Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[OH-].[Na+].[F:54][B-](F)(F)F.F[B-](F)(F)F.O[N+]12CC[N+](F)(CC1)CC2.C(Cl)Cl>C(O)(=O)C.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:54])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: F[B-](F)(F)F
Agent: O[N+]12CC[N+](F)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Erythromycin A (5 g, 6.813 mmole) was dissolved in glacial acetic acid (20 mL) at room temperature and stirred for 2 hours. The pH of the mixture was adjusted to 4.3 with 6N sodium hydroxide (approx. 12.5 mL) while the temperature was maintained below 20° C. 1-Hydroxyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (2.2 g, 6.813 mmole) was added and stirring continued for an additional 18 hours at 22° C. Methylene chloride (100 mL) was added, the solution placed in an ice bath while the pH of the mixture was adjusted to 9 with 6N sodium hydroxide (approx. 85 mL) and the temperature maintained below 20° C. Next, water (100 mL) was added, the layers separated and the aqueous layer washed an additional two times with methylene chloride (100 mL each). The methylene chloride serves as an extractant for the flurithromycin product. The combined organic phases were washed 2 to 4 times with 5% sodium hydroxide (100 mL each) and dried over magnesium sulfate. After filtration, the organic phase was concentrated under vacuum at room temperature to afford 4.6 g of crude flurithromycin. The crude material was dissolved in ethanol concentrated to 20 mL. This process was repeated two more times. After standing at 0° C. for one night, the product was filtered under vacuum, washed with 5 mL cold ethanol and dried under vacuum at 40° C. to afford 2.18 g (43% yield) of flurithromycin.
Reaction SMILES: [CH:1]1([C:4]([O:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH:16]3[O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[CH:11][CH:10]=2)=[O:5])[CH2:3][CH2:2]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH:1]1([C:4]([O:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH:16]3[O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[CH:13][CH:14]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(=O)C3CC3)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCCc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cc1)C1CC1

Procedure:
In an analogous manner to that described in Example 22(l), by cleavage of the BOC group from tert-butyl (3RS,4RS)-4-[4-(2-cyclopropylcarbonyloxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate using trifluoroacetic acid in methylene chloride there was obtained (3RS,4RS)-2-[4-(3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-ethyl cyclopropanecarboxylate trifluoroacetate as a white solid; MS: 430 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:28]O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:13][CH3:28])([CH2:12][OH:16])[CH2:14][CH2:15]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-1-oxa-6-azaspiro[2,5]octane (17.5 g) in methanol (250 ml) was added p-toluene sulfonic acid hydrate (285 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with sodium bicarbonate solution and saturated brine, dried and concentrated, and the residue was crystallized from ice-cooled hexane to give colorless solid of 1-(tert-butoxycarbonyl)-4-methoxy-4-piperidinemethanol (9.32 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([F:12])[C:6]([F:11])=[C:7]([CH:10]=1)[C:8]#[N:9].Cl.[CH3:14][NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[C:5]([F:12])[C:6]=1[F:11])[CH2:2][N:15]([CH3:14])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])#[N:9]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: N#Cc1cc(CBr)cc(F)c1F
Agent: Cl
Product: CN(CC(=O)OC(C)(C)C)Cc1cc(F)c(F)c(C#N)c1

Procedure:
The title compound was prepared following general procedure 10, starting from 5-(bromomethyl)-2,3-difluorobenzonitrile and tert-butyl N-methylglycinate hydrochloride. It was obtained as a yellow oil (618 mg, 88%). HPLC (Method A) Rt 2.75 (Purity: 97%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+].ClC1C=CC(N)=CC=1F>CCOCC.CCCCCC>[Cl:9][C:6]1[CH:5]=[CH:4][C:3]([NH:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])=[CH:2][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(Cl)c(F)c1Br)C(F)(F)F
Agent: Nc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(F)c1)C(F)(F)F
Reaction time: 1 h

Procedure:
