Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34](O)[CH:33]=1)[CH3:29].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH2:28]([O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:33]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc(C)c(O)c1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: CCOC(=O)c1ccc(C)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 3-hydroxy-4-methyl-benzoic acid ethyl ester and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (16%). MS (Turbo Spray): m/z=539.2 [M+H].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.B([C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(O)O>>[N:29]1([S:26]([C:23]2[CH:24]=[CH:25][C:20]([C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[C:6](=[O:12])[NH:7]4)=[CH:21][CH:22]=2)(=[O:27])=[O:28])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCOCC1
Product: O=c1[nH]c2nccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)c2c2ccccc12
Yield: 80 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 171 using Compound 83 (100 mg, 0.43 mmol) and 4-(4-boronobenzenesulfonyl)morpholine (235 mg, 0.87 mmol) to provide 176 (145 mg, 79% yield) as a grey solid. LC-MS (M+H=422, obsd.=422).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14]1[N:18]=[C:17]([CH3:19])[O:16][N:15]=1.CN(CCN(C)C)C.[C:28](=[O:30])=[O:29].Cl>CCCCCC.C1(C)C=CC=CC=1.O.C(OCC)C>[Cl:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=1[C:14]1[N:18]=[C:17]([CH2:19][C:28]([OH:30])=[O:29])[O:16][N:15]=1
Reactant: Cc1nc(-c2c(Cl)cccc2Cl)no1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: O=C(O)Cc1nc(-c2c(Cl)cccc2Cl)no1
Temperature: -60 °C
Yield: 63 %

Procedure:
A solution of an approximately equivalent amount of n-butyl lithium in 22.2 ml of n-hexane was added dropwise to a solution of 10 g of 3-(2,6-dichlorophenyl)-5-methyl-1,2,4-oxadiazole (m.p. 83°-85° C.) and 6.4 ml of TMEDA in 140 ml of dry toluene using the procedure of Example 1 over a period of about 30 minutes. The reaction temperature was -55° to -60° C. After stirring the reaction mixture for another hour at about -60° C. the mixture was added to powdered carbon dioxide covered with dry diethyl ether. After standing a few hours, water and dilute hydrochloric acid were added until a pH of 8.0 was reached. The layers were separated, and the organic layer was extracted with 50 ml of water. The organic layer was discarded and the combined aqueous layers of about 300 ml were washed twice with 100 ml of diethyl ether. Then, the aqueous layer was extracted three times with 100 ml portions of diethyl ether at a pH of 2.0 These extracts were combined, washed twice with a small amount of ice-water and completely evaporated in vacuo. The solid residue was stirred up first with n-heptane and then with a small volume of toluene. After extensive drying in the desiccator, the final product of 3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl-acetic acid weighed 7.6 g (63% yield) and had a m.p. of 124.5°-125.5° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([CH2:15]I)OC(C)(C)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Zn]>[CH2:1]([O:8][CH2:9][C@H:10]([OH:11])[CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@@H](COCc2ccccc2)[C@@H](CI)O1
Agent: [Zn]
Solvent: CCO
Product: C=C[C@@H](O)COCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
A mixture of 49.20 g of the crude (4S,5S)-4-[(benzyloxy)methyl]-5-(iodomethyl)-2,2-dimethyl-1,3-dioxolane obtained in Reference Example (1c) (136 mmol) and 26.66 g of zinc powder (408 mmol) in ethanol (420 ml) was stirred at 80° C. for three hours. After cooling the reaction mixture, the unreacted zinc powder was separated by filtration using Celite 545 and washed with ethanol. The filtrate was concentrated under reduced pressure and diluted with 1 M hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, a 1.5 M sodium sulfite aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 24.29 g of the crude title compound.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14]CC)=O)=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:1]1([C:7]2[C:8]([C:12]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:14])=[N:9][NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1n[nH]cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1n[nH]cc1-c1ccccc1

Procedure:
5.0 g (23.12 mmol) of ethyl 4-phenyl-3-pyrazolecarboxylate were heated to 120° under reduced pressure for 2 hours with 7.4 g (46.19 mmol) of t-butyl (2-aminoethyl)carbamate, whereby the ethanol formed was distilled off continuously. The reaction mixture was then taken up in methylene chloride and chromatographed on 150 g of silica gel with 9:1, 8:2 and 7:3 mixture of methylene chloride and ethyl acetate as the eluting agent. The fractions which were pure according to the thin-layer chromatogram were combined and evaporated, ant the residue was crystallized from ethyl acetate/hexane, whereby there were obtained 5.1 g (66.8%) to t-butyl [2-(4-phenylpyrazole-3-carboxamido)ethyl]carbamate as white crystals, melting point 71°/162°-163° (still containing 0.05 mol of hexane).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1.Cl>CCO>[NH2:3][CH:12]1[CH2:17][CH2:16][CH:15]([S:18]([NH2:21])(=[O:19])=[O:20])[CH2:14][CH2:13]1
Reactant: NS(=O)(=O)C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(S(N)(=O)=O)CC1
Yield: 40.5 %

