Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:12]2[NH:16][C@H:15]([C:17]([OH:19])=[O:18])[CH2:14][S:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:20]=[C:21]([CH3:23])[CH3:22].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:6]1([CH:12]2[NH:16][C@H:15]([C:17]([O:19][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:18])[CH2:14][S:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2)N1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H]1CSC(c2ccccc2)N1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
C--tert-Butyl (2RS,4R)-2-phenyl-4-thiazolidinecarboxylate may be prepared as follows: 15 cm3 of concentrated sulphuric acid are added dropwise to a suspension of 53.7 g of (2RS,4R)-2-phenyl-4-thiazolidinecarboxylic acid in 590 cm3 of chloroform cooled to a temperature in the vicinity of 5° C. The reaction mixture is saturated with isobutene for 5 hours while stirring and while maintaining the temperature at 5° C. After returning to a temperature in the vicinity of 20° C., stirring is continued for 20 hours. The solution is brought to a pH of 8 by addition of a saturated aqueous sodium bicarbonate solution, then the aqueous phase is separated and extracted with 2 times 300 cm3 of chloroform. The combined organic phases are washed with 2 times 300 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. The oily residue obtained is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (20/80 by volume)]. The fractions containing the expected product are combined, then concentrated to dryness under reduced pressure. 42.8 g of tert-butyl (2RS,4R)-2-phenyl-4thiazolidinecarboxylate are thus obtained in the form of a pale yellow oil, a (40/60 by weight) mixture of the (2R,4R) and (2S,4R) isomers, used as it is in subsequent syntheses.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[N+:10]([C:13]1[CH:18]=[CH:17][C:16](Cl)=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])([O-:12])=[O:11]>C(O)C.[Cu]>[F:21][C:20]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([N:4]2[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]2=[O:7])[CH:17]=[CH:18][C:13]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: CC1(C)NC(=O)NC1=O
Agent: [Cu]
Solvent: CCO
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Temperature: 200 °C

Procedure:
71.5 grams of copper in powder form were added to 96.10 grams of 5,5-dimethyl-hydantoin and 170.86 grams of 2-nitro-5-chloro trifluoromethylbenzene. The mixture was heated to 200° C. for about 21 hours, the pressure being maintained at 450 millibars, then, was cooled to 20° C. and taken up in 480 ml of ethanol. The product was characterized and determined by thin layer chromatography of the ethanol solution.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1.[CH3:29][O:30][C:31]1[CH:65]=[CH:64][C:34]([CH2:35][N:36]2[C:40]3=[N:41][CH:42]=[CH:43][C:44]([O:45][C:46]4[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][C:47]=4[F:53])=[C:39]3[C:38]([N:54]3[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][O:62][CH3:63])[CH2:56][CH2:55]3)=[N:37]2)=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][N:36]2[C:40]3=[N:41][CH:42]=[CH:43][C:44]([O:45][C:46]4[CH:51]=[CH:50][C:49]([NH:52][C:26]([C:23]5[C:24](=[O:25])[N:19]([C:16]6[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=6)[N:20]=[CH:21][CH:22]=5)=[O:28])=[CH:48][C:47]=4[F:53])=[C:39]3[C:38]([N:54]3[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][O:62][CH3:63])[CH2:56][CH2:55]3)=[N:37]2)=[CH:64][CH:65]=1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COCCN1CCN(c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(N)cc4F)c23)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCN1CCN(c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10 %

Procedure:
EDCI (27 mg, 0.14 mmol) was added to a stirred mixture of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (11 mg, 0.047 mmol, prepared according to the procedure described for Example 19, Step C) and HOBt-hydrate (22 mg, 0.14 mmol) in DMF (0.3 mL) at ambient temperature, and the reaction mixture was stirred for 15 minutes at ambient temperature. 4-(1-(4-Methoxybenzyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (12 mg, 0.024 mmol) and triethylamine (0.020 ml, 0.14 mmol) were then added, and the resulting mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with EtOAc and washed with water. The aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by preparative TLC (0.5 mm) and eluted with 15% MeOH/DCM (Rf=0.74). The product was obtained as a waxy solid (2 mg, 10%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([NH:11][NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])=O)[CH:5]=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][C:9]2[O:14][C:13]([CH:15]3[CH2:17][CH2:16]3)=[N:12][N:11]=2)[N:7]=1
Reactant: O=C(Cc1cccc(Br)n1)NNC(=O)C1CC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Brc1cccc(Cc2nnc(C3CC3)o2)n1
Temperature: 100 °C

