilino)terephthalic acid are introduced at 125° C. with stirring and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction midure is subsequently metered with stirring over 2 minutes (CG; 50%/min) into 2187.9 parts of 85% strength phosphoric acid at 140° C., during which it is hydrolyzed. During this hydrolysis the temperature rises to 155° C. The phosphoric acid concentration after the hydrolysis is 90%. Then 1768.9 parts of 40% strength phosphoric acid are added dropwise and the suspension is cooled to 120° C. The phosphoric acid concentration thereafter is 70%. The mixture is stirred at 120° C. for 1 hour. Subsequently the mixed crystal pigment is filtered off with suction at 110° C., washed with 70% strength phosphoric acid until the runoff is colorless, washed to neutrality with water, and dried at 80° C. This gives 132.8 parts of mixed crystal pigment (Pigment Violet 19, γII phase). At twice the Bragg angle, 2θ, X-ray spectrum shows three strong lines at 6.3°, 13.5° and 26.4°, four moderate lines at 16.6°, 20.6°, 24.0° and 28.3°, and one weak line at 30.3°. In the AM lacquer, transparent, pure and strongly colored coatings of deep hue are obtained. The rheology is evaluated as 3-4 and the viscosity is 4.5 s. The gloss measurement gives a value of 60.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[S:17][C:16]([NH2:18])=[N:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:29][NH:30][C@@H:31]([CH2:36][OH:37])[CH2:32][CH:33]([CH3:35])[CH3:34]>CN1C(=O)CCC1>[NH2:18][C:16]1[S:17][C:12]2[C:11]([N:30]([CH3:29])[C@H:31]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:36][OH:37])=[N:10][C:9]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:14][C:13]=2[N:15]=1
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reactant: CN[C@@H](CO)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)C[C@H](CO)N(C)c1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 110 °C
Reaction time: 48 h
Yield: 72.4 %

Procedure:
5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidin-2-amine (1.5 g, 4.86 mmol), DIPEA (691 mg, 5.35 mmol) and (R)—N-methylleucinol (956 mg, 7.29 mmol) were mixed in NMP (7.5 mL). The resulting solution was stirred at 110° C. under a nitrogen atmosphere for 2 days. After cooling to room temperature the reaction mixture was poured onto ice. The resulting yellow precipitate was collected by filtration, washed with water and dried in vacuo. The crude product was purified by flash column chromatography on silica (DCM:EtOAc 50:50 to 0:100) to give 1.42 g (72% yield) of the title compound as a yellow solid.
Reaction SMILES: C1(CN2CCN(C3SC(C(O)=O)=CN=3)C2=O)CC1.[F:19][C:20]1[CH:44]=[CH:43][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[S:31][C:32]([C:39]([OH:41])=O)=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=3)[C:26]2=[O:42])=[CH:22][CH:21]=1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][NH2:52])[CH:46]=1>>[F:19][C:20]1[CH:44]=[CH:43][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[S:31][C:32]([C:39]([NH:52][CH2:51][C:47]4[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=4)=[O:41])=[C:33]([C:35]([F:37])([F:36])[F:38])[N:34]=3)[C:26]2=[O:42])=[CH:22][CH:21]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C(F)(F)F
Agent: O=C(O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Product: O=C(NCc1cccnc1)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C(F)(F)F
Yield: 37 %

Procedure:
Following the procedure as described in Example 26, making variations as required to replace 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 37% yield: mp 161-162° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.56-8.52 (m, 2H), 7.69-7.66 (m, 1H), 7.31-7.22 (m, 3H), 7.05-7.00 (m, 2H), 6.55-6.47 (m, 1H), 4.61 (d, J=5.8 Hz, 2H), 4.43 (s, 2H), 4.09-4.03 (m, 2H), 3.48-3.43 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 160.9, 159.5, 159.0, 155.2, 149.2, 135.6, 132.9, 131.0, 130.1, 127.2, 123.7, 122.2, 118.6, 116.0, 47.3, 41.9, 41.6, 30.9; MS (ES+) m/z 480.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][CH2:63][C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH2:74][CH3:75])([CH2:72][CH3:73])[O:70][B:69]([OH:76])[C:68]=2[CH:77]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:26])([F:25])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:62][CH2:63][C:64]4[CH:65]=[CH:66][C:67]5[C:71]([CH2:72][CH3:73])([CH2:74][CH3:75])[O:70][B:69]([OH:76])[C:68]=5[CH:77]=4)=[O:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)cc3C)ccc21
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
A solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (100 mg, 0.24 mmol) and DIPEA (151 mg, 1.17 mmol) in DMF (5.0 mL) was stirred at rt for 5 min and then HATU (180 mg, 0.47 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (63 mg, 0.25 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by column chromatography and prep-HPLC to provide the final title compound (118 mg, yield 79%). 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.88 (t, 1H), 7.80 (t, 1H), 7.60 (m, 5H), 7.42 (d, 1H), 7.40 (d, 1H), 7.24 (d, 1H), 4.47 (d, 2H), 4.36 (d, 2H), 4.27 (d, 2H), 2.35 (s, 3H), 1.78 (m, 4H), 0.52 (t, 6H) ppm; HPLC purity: 92.43% at 220 nm and 93.69% at 254 nm; MS: m/z=620; 661 [M+CH3CN].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=O)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][C:47]=1[C:58]([F:61])([F:60])[F:59].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:16](=[O:18])[CH2:15][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[N:7]3)[CH2:54][CH2:53]2)=[CH:48][C:47]=1[C:58]([F:60])([F:59])[F:61]
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A vial was charged with 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (55 mg, 0.226 mmol), HBTU (125 mg, 0.33 mmol), 1-(4-Chloro-3-trifluoromethyl-phenyl)-piperazine dihydrochloride (170 mg, 0.50 mmol), anhydrous DMF (2.0 mL), and DIPEA (0.5 mL). The vial was capped, heated to 45° C., and stirred overnight. The following day, the volatiles were removed in vacuo and separation by preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone: MS (ES) [M+H]+ found: 490.4