Procedure:
A mixture of 4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-sulfonamide (3 g, 9.7 mmol) and NH2NH2H2O (1 mL) in EtOH (15 mL) was heated at reflux for 30 min. After cooling, the pH was adjusted with diluted HCl to 5. The mixture was concentrated in vacuo. The residue was dissipated with 35% HCl (10 mL) and heating until all solid material was dissolved. Upon cooling, a crystalline material was filtered and the filtrated was concentrated to give crude 4-aminocyclohexane-1-sulfonamide (700 mg, 40%) as a yellow solid, which was used in the next step directly.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.[Br:12][CH:13](C)[C:14](C1C=CC(Br)=CC=1C)=O>>[Br:12][CH:13]([CH3:14])[C:6]([C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[Cl:11])=[O:8]
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: Cc1cc(Br)ccc1C(=O)C(C)Br
Product: CC(Br)C(=O)c1ccc(Br)cc1Cl

Procedure:
This compound is prepared from 4-bromo-2-chloro-benzoic acid analgously to 2-bromo-1-(4-bromo-2-methyl-phenyl)-propan-1-one (Intermediate MA). 1H NMR (400 MHz, CDCl3) δ 1.90 (2H, d), 5.21 (1H, q), 7.40 (1H, d), 7.50 (1H, d), 7.62 (1H, s).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](C1C2N=NNC=2C=CC=1)=[O:4].[CH2:16]([CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]2)[CH2:20][CH2:19]1)[CH3:17]>C1COCC1>[CH2:16]([CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:29][CH2:28][CH:27]([O:30][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[CH2:26][CH2:25]2)[CH2:20][CH2:19]1)[CH3:17]
Reactant: CCC1CCC(C2CCC(O)CC2)CC1
Reactant: O=C(c1cccc2[nH]nnc12)C(F)(F)F
Solvent: C1CCOC1
Product: CCC1CCC(C2CCC(OC(=O)C(F)(F)F)CC2)CC1

Procedure:
Trifluoroacetylbenzotriazole in an amount of 4.0 g (18.6 mmol) was dissolved in 50 ml of THF, 2.3 g (10.9 mmol) of 4-(4-ethylcyclohexyl)cyclohexanol was added thereto, they were subjected to a reflux for 1 hour, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=8/1), the solvent was distilled off, and the residue was subjected twice to recrystallization by using heptane to give 1.8 g (5.9 mmol) of trifluoroacetic acid 4-(4-ethylcyclohexyl)cyclohexyl ester. Yield of this compound based on 4-(4-ethylcyclohexyl)cyclohexanol was 54%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][C@H:22]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][C:24](OC)=[O:25].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:21][C@H:22]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][C:24](=[O:25])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCCC[C@@H](C)CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[C@@H](C)CC(=O)CC(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
In a 1 flask were charged 370 ml of dried THF and 38.4 g of diisopropylamine in a nitrogen stream, and the solution was cooled to -10° to -5° C. To the solution was added dropwise a 1.6 mole/l hexane solution of 238 ml of n-butyllithium at that temperature over 30 minutes, followed by stirring at that temperature for 1 hour. To the mixture was further added dropwise a solution of 44 g of t-butyl acetate in 44 ml of dried THF over 30 minutes while keeping at that temperature, followed by stirring for 1 hour. The resulting reaction mixture was cooled to -50° C., and a solution of 24 g of methyl (R)-3-methylheptanoate in 24 ml of dried THF was added thereto dropwise over 30 minutes, followed by allowing the mixture to further react at that temperature for 1.5 hours. After the reaction, a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed twice with a sodium chloride aqueous solution, and the solvent was removed by distillation under reduced pressure to obtain 45.2 g of a crude product. Purification by silica gel column chromatography gave 31.0 g (84.0%) of the titled compound.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C[Si](C)(C)[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].[CH:23]1[N:24]=[CH:25][N:26]2[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[C:27]=12>O1CCCC1>[OH:32][C:28]1([CH:17]2[CH2:18][CH2:19][NH:15][C:16]2=[O:20])[CH2:29][CH2:30][CH2:31][N:26]2[CH:25]=[N:24][CH:23]=[C:27]12
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: O=C1CCCn2cncc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1NCCC1C1(O)CCCn2cncc21
Reaction time: 0.5 h