Procedure:
N′-[2-(6-Bromopyridin-2-yl)acetyl]cyclopropanecarbohydrazide (200 mg, 0.67 mmol) and Burgess reagent (320 mg, 1.34 mmol) were combined in THF (4.0 mL) and heated at 100° C. for 25 min in a microwave. The reaction mixture was concentrated and directly purified by flash chromatography (10-100% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=1.COB(OC)OC.[C:21]([O:25][C:26](=[O:47])[NH:27][C:28]([C:30]1[S:31][C:32]([S:45][CH3:46])=[C:33]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40](Br)[CH:39]=2)(=[O:37])=[O:36])[CH:34]=1)=[NH:29])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[Na+].[Na+]>CCOCC.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.C1(C)C=CC=CC=1.C(O)C>[C:21]([O:25][C:26](=[O:47])[NH:27][C:28]([C:30]1[S:31][C:32]([S:45][CH3:46])=[C:33]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:7]3[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:39]=2)(=[O:37])=[O:36])[CH:34]=1)=[NH:29])([CH3:24])([CH3:23])[CH3:22]
Reactant: Clc1ncccc1Br
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccnc2Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
Butyllithium (2.5 M, 1.0 mL, 2.5 mmol) was added dropwise to a −78° C. solution of 3-bromo-2-chloropyridine (384 mg, 2.0 mmol) in Et2O (10 mL). The solution was stirred at −78° C. for 1 h and trimethylborate (2.3 mL, 20 mmol) was added in one portion. The solution was warmed to rt over 15 min and stirred for 2 h at rt . The volatile components were removed and the solid material was dried under high vacuum for 2 h. A portion of the crude solid (105 mg, 0.63 mmol) was reacted with {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), Pd(PPh3)4 (29 mg, 0.025 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 mL) according to the procedure used in Example 1: step c. Analogous aqueous workup and purification of the crude material by preparative TLC (50% EtOAc in hexanes) yielded the title compound (31 mg, 58%) as a light-yellow glass.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.[Br-].[CH2:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH:13]1([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(=O)c1ccc(O)cc1F
Reactant: C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)c1ccc(OC2CCCC2)cc1F
Temperature: 70 °C

Procedure:
A suspension of 2.5 g 4′-hydroxy-2′-fluoroacetophenone, 2.0 mL cyclopentane bromide and 7.9 g cesium carbonate in acetonitrile (35 mL) was heated for 1 hour under reflux and then heated at 70° C. for 15 hours. Further, 1.0 mL cyclopentane bromide was added thereto, and the mixture was heated for 3 hours under reflux. The reaction mixture was diluted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate, and the solvent was removed, whereby 3.65 g of the title compound in a crude state (yellow oil) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([NH:7][CH3:8])=[CH:5][CH:4]=1.Br[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([N:7]([CH3:8])[CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CNc1ccc(OC)cc1
Reactant: Oc1ccc(OCCBr)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(C)CCOc2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 24.7 %

Procedure:
Compound 6a (0.20 g, 1.46 mmol) and compound 5a (0.32 g, 1.46 mmol) were stirred in acetonitrile (10.0 mL) for 30 mins and then diisopropylethylamine was added dropwise (0.40 mL, 2.92 mmol). The reaction was then stirred at 60° C. for 12 hours and monitored by TLC. The reaction mixture was concentrated, purified by column chromatography to isolate the compound 6 as a colorless oil (0.10 g, 0.36 mmol, 25% yield). MS (ESI, positive) m/z calcd. for C16H20NO3 [M+H]+: 274.14, found: 273.96. 1H NMR (CDCl3, 400 MHz) δ 6.86 (d, J=8 Hz, 2H), 6.70-6.78 (m, 6H), 4.06 (t, J=5.6 Hz, 2H), 3.78 (s, 3H), 3.64 (t, J=5.6 Hz, 2H), 2.98 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O.O>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[C:9]([CH3:36])=[N:8][C:7]([N:39]5[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:12][CH:11]=4)[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:30])([F:29])[F:31])=[CH:23][CH:24]=1
Reactant: C1CCNCC1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCCCC2)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 7 h
Yield: 167.4 %