N-(2-bromo-4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide: 2,2,2-trifluoroacetic anhydride (5.77 mL, 41.2 mmol) was added dropwise to a stirring mixture of sodium carbonate (6.19 g, 58.4 mmol) and 4-chloro-3-fluoroaniline (5.0 g, 34.3 mmol) in Et2O (50 mL) at −10° C. After 1 h, hexane (30 mL) was added and the reaction mixture filtered. The filtrate was washed with ice-water, 10% aq. NaHCO3 solution, and then brine. The organic phase was treated with activated charcoal, dried over sodium sulfate, filtered through a plug of Celite®, and concentrated to give N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide as a white solid. A solution of tert-Butyllithium (1.7M in pentane) (40.4 mL, 68.7 mmol) was added dropwise to N,N,N′,N′-tetramethylethylenediamine (10.37 mL, 68.7 mmol) in THF (60 mL) at −78° C. After 1 h, N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide in THF (40 mL) was added drop-wise to this yellow solution. After stirring for an additional hour, bromine (2.12 mL, 41.2 mmol) was slowly added and the complete mixture stirred for 1.5 h before quenching and neutralized with 1.0N HCl solution (final pH ˜6-7). The mixture was brought to rt, treated with brine (100 mL), and THF evaporated. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with water, saturated NaHCO3 solution, brine, dried over sodium sulfate, filtered and dry-loaded onto silica gel. Purification by flash chromatography (120 g column; (hexane/EtOAc solvent system) gave Intermediate 7A (3.95 g, 36%) as a slowly solidifying tan solid. 1H NMR (400 MHz, CDCl3) δ: 8.42 (1H, br. s.), 8.13 (1H, dd, J=9.09, 1.77 Hz), 7.43-7.49 (1H, m) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([NH:24]C(=O)OCC=C)[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.CC(O)=O.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.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>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=2[F:23])[NH2:24])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cc(N)ccc2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluorophenyl}carbamate (11 g, 24.6 mmol) in DCM (200 mL), HOAc (3.6 g, 59.2 mmol), Pd(PPh3)2Cl2 (345 mg, 0.5 mmol) were added. Then tri-n-butyl tin hydride (8.6 g, 29.6 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by adding saturated NaHCO3 (100 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (100 mL×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure and washed with petroleum ether (200 mL) to afford the crude product, 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluoroaniline (7.62 g, 85.3% yield), 7.4 g of which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:24]([C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)(=[O:26])=[O:25])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)c1ccco1
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1ccco1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with furan-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.53 (br s, D2O exchangeable, 1H), 7.38 (dd, J=1.8 & 10.5 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.21 (d, J=3.0 Hz, 1H), 6.96 (dd, J=8.7 & 16.5 Hz, 1H), 6.87 (ddd, J=1.8, 5.1 & 9.0 Hz, 1H), 6.53 (dd, J=1.8 & 3.6 Hz, 1H), 6.44 (dt, J=5.1, 8.7 & 13.8 Hz, 1H), 6.22 (br s, D2O exchangeable, 1H).
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1)=[O:2].[Cl:13][C:14]1[CH:15]=[N:16][C:17](I)=[N:18][CH:19]=1.C([Li])CCC.[Cl-].[NH4+]>C1COCC1>[Cl:13][C:14]1[CH:15]=[N:16][C:17]([CH:1]([OH:2])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]2)=[N:18][CH:19]=1
Reactant: Clc1cnc(I)nc1
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(O)c2ncc(Cl)cn2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a mixture of methyl trans-4-formylcyclohexanecarboxylate (150 mg, 0.88 mmol) and 5-chloro-2-iodopyrimidine (210 mg, 0.88 mmol) in THF (4 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 0.35 mL, 0.88 mmol) dropwise. The reaction mixture was stirred at −78° C. for 2 hours and then saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate/petroleum ether) to afford methyl trans-4-[(5-chloropyrimidin-2-yl)(hydroxy)methyl]cyclohexanecarboxylate. MS ESI calc'd for C13H18ClN2O3 [M+H]+ 285. found 285. 1H NMR: (400 MHz, CDCl3) δ 8.70 (s, 2H), 4.68 (s, 1H), 3.65 (s, 3H), 2.24 (s, 1H), 2.03-1.82 (m, 3H), 1.48-1.42 (m, 3H), 1.31-1.27 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C([Al](CC)CC)C.[CH2:23]=[C:24]([CH3:26])[CH3:25]>CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:24]([CH3:26])([CH3:25])[CH3:23])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: CC[Al](CC)CC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
By the method used in Examples 1-33, 171 g (0.83 mol) 2,4-di-tert-butylphenol (2,4-DTBP) was dissolved in 350 ml hexane, and the amount (if any) of various polyhalophenols indicated in Table VI was added to the mixture, followed by addition of 5.8 mmol triethylaluminum to said mixture, at room temperature. The 2,4-DTBP was then reacted with 1.2-1.6 mol isobutene at 1.7 bar and 30° C., to form 2,4,6-tri-tert-butylphenol (2,4,6-TTBP).