Procedure:
1.25 ml of n-butyllithium (1.6M in hexane) are added dropwise to a solution to 0.29 ml of diisopropylamine and 2 ml of tetrahydrofuran at −78° C. After 30 minutes, a solution, cooled to −78° C., of 0.31 g of 1-trimethylsilanylpyrrolidin-2-one and 5 ml of tetrahydrofuran is added dropwise. The mixture is stirred for a further 30 minutes and then a solution of 0.27 g of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] and 5 ml tetrahydrofuran is added dropwise. The reaction mixture is stirred at −78° C. for 1 hour and then at 0° C. for 2 hours. The mixture is quenched with saturated aqueous ammonium chloride solution/water (1:1), the tetrahydrofuran is evaporated, and the residue is extracted with dichloromethane (3×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO2 60F) on the basis of the Rf.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O-:16])(=O)[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10].S([O-])([O-])(=O)=O.[Na+].[Na+].CCOCC.[CH2:29]1[CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH2:7][OH:16]
Reactant: C1CCOC1
Reactant: Nc1ccccc1C(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COCCCNc1ccccc1CO
Yield: 94 %

Procedure:
To a suspension of 0.96 g (25.3 mmol) of lithium aluminium hydride in 40 ml of dry THF was dropwise added a solution of 4.0 g (16.9 mmol) of methyl N.(3.methoxypropanoyl) anthranilate in 10 ml of dry THF under chilling with ice for a period of 15 min. The mixture was then heated under reflux for 1 hr. To the resulting mixture, a saturated aqueous sodium sulfate was added under chilling with ice to decompose the excess lithium aluminium hydride. After the addition of 40 ml of ether, insolubles were removed by sellaite filtration. The organic portion was collected and dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure to leave 3.1 g of the desired compound as a pale yellow oil. (Yield: 94.0 %)
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([O:26]C3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=O)=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][NH:43][C:44]1[S:45][CH:46]=[CH:47][N:48]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][N:43]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)[S:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[N:14][CH:15]=[CH:16]2)(=[O:25])=[O:26]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)nccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4)nccc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of perfluorophenyl 1-(pyrrolidin-2-yl)isoquinoline-6-sulfonate 2,2,2-trifluoroacetate (Intermediate ZZZ; 0.350 g, 0.627 mmol) and N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.173 g, 0.689 mmol) in tetrahydrofuran (6.27 ml) was cooled in a dry ice-acetone bath for 10 min. Lithium bis(trimethylsilyl)amide (1M in THF) (1.316 ml, 1.316 mmol) was added drop wise, then the reaction was stirred for 5 minutes. The cooling bath was removed and the reaction was stirred for 30 minutes. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution (aq), diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by chromatography on an 80-g silica gel column with 0-100% EtOAc/Heptane followed by a 20% 2.0M ammonia in MeOH/DCM flush to afford N-(2,4-dimethoxybenzyl)-1-(pyrrolidin-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. m/z (ESI) 511.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:12])=[CH:8][C:9]=2Br)[CH:4]=[CH:3]1.C([Li])(C)(C)C.[C:18](OC)(=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[C:18]([C:9]1[CH:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:23]
Reactant: Cc1cc(Br)c2c(ccn2C)c1
Reactant: COC(=O)C(=O)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cc(C)cc2ccn(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
A solution of 1,5-dimethyl-7-bromoindole (4.27 g, 19.05 mmol) in THF (130 mL) was cooled to −78° C. and a solution of tert-butyl lithium in pentanes (1.7 M, 24.6 mL, 41.8 mmol) added dropwise over 30 min. After 30 min at −78° C., the mixture was treated with dimethyl oxalate (5.62 g, 47.6 mmol) in one portion. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The reaction mixture was quenched with water, extracted with ethyl acetate, and the extracts washed with brine, dried (Na2SO4) and concentrated. Flash chromatography (EtOAc/hexanes) afforded the title compound (4.2 g, 95%) as bright yellow oil. 1H NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 3.85 (s, 3H), 4.01 (s, 3H), 6.51 (dd, J1=1.17 Hz, J2=3.13 Hz, 1 H), 7.06 (d, J=3.13 Hz, 1H), 7.36 (s, 1H), 7.69 (s, 1H); MS (ES, m/z): C13H13NO3: 232.19 (M++1).
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:47][CH2:48][CH2:49][N:50]1[C:54](=[O:55])[C:53]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:52]2[C:51]1=[O:60].C(OCC)(=O)C>CN(C=O)C>[C:51]1(=[O:60])[N:50]([CH2:49][CH2:48][CH2:47][NH:1][C@H:2]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:3][N:4]2[C:9](=[O:10])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]3[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=3[F:32])[C:5]2=[O:33])[C:54](=[O:55])[C:53]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:52]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3S(C)(=O)=O)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3S(C)(=O)=O)c(=O)n(C[C@H](NCCCN3C(=O)c4ccccc4C3=O)c3ccccc3)c2=O)c1F
Temperature: 80 °C
Yield: 68.1 %