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (102.1 mg, 0.172 mmol) in N,N-dimethylformamide (1.5 mL) was added piperidine (85.0 μL, 0.858 mmol). The reaction mixture was stirred, at 80° C. for 7 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (78.7 mg, 0.288 mmol, 86%).
Reaction SMILES: NC1C=CC([N:8]2[CH2:13][CH2:12][CH:11]([CH:14](C3C=CC=CC=3)[C:15]([O:17]C)=[O:16])[CH2:10][CH2:9]2)=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1
Reactant: COC(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)CC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 399.1 %

Procedure:
DMF (0.5 ml) was added to a solution of 2-biphenylcarboxylic acid (0.077 mol) in DCM (250 ml). Thionyl chloride (0.154 mol) was added. The mixture was stirred and refluxed for 1 hour. The solvent was evaporated and then co-evaporated twice with DCM (100 ml). The residue was dissolved in DCM (100 ml) to give solution (A). Intermediate (18) (0.077 mol) and DIPEA (0.154 mol) were stirred in DCM (400 ml). Solution (A) was added. The mixture was stirred at room temperature for 3 hours and then washed with water. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 44 g of 4-piperidineacetic acid, 1-[4-[([1,1′-biphenyl]-2-ylcarbonyl)amino]phenyl]-α-phenyl-, methyl ester (intermediate 21).
Reaction SMILES: [Br:1]Br.[N+]([C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-])=O.[N+](C1C=CC=CC=1)([O-])=O>O>[Br:1][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: BrBr
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c(Br)cccc21
Temperature: 200 °C

Procedure:
A 1 liter double mantle flask equipped with propeller or anchor stirrer, bromine inlet with metering pump, and reflux condenser attached to a waste gas adsorption unit, is charged with 1265 parts by weight of 1-nitroanthraquinone and 60 parts by weight of nitrobenzene. The mixture is heated to 240° C. and, at this temperature and with efficient stirring, elementary bromine is pumped in by means of the metering pump. The rate of addition is so chosen that gentle bromine reflux is always maintained in the reflux condenser. After about 200 to 220 ml of bromine have been added over 10 hours, no more bromine is taken up by the reaction mixture and the presence of 1-nitroanthraquinone can no longer be detected in a thin-layer chromatogram. The mixture is then cooled to 200° C. and the melt is discharged through the bottom outlet into 2 liters of vigorously stirred water. The resultant suspension is then refluxed and nitrobenzene is separated in a water separator. After about 1 hour the suspension is cooled to about 80° C., filtered, and the filter cake is washed with hot water and dried in vacuo at 120° C., affording 1400 parts by weight of 1-bromoanthraquinone in 96-97% purity. The yield, based on 1-nitroanthraquinone, is 97.5 %.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[CH2:34]([O:36][C:37]([C:39]1[N:40]([CH3:62])[C:41](CC)=[C:42]([C:58]#[N:59])[C:43]=1[C:44]1[CH:49]=[CH:48][C:47](OS(C(F)(F)F)(=O)=O)=[CH:46][CH:45]=1)=[O:38])[CH3:35].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.O>[CH2:34]([O:36][C:37]([C:39]1[N:40]([CH3:62])[CH:41]=[C:42]([C:58]#[N:59])[C:43]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:7]1[CH:6]=[CH:5][C:4]2[C:8]=1[O:9][CH:10]=[CH:2][CH:3]=2)=[O:38])[CH3:35]
Reactant: Brc1cccc2ccoc12
Reactant: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(CC)n1C
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2-c2ccc3cccoc2-3)c(C#N)cn1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.5 %