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2cccc(F)n2)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2cccc(F)n2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.4 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-4-[(6-fluoro-2-pyridinyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 73) (260.2 mg, 0.498 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 45 min then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined to give a residue which was purified by MDAP (modifier: formic acid) to give a second residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.24 mL, 0.24 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-N-(6-fluoro-2-pyridinyl)-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (100.6 mg, 0.201 mmol, 40.4% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:21][NH2:22])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[CH:18][CH:17]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)-(6-chloro-pyridin-3-yl)-amine and hydrazine monohydrate.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH2:31][C:32]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:33]
Reactant: Cc1ccc(F)c(CC(=O)O)c1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(CC(=O)N2CCc3cc(-c4nn(C)c5ncnc(N)c45)ccc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (2-fluoro-5-methylphenyl)acetic acid (34.7 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, off-white solid formed. The solid was filtered to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H), 3.28 (t, J=8.46 Hz, 2H), 3.89 (s, 2H), 3.93 (s, 3H), 4.29 (t, J=8.46 Hz, 2H), 7.07 (s, 1H), 7.09-7.16 (m, 2H), 7.43 (d, J=8.34 Hz, 1H), 7.52 (s, 1H), 8.15 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.F[C:11]1[C:16]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)=[CH:15][C:14]([CH2:43][N:44]2[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][C@@H:45]2[CH3:54])=[CH:13][N:12]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:51])=[O:52])[CH2:46][C@@H:45]3[CH3:54])=[CH:13][N:12]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Product: COc1ncc(Nc2ncc(CN3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared from 2-methoxypyrimidin-5-amine (Aces Pharma, Inc.) and (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (preparation similar as reported in Example 316, Steps 1 to 2; from (S)-tert-butyl 3-methylpiperazine-1-carboxylate (Sigma Aldrich, Inc.)) via similar steps as previously described in Example 316 and isolated as a yellow solid. m/z (ESI, +ve ion) 501 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.77 (s, 1H) 9.03 (s, 2H) 8.71 (d, J=1.96 Hz, 1H) 8.24 (d, J=2.15 Hz, 1H) 7.90 (br. s., 1H) 7.74 (br. s., 1H) 3.91 (s, 3H) 3.24 (d, J=13.50 Hz, 2H) 2.86-2.96 (m, 1H) 2.85 (s, 3H) 2.55-2.79 (m, 4H) 2.44 (s, 3H) 2.11-2.37 (m, 2H) 1.16 (d, J=6.26 Hz, 3H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][C@H:8]1[O:12][C@@H:11]([N:13]2[CH:20]=[C:19]([CH2:21][CH3:22])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:10][C@@H:9]1[O:23]C(=O)C)(=O)C.C[O-].[Na+]>CO>[CH2:21]([C:19]1[C:17](=[O:18])[NH:16][C:14](=[O:15])[N:13]([CH:20]=1)[C@@H:11]1[O:12][C@H:8]([CH2:7][CH2:6][CH2:5][OH:4])[C@@H:9]([OH:23])[CH2:10]1)[CH3:22]
Reactant: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CCCOC(C)=O)O2)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CCCO)O2)c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 58.3 %

Procedure:
0.10 g of 5'-(2-acetoxyethyl)-3'-O-acetyl-2',5'-dideoxy-5-ethyluridine was treated with 5 ml of a dilute solution of sodium methoxide in methanol. After standing at room temperature for 2 hours the solution was neutralized by the addition of a cross-linked polystyrene/divinylbenzene cation exchange resin containing sulfonic acid groups (H+ form) and then filtered. The filtrate was evaporated to dryness to give 0.045 g of 2',5'-dideoxy-5-ethyl-5'-(2-hydroxyethyl)uridine in the form of a white solid of melting point 113°-115° C.
Reaction SMILES: C([NH:4][C:5]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1)(=O)C.CC(C)([O-])C.[K+].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30].O>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([S:31]([NH:4][C:5]1[C:15]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1)(=[O:33])=[O:32])[CH3:30]
Reactant: CC(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Reactant: CCS(=O)(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
2.95 g of 7-acetylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 30 ml of N,N-dimethylformamide. 1.35 g of potassium tert-butoxide was added with ice-cooling. The mixture was stirred for 30 minutes at the same temperature. Then, 1.55 g of ethanesulfonyl chloride was added thereto dropwise. The mixture was stirred for 1 hour at 20°-25° C. 200 ml of water and 200 ml of ethyl acetate were added. The organic layer was separated. The solvent was removed by distillation under reduced pressure. The resulting crystal was mixed with 20 ml of a 1N aqueous sodium hydroxide solution and 10 ml of ethanol. The mixture was refluxed for 2 hours. 100 ml of water and 100 ml of ethyl acetate were added thereto. The mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated. The layer was washed with water and a saturated aqueous NaCl solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a mixture of 5:1 toluene and ethyl acetate) to obtain 0.75 g (yield: 21.7%) of 7-ethylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3c2ccn3Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(bromomethyl)-4-(trifluoromethyl)benzene in a manner similar to that described in Example 25 as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.69-7.63 (m, 1 H), 7.60 (d, J=8.0 Hz, 2 H), 7.44-7.32 (m, 5 H), 7.06 (d, J=3.5 Hz, 1 H), 6.28 (d, J=3.5 Hz, 1 H), 5.71-5.51 (m, 3 H), 2.76 (s, 3 H), 2.48 (s, 3 H), 0.96 (s, 9 H); LCMS (m/z) ES+=511 (M+1).