Procedure:
To a solution of compound 6d (4.0 g, 7.2 mmol) in anhydrous DMF (8 mL) was added sodium carbonate (0.76 g, 7.2 mmmol) and N-(3-bromopropyl)phthalimide (2.4 g, 9.0 mmmol). The reaction mixture was heated to 80° C. under nitrogen for 4 hr. The reaction mixture was cooled and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane, 50% ethyl acetate in hexane and then ethyl acetate to yield 6e as a pale yellow solid (3.6 g, 4.9 mmol, 67%). MS (CI) m/z 743.1 (M+H+), tR=2.539 min. (method 4). 1H NMR (CDCl3): δ 1.62–1.70 (m, 2H), 2.26 (s, 1.5H), 2.27 (s, 1.5H), 2.29–2.33 (m, 1H), 2.40–2.48 (m, 1H), 3.51 (s, 1.5H), 3.52 (s, 1.5H), 3.54–3.74 (m, 2H), 3.90 (s, 1.5H), 3.91 (s, 1.5H), 3.93–4.26 (m, 3H), 5.60 (brs, 2H), 6.80–6.89 (m, 1H), 6.99 (dd, 1H), 7.11–7.36 (m, 8H), 7.42–7.49 (m, 1H), 7.71–7.75 (m, 2H), 7.84–7.89 (m, 1H), 7.95 (d, J=8.4 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:5]=[C:4]([NH:12][C:13]2[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=2)[C:3]=1[F:19].[CH:20]1([C:23]2([F:27])[CH2:26][NH:25][CH2:24]2)[CH2:22][CH2:21]1>C(#N)C.C(OC(=O)C)C.O>[CH:20]1([C:23]2([F:27])[CH2:26][N:25]([C:2]3[N:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:5]=[C:4]([NH:12][C:13]4[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=4)[C:3]=3[F:19])[CH2:24]2)[CH2:22][CH2:21]1
Reactant: FC1(C2CC2)CNC1
Reactant: Cc1cc(Nc2nc(S(C)(=O)=O)nc(Cl)c2F)[nH]n1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Nc2nc(S(C)(=O)=O)nc(N3CC(F)(C4CC4)C3)c2F)[nH]n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A suspension of 6-chloro-5-fluoro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (100 mg, 0.33 mmol) and 3-cyclopropyl-3-fluoroazetidine (50 mg, 0.33 mmol) in acetonitrile (5 ml) was heated to 50° C. and stirred for 1 hr. The mixture was allowed to cool and diluted with ethylacetate (20 ml) and water (20 ml). The organic layer was dried (Na2SO4) and concentrated to give a solid. Purification by flash column chromatography eluting with 40% ethylacetate/hexanes and ethyl acetate gave the title compound as an off white solid (64 mg, 51%). 1H NMR (DMSO, 400 MHz) 0.51-0.52 (2H, m), 0.68-0.76 (2H, m), 1.42-1.59 (1H, m), 2.29 (3H, s), 3.31 (3H, s), 4.20-4.36 (4H, m), 6.41 (1H, s), 9.98 (1H, s), 12.13 (1H, s). ES+385.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[N:23][C:22]=2[CH:31]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[O:25][C:24]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[N:23][C:22]=3[CH:31]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1ccc2oc(-c3cccs3)nc2c1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Product: c1cc(CCCn2ccnc2)cc(OCc2ccc3oc(-c4cccs4)nc3c2)c1
Yield: 76 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 5-chloromethyl-2-(2-thienyl)benzoxazole to give 5-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)benzoxazole. The yield was 76%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 86-87° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[O:18])[CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]4)=[CH:23][CH:24]=3)=[O:18])[CH:8]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)C1(c2ccc(C(=O)Nc3cc(N4CCOCC4)n4nccc4n3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1cc(N2CCOCC2)n2nccc2n1)c1ccc(C2(C(=O)O)CC2)cc1
Reaction time: 8 h
Yield: 24.2 %

Procedure:
Methyl 1-(4-(7-morpholinopyrazolo[1,5-a]pyrimidin-5-ylcarbamoyl)phenyl)cyclopropanecarboxylate (Compound 441, 31 mg, 0.07 mmol) was dissolved in methanol, and 1N NaOH solution (1 ml) was then added. After 8 hours at room temperature, the mixture was acidified with 2N HCl to pH 1. The mixture was concentrated in vacuo. The residue was dissolved in DMSO, and was purified by preparatory HPLC (30-65% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound (6.9 mg, 23%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ=12.67-12.24 (m, 1H), 10.98 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.98 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 7.41 (s, 1H), 6.37 (d, J=2.3 Hz, 1H), 3.85 (m, 2H), 3.74 (m, 2H), 1.56-1.45 (m, 2H), 1.26-1.17 (m, 2H); ESI-MS: m/z 408.4 (M+H)+.