Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:24]3[CH:29]=[CH:28][C:27]([S:30][C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])#[CH:39]>[Pd]>[CH3:41][Si:40]([C:38]#[C:39][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:24]3[CH:25]=[CH:26][C:27]([S:30][C:31]4[CH:36]=[CH:35][C:34]([C:39]#[C:38][Si:40]([CH3:43])([CH3:42])[CH3:41])=[CH:33][CH:32]=4)=[CH:28][CH:29]=3)([C:20]([F:22])([F:23])[F:21])[C:16]([F:17])([F:19])[F:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)([CH3:43])[CH3:42]
Reactant: FC(F)(F)C(c1ccc(Sc2ccc(I)cc2)cc1)(c1ccc(Sc2ccc(I)cc2)cc1)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: [Pd]
Product: C[Si](C)(C)C#Cc1ccc(Sc2ccc(C(c3ccc(Sc4ccc(C#C[Si](C)(C)C)cc4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1

Procedure:
Compound 10 was prepared by treating Compound 9 with the palladium catalyst system and ethynyltrimethylsilane according to the general procedure described in Example 1, Section D herein.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]=[C:24]=[O:25].O>ClCCl>[Cl:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:25])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: O=C=NCCCCl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)NCCCCl)cc1
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-aminobenzoate (496 mg) and pyridine (60 μL) was dissolved in dichloromethane (3 mL), 1-chloro-3-isocyanatopropane (323 μL) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give ethyl 4-[3-(3-chloropropyl)ureido]benzoate (810 mg). The obtained ethyl 4-[3-(3-chloropropyl)ureido]benzoate (810 mg) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (250 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solvent was evaporated from the organic layer. To the obtained residue was added diisopropyl ether, and the precipitate was collected by filtration to give the title compound (84 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[CH2:11]([Mg]Br)[CH:12]=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][CH2:13][CH:12]=[CH2:11]
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCCc1cc(F)ccc1Br
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 2-bromo-5-fluorobenzyl bromide (1 g, 3.73 mmol) in THF (15 mL) was added allylmagnesium bromide (5.60 mL, 5.60 mmol) at 0° C. It was warmed to rt and then refluxed for 5 h. The reaction mixture was quenched with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil. It was then purified by 5% EtOac/hexane to isolate 1-bromo-2-(but-3-en-1-yl)-4-fluorobenzene (0.7 g, 3.06 mmol, 82% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.53-7.45 (m, 1H), 6.99-6.94 (m, 1H), 6.82 (td, J=8.3, 2.9 Hz, 1H), 5.89 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.14-4.98 (m, 2H), 2.89-2.76 (m, 2H), 2.45-2.33 (m, 2H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1>CCOC(C)=O.CCCCCC>[C:18]1([C:15]2[CH:14]=[C:13]([CH2:12][N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[O:17][N:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrCc1cc(-c2ccccc2)no1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(-c2cc(CN3CCc4ccccc4C3)on2)cc1
Yield: 81 %

Procedure:
Prepared from 1,2,3,4-tetrahydroisoquinoline and 5-(bromomethyl)-3-phenylisoxazole under typical conditions. Purification by flash chromatography on silica gel 60, eluting with 25% EtOAc in hexane produced adduct 21A (81% yield). 1H NMR(300 MHz, CDCl3, δ): 7.83-7.80 (m, 2H), 7.48-7.40 (m, 3H), 7.16-7.11 (m, 3H), 7.08-6.99 (m, 1H), 6.57 (s, 1H), 3.91 (s, 2H), 3.76 (s, 2H), 3.00-2.80 (m, 4H). 13C NMR(300 MHz, CDCl3, δ): 170.25, 162.45, 134.04, 133.75, 129.97, 129.12, 128.92, 128.72, 126.81, 126.56, 126.36, 125.78, 101.26, 85.61, 53.20, 50.75, 29.03. MS(CI, NH3) m/e 291 (base, M+H+). HRMS(CI, NH3) m/e Calc'd for (M+H+): 291.1497. Found: 291.1512.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:7]=[C:6]([CH3:21])[C:5]=1[S:22]C#N.O.Cl>C(O)C.C(COC)OC>[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:7]=[C:6]([CH3:21])[C:5]=1[SH:22]
Reactant: Cc1ccccc1CC(=O)Nc1cc(C)c(SC#N)c(C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1CC(=O)Nc1cc(C)c(S)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (2.5 g, 66 mM) was added in portions to an ice-water cooled suspension of 2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]phenyl thiocyanate (B) (5.0 g, 16 mM) in ethanol (100 mL) and dimethoxyethane (100 mL). After 2 hours, water (200 mL) was added to the clear yellow solution. The mixture was acidified to pH4 with 2M HCl and extracted with ethyl acetate. The combined extracts were washed with water, then with saturated sodium chloride solution, and dried (MgSO4). The solvent was removed by evaporation to yield 2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]benzenethiol as a cream coloured solid (4.89 g) which was used without characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17]OCC)[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: CCOC=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21
Solvent: CCO
Product: CCN(C=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21)CC
Reaction time: 24 h