Procedure:
Add together 7-bromo-benzofuran (300 mg, 1.50 mmol), potassium acetate (431 mg, 2 Eq.), and bis(pinacolato)diboron (390 mg, 1.6 Eq.) in DMF (30 mL) and stir for 10 minutes while degassing with nitrogen. Add [11′bis(diphenylphosphino) ferrocene]dichloro-palladium(II) (30 mg) to the reaction mixture and stir at 80° C. for 2 hours under a nitrogen atmosphere. Cool mixture to room temperature and add 4-cyano-5-ethyl-1-methyl-3-(4-trifluoromethanesulfonyloxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-97a or E-97b) (1.3 g, 2 Eq.), 2.0M sodium carbonate/water (3.6 mL ), and [11′bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (30 mg) to the mixture and heat at 80° C. overnight. Cool to room temperature and pour into water and extract the desired product into ethyl acetate. Separate layers, and wash the organic layer once with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum to give 1.08 g as a dark solid. Purify the material by silica gel chromatography (Chromatotron™) eluting with hexane/ethyl acetate 7:3 to provide 275 mg of the title compound as a white solid. Mass spectrum (m/e): 399.2 (M*+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[C:35]([CH3:34])[C:36]([N:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]4)=[CH:37][C:38]=3[O:42][CH3:43])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 49.1 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (90 mg, 0.195 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (57 mg, 0.175 mmol), and p-toluenesulfonic acid (89 mg, 0.47 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (65 mg, 0.086 mmol, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.39 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.22 (d, J=5.31 Hz, 1H), 8.04 (d, J=7.69 Hz, 1H), 7.80 (d, J=7.87 Hz, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.59 (t, J=7.69 Hz, 1H), 7.42-7.51 (m, 2H), 7.34-7.42 (m, 1H), 7.13-7.23 (m, 2H), 6.97 (t, J=6.68 Hz, 1H), 6.75 (s, 1H), 6.48 (d, J=5.31 Hz, 1H), 3.79 (s, 3H), 3.30-3.35 (m, 2H), 3.05 (s, 3H), 2.82-2.90 (m, 4H), 2.76 (t, J=6.68 Hz, 2H), 2.53-2.64 (m, 4H), 2.13 (s, 3H). MS (ESI): 753 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:25])[CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:9][C:8]=1[NH:26][C:27](=[O:43])[CH2:28][CH:29]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:36][C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)([CH3:6])([CH3:5])[CH3:4]>>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([OH:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:9][C:8]=1[NH:26][C:27](=[O:43])[CH2:28][CH:29]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=2[O:36][C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)c1ccc(CCCCC(=O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCCC(O)CCCCc1ccc(C(C)(C)C)c(NC(=O)CC2c3ccccc3Oc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
37 mg (0.99 mmol) of sodium borohydride were added to 10 ml of a methanolic suspension containing 544 mg (0.986 mmol) of N-[2-t-butyl-5-(6-cyclohexyl-5-oxohexyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 21), in an ice bath. The ice bath was then removed, and the reaction mixture was stirred for 1 hour at room temperature. At the end of this time, the reaction solution was diluted with diethyl ether, washed with a saturated aqueous solution of ammonium chloride and then with water several times. The solvent was then removed by distillation under reduced pressure, to obtain 532 mg (yield 97%) of the title compound as a foam-like substance.
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[N:10]=[C:9]([CH2:11][Cl:12])[N:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]=1)=O>CO>[C:20]([C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[N:8]1[C:9]([CH2:11][Cl:12])=[N:10][C:6]([C:4]([NH2:1])=[O:3])=[N:7]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N
Reactant: COC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Solvent: CO
Product: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Temperature: 25 °C

Procedure:
30 ml of concentrated aqueous ammonia solution is added dropwise at 30° in the course of 5 minutes, with stirring, to the suspension of 6.0 g (0.015 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester in 220 ml of methanol. There has formed after 4 hours a clear reaction solution, and a short time later a crystalline product commences to precipitate. Stirring is maintained for one hour at room temperature and for one hour at 0°-5°. The formed crystals are thereupon filtered off and recrystallised from 50 ml of methanol. The product is filtered off with suction and washed with methanol and hexane. After drying in vacuum, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide, m.p. 128°-130°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[H-].[Na+].[CH3:12]I>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH3:12]
Reactant: CI
Reactant: OCc1ccncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccncc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of Intermediate 65A (1.0 g, 5.32 mmol) in THF (Volume: 26.6 ml) was added sodium hydride (0.255 g, 6.38 mmol). The ice bath was removed and the reaction mixture was allowed to stir at room temperature for 30 min, then cooled to 0° C. and followed by addition of methyl iodide (0.366 ml, 5.85 mmol). The ice bath was removed and the reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was then quenched with water and concentrated to remove the THF. The resulting aqueous layer was extracted with DCM (3×). The combined organics were washed with water and brine, dried, and concentrated to give an oil. The oil was purified by silica gel chromatography (hexane: ethyl acetate 70:30) to afforded the title compound as a colorless oil. MS (ES): m/z=203.9 [M+H]+. Intermediate 65 was used in the synthesis of Example 254.