Procedure:
1-(3-Chlorophenyl)-3-(ethoxymethylene)-2(1H,3H)-indolone (0.15 g, 0.5 mmole), diethylamine (5 ml, 48 mmole) and ethanol (30 ml) were combined and stirred 24 hours at 25°. The reaction mixture was concentrated in vacuo to an oil. The oil was taken up in ethyl acetate, washed with H2O and then brine, dried over MgSO4 and evaporated to yield title product which crystallized on cooling and trituration with ether/pentane, 96 mg. m.p. 74°-75.5°.
Reaction SMILES: [N:1]([CH2:4][CH:5]([S:10]([OH:13])(=[O:12])=[O:11])[CH2:6][C:7]([OH:9])=[O:8])=[N+]=[N-]>[Pd].CO>[NH2:1][CH2:4][CH:5]([S:10]([OH:13])(=[O:11])=[O:12])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: [N-]=[N+]=NCC(CC(=O)O)S(=O)(=O)O
Agent: [Pd]
Solvent: CO
Product: NCC(CC(=O)O)S(=O)(=O)O
Reaction time: 8 h
Yield: 95.1 %

Procedure:
In a 500 ml of hydrogenation bottle was added 4-azido-3-sulfobutanoic acid (3.00 g, 14.35 mmol), 150 ml of methanol and 0.32 g of Pd/C (10% Pd, 50% wet). After sucked out air, 30 psi of H2 was conducted, and the mixture was shaken overnight, filtered through celite, evaporated, and coevaporated with dry EtOH to afford about 2.50 g (95%) of 4-amino-3-sulfobutanoic acid. 1H NMR (CD3OD) 3.24 (m, 1H), 3.17 (m, 1H), 2.90 (dd, 1H, J=2.6, 16.5 Hz), 2.33 (dd, 1H, J=10.1, 16.5 Hz), ESI MS m/z−181.60 (M−H). The resulted compound was unstable and was used directly without further purification.
Reaction SMILES: C(OC(=O)[N:7]([C:10]1[S:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][C:11]=1[Cl:21])[CH2:8][CH3:9])(C)(C)C.O1CCOCC1.Cl.O1CCOCC1>CCOCC>[ClH:21].[Cl:21][C:11]1[N:12]=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:14][C:10]=1[NH:7][CH2:8][CH3:9]
Reactant: CCN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCNc1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 0 h
Yield: 209 %

Procedure:
Into a 1 L three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer, and nitrogen inlet was added (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-ethyl-carbamic acid tert-butyl ester (63.5 g, 187 mmol) and 1,4-dioxane (125 mL). To the solution was added 4 M HCl/dioxane (100 mL, 400 mmol). The mixture exothermed from 31° C. to 49° C. over 10 seconds and slowly turned from an auburn solution to a green-black solution. After 10 minutes the reaction had cooled back to 25° C. After 30 min a green-yellow precipitate began to form in the reaction mixture. The reaction conversion was 31% after 10 min, 32% after 1.5 hours and 67% after 16 hours. Additional 4M HCl/dioxane (75 mL, 300 mmol) was added (note: no exotherm this time) and the reaction stirred at 23° C. for 1.5 hours (no change in reaction progress by HPLC analysis). The reaction was heated to 40° C. for 4 hours which led to complete conversion. The reaction was allowed to cool to 25° C. and ether (200 mL) was added. The green-yellow suspension was stirred for 30 min and the solid collected by vacuum filtration and washed with ether (2×50 mL). This gave a green-yellow filter cake which was allowed to stand in the air for 16 hours. This gave 67.99 g (131%) of a green-yellow wet cake that assayed to >99% purity by HPLC at 254 nm. The sample was placed into a vacuum oven (55° C., 74 mmHg vacuum, 4 hours). This gave 53.96 g (quantitative yield) of a green solid: mp 180-182 C; 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=2.1 Hz, 1H), 8.75 (dd, J=5.5, 0.9 Hz, 1H), 8.66 (ddd, J=8.3, 2.2, 1.3 Hz, 1H), 7.97 (ddd, J=8.3, 5.5, 0.6 Hz, 1H), 3.21 (q, J=7.1 Hz, 2H), 2.51 (dt, J=3.7, 1.8 Hz, 1H), 1.24 (dd, J=9.2, 5.1 Hz, 3H); ESIMS m/z 240 (M+1).
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=[O:7])(C)C.[CH2:13]([C@@:16]1(C2C=CC=CC=2C([O-])=O)[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:19]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:18][C@@H:17]1OC)[CH:14]=[CH2:15].[NH:49]1[CH:56]=[CH:55][C:53](=[O:54])[NH:52][C:50]1=[O:51].[Sn](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:13]([C@@:16]1([OH:7])[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:19]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:18][C@H:17]1[N:49]1[CH:56]=[CH:55][C:53](=[O:54])[NH:52][C:50]1=[O:51])[CH:14]=[CH2:15]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Reactant: C=CC[C@]1(c2ccccc2C(=O)[O-])[C@@H](OC)O[C@H](COCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CC[C@@]1(O)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Bis(trimethylsilyl)acetamide (BSA; 29.2 mL, 118 mmol) was added to a mixture of 6 (14.0 g, 23.1 mmol) and uracil (5.99 g, 53.4 mmol) in anhydrous acetonitrile (300 mL). The reaction mixture was refluxed for 1 hour and the clear solution was allowed to cool down to room temperature. Tinchloride (11.55 mL, 99 mmol) was added dropwise at room temperature and the mixture was further stirred for 1 hour. The mixture was then stirred at reflux for 1.5 hour and again cooled to room temperature. Ethyl acetate (250 mL) was added, followed by saturated aqueous NaHCO3 (250 mL) and the mixture was stirred for 15 minutes. After filtration through Celite, the organic layer was separated and washed with saturated aqueous NaHCO3 (250 mL). The combined aqueous layer was extracted with ethyl acetate (250 mL) and the combined organic layer was dried (MgSO4), filtered and evaporated to dryness under reduced pressure. The resulting yellow oil was dissolved in methanol and 25% sodium methanolate (25 mL) was added. Stirring continued overnight. More 25% sodium methanolate (15 mL) was added and stirring was continued overnight. Acetic acid (30 mL) was added and the solvent was removed. The residue was purified by column chromatography with heptane/ethyl acetate 50:50 to 100% ethyl acetate. Intermediate 7 (9.38 g, 76%) was obtained as a colorless oil. HPLC Condition A, Rt: 2.49 min, m/z=465 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.39 (1H, NH), 7.75 (d, 1H, J=8.0 Hz), 7.22-7.43 (m, 10H), 6.05 (s, 1H), 5.71-5.84 (m, 1H), 5.35 (d, 1H, J=8.0 Hz), 5.00-5.11 (m, 2H), 4.70 (d, 1H, J=11.5 Hz), 4.53 (d, 1H, J=11.5 Hz), 4.47 (d, 1H, J=11.1 Hz), 4.47 (d, 1H, J=11.1 Hz), 4.11-4.16 (m, 1H), 4.04 (d, 1H, J=8.0 Hz), 3.81-3.87 (m, 1H), 3.45-3.52 (m, 1H), 3.17 (bs, OH), 2.15-2.33 (m, 2H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2Cl)s1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
Under argon, 310 mg (1.40 mmol) of methyl 5-bromothiophene-2-carboxylate together with 328 mg (2.10 mmol) of 2-chlorophenylboronic acid were dissolved in 10 ml of dioxane, and 81 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium(0) were added. The mixture was heated to 110° C., 1.4 ml (2.80 mmol) of 2 M aqueous sodium carbonate solution were added and the mixture was stirred at this temperature for 20 h. For work-up, the reaction mixture was allowed to cool to RT and diluted with 20 ml of ethyl acetate and 20 ml of water. After phase separation, the aqueous phase was extracted two more times with in each case 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 15:1, then 10:1). This gave 289 mg (61% of theory) of the target compound in a purity of 75%.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[C:19]([O:23][CH2:24][CH2:25][NH2:26])([CH3:22])([CH3:21])[CH3:20]>C(O)(C)C.C(OCC)(=O)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:26][CH2:25][CH2:24][O:23][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CC(C)(C)OCCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OCCNc1ccc2ncc(Br)n2n1
Yield: 2.6 %

Procedure:
A solution of 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (216 mg, 1.0 mmol), triethyl amine (0.35 mL, 2.5 mmol) and 2-(tert-butoxy)ethanamine (180 mg, 1.5 mmol) in isopropanol (2 mL) was heated at 65° C. for overnight. The mixture was cooled, diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated to give brown solid as crude in quantitative yield for further synthesis. 20 mg was further purified by Prep HPLC to give pure 3-bromo-N-(2-(tert-butoxy)ethyl)imidazo[1,2-b]pyridazin-6-amine as white solid (8 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.57 (d, J=9.85 Hz, 1H), 7.42 (s, 1H), 6.76 (d, J=9.60 Hz, 1H), 4.56 (s, 1H), 3.67 (t, J=5.94 Hz, 2H), 3.53 (t, J=5.94 Hz, 2H), 1.24 (s, 9H) LRMS (ESI) m/e 315.0 [(M+H)+, calcd for C12H18BrN4O 314.2].
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]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.C(O)(C(F)(F)F)=O.[N:47]1([C:53]2[CH:54]=[CH:55][C:56]([C:59]3[CH:60]=[C:61]([O:68][C@@H:69]([C@H:71]4[CH2:75][NH:74][C:73](=[O:76])[CH2:72]4)[CH3:70])[C:62]4[S:66][CH:65]=[N:64][C:63]=4[CH:67]=3)=[N:57][CH:58]=2)[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C=O)C>[CH:1]1([C:4]([N:50]2[CH2:49][CH2:48][N:47]([C:53]3[CH:54]=[CH:55][C:56]([C:59]4[CH:60]=[C:61]([O:68][C@@H:69]([C@H:71]5[CH2:75][NH:74][C:73](=[O:76])[CH2:72]5)[CH3:70])[C:62]5[S:66][CH:65]=[N:64][C:63]=5[CH:67]=4)=[N:57][CH:58]=3)[CH2:52][CH2:51]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: C[C@@H](Oc1cc(-c2ccc(N3CCNCC3)cn2)cc2ncsc12)[C@H]1CNC(=O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Oc1cc(-c2ccc(N3CCN(C(=O)C4CC4)CC3)cn2)cc2ncsc12)[C@H]1CNC(=O)C1
Reaction time: 0.17 h

Procedure:
Cyclopropanecarboxylic acid (9.6 μL, 0.12 mmol) was dissolved in DMF (0.5 mL) along with iPr2NEt (30 μL, 0.17 mmol). To this mixture was added HATU (46 mg, 0.12 mmol). After 10 min, a mixture of the crude TFA salt of 4.23 (0.06 mmol) and iPr2NEt (50 μL, 0.29 mmol) in DMF (0.5 mL) was added. Additional DMF (2×0.25 mL) was used to ensure complete transfer. After 1.5 h, the reaction mixture was partitioned between EtOAc, water, and sat. aq. NaHCO3. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-25% MeOH in DCM) to afford (R)-4-((R)-1-((5-(5-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol-7-yl)oxy)ethyl)pyrrolidin-2-one (4.33).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:11]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]=12)=[O:5].[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([CH2:36][Mg]Cl)=[CH:34][CH:33]=1>C1COCC1>[CH2:23]([N:11]1[CH:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][C:14]([CH3:16])([CH3:15])[N:9]2[N:8]=[CH:7][C:6]([C:4](=[O:5])[CH2:31][C:32]3[CH:40]=[CH:39][C:35]([CH3:36])=[CH:34][CH:33]=3)=[C:10]12)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(C[Mg]Cl)cc1
Reactant: CON(C)C(=O)c1cnn2c1N(Cc1ccccc1)C(c1ccccc1)CC2(C)C
Solvent: C1CCOC1
Product: Cc1ccc(CC(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To 0.65 g (1.61 mmol) of 3 dissolved in 20 mL of THF was added 6.4 mL (3.2 mmol) of a 0.5 M solution of 4-methylbenzylmagnesium chloride in THF via syringe over 10 min. After stirring at room temperature for 1 h, the reaction was quenched by addition of approximately 2 mL of saturated aqueous ammonium chloride. The reaction was then diluted with AcOEt and dried over sodium sulfate. Filtering the solution through a short plug of silica gel and concentrating in vacuo provided the crude product as an oil. Purification of this oil by flash chromatography eluting with 75% hexanes/AcOEt gave 0.64 g (89%) of the title compound as a white foam. MS Calcd.: 449. Found: 450 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=2I)[N:5]=[C:4]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:19][CH2:18]2)[N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>CCOC(C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=2[C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)[N:5]=[C:4]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:19][CH2:18]2)[N:3]=1
Reactant: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2c(I)c1OC
Reactant: OB(O)c1ccc(F)cc1
Solvent: CCOC(C)=O
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2c(-c2ccc(F)cc2)c1OC

Procedure:
This was prepared by the method of Example 1(a) from the product of step (c) (1.2/1 mixture, w/w) and 4-fluorophenylboronic acid. The crude product was purified on silica gel, eluting initially with hexane/EtOAc (4/1, v/v) followed by EtOAc. The title compound (63% based on the compound of step (c)) was obtained as a white foam. Rf 0.18 (EtOAc). MS m/z 511 (MH+). 1H NMR (CDCl3) δ: 2.00 (2H, m), 3.14 (4H, m), 3.35 (2H, m), 3.48 (3H, s), 3.55 (2H, m), 3.66 (4H, m), 3.84 (2H, m), 3.94 (2H, m), 3.97 (3H, s), 4.52 (2H, bs), 6.90 (1H, bs), 7.16 (2H, m), 7.32 (2H, m). Found: C,60.91; H,6.32; N,15.73; C26H31N6O4F 0.2.EtOAc requires C,60.90; H,6.17; N,15.91%.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C:13]([CH2:15][C:16]#[N:17])=[C:12]([CH2:18][Br:19])[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:11][C:12]([CH2:18][Br:19])=[C:13]([CH2:15][CH2:16][NH2:17])[CH2:14]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CC#N)C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CCN)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
4 g of N-(p-toluenesulfonyl)-3-(bromomethyl)4-(cyanomethyl)-3-pyrroline, prepared in Preparation 6, was dissolved in 100 ml of ethyl ether. The solution was slowly added to the suspension of 1 g of lithium aluminum hydride (LAH) in 20 ml of ethyl ether, and heated with refluxing for 3 hours. The reaction mixture was cooled by ice water. After adding 3 ml of water, it was stirred for 30 minutes and filtered off. The filtrate was concentrated. 2 g of the title compound was obtained (yield 49%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: Oc1cccc(F)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCOc1cccc(F)c1
Yield: 82.7 %

Procedure:
A stirred mixture of 24.3 grams (0.174 mole) of 3-bromopropanol, 20.6 grams (0.180 mole) of 3-fluorophenol, and 37.0 grams (0.270 mole) of potassium carbonate in 300 mL of acetone was heated at reflux for about 18 hours. The reaction mixture was then cooled and concentrated under reduced pressure to a residue, which was stirred with water and extracted with diethyl ether. The ether extract was washed with an aqueous 10% sodium hydroxide solution and then with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 24.5 grams of 3-(3-fluorophenoxy)propanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.O[Li].O.CO>C1COCC1.O>[CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(N2CCC(C)(C)CC2)cc1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of Example 119B (260 mg, 1.0 mmol) and LiOH.H2O (158 mg, 4.0 mmol) in THF (19 mL), water (5 mL), and methanol (5 mL) was heated to 75° C. for 18 hours, cooled to room temperature, concentrated, and adjusted to pH 3-4 with 1N HCl. The precipitate was collected by filtration, washed with water, and dried under vacuum to provide the desired product. MS (DCI(+)) m/e 234 (M+H)+.