Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[C:13]([Cl:19])=[N:14][CH:15]=[CH:16][C:17]=1[NH2:18].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH:31]=[C:30]([CH2:33]Cl)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl-].[NH4+]>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH:29]=[C:30]([CH2:33][NH:18][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([Cl:19])[C:12]=2[Br:11])[CH2:31][CH2:32]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Nc1ccnc(Cl)c1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(CCl)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CNc2ccnc(Cl)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (1M solution in THF, 5.1 ml) was added dropwise to a stirred solution of 3-bromo-2-chloro-4-aminopyridine (1.04 g) in tetrahydrofuran (15 ml) at −78° C. under N2. The resulting solution was then stirred at room temperature for 30 min., warmed to 0° C. then cooled again at −78° C. 4-Chloromethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.16 g, prepared according to WO 98/25605) dissolved in a minimum volume of THF was added dropwise then the solution was refluxed for 14 hours. The reaction mixture was cooled to room temperature, poured into diluted aqueous ammonium chloride, extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 then CH2Cl2/EtOAc 8:2 cyclohexane:ethyl acetate 8:2) to afford 4-[(3-bromo-2-chloro-pyridin-4-ylamino)-methyl]-3,6-dihydro-2H -pyridine-1-carboxylic acid tert-butyl ester (1.42 g), which was identified by its mass and 1H NMR spectra. MS (ES+) 346/348/350 (MH+-isoprene), 402/404/406 (MH+).
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC=CC=1>[Zn].O>[Cl:1][C:2](=[CH2:3])[CH2:4][C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C=C(Cl)CCl
Reactant: O=C1CCCCC1
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(Cl)CC1(O)CCCCC1

Procedure:
45.23 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 20.00 g of cyclohexanone, 60 g of toluene, 60 g of water and 26.65 g of zinc powder at 35° C., and after the addition, the resultant mixture was maintained at the same temperature for 5 hours. After the reaction was completed, zinc-derived insolubles were filtered off, and the resultant filtrate was separated. The organic phase thereof was washed with a 7% sodium carbonate aqueous solution, and dried over magnesium sulfate. The desiccant was filtered off, and the resultant toluene solution was concentrated under reduced pressure to give 32.75 g of 1-(2'-chloroallyl)-1-cyclohexanol; nD20 =1.495, EI-MS m/e 156 (M-H2O+), 158 (M-H2O+2+).
Reaction SMILES: C([Li])CCC.C([Mg]Cl)CCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=1.CN(C)[CH:22]=[O:23]>CCCCCC.C1(C)C=CC=CC=1.O1CCCC1.C(O)(=O)C>[Br:19][C:15]1[N:14]=[C:13]([CH:22]=[O:23])[CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(Br)n1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Br)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
n-Butyllithium (337 mmol) in 1.52M hexane solution (222 mL) was dissolved in toluene (500 mL) cooled at −10° C., and n-butylmagnesium chloride (169 mmol) in 2.00M tetrahydrofuran solution (84.5 ml) was added dropwise below −10° C. over a period of 25 minutes. After stirring at −10° C. for one hour, 2,6-dibromopyridine (100 g, 422 mmol) in toluene (1000 mL) was added dropwise to the mixture at an inside temperature of −10° C. to −6° C. over one hour. The mixture was further stirred at −10° C. for 1.5 hours and then N,N-dimethylformamide (65 mL, 840 mmol) was added dropwise below −2° C. over 20 minutes. After further stirring at 0° C. for one hour, 10% aqueous acetic acid solution (750 mL) was added. The mixture was stirred under ice-cooling and the organic phase was separated. The extract was washed with saturated aqueous sodium chloride (25 mL), dried over anhydrous sodium sulfate and concentrated to give 6-bromo-2-formylpyridine (74.68 g, 98% purity, 95% yield) as a pale yellowish solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:10]([O:12][CH3:13])=[O:11])[CH2:4][CH2:5][C:6]([O:8]C)=O.[OH-].[Na+].C(O)(=O)C.[C:20]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21]1.[BH4-].[Na+]>CO.C1(C)C=CC=CC=1.O1CCCC1>[CH:20]1([N:2]2[C:6](=[O:8])[CH2:5][CH2:4][C@H:3]2[C:10]([O:12][CH3:13])=[O:11])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCC1
Reactant: COC(=O)CC[C@@H](N)C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1C1CCCC1
Temperature: 0 °C
Reaction time: 0.21 h

Procedure:
Dimethyl D-glutamate hydrochloride (2.1 g, 10.00 mmol) was dissolved in methanol (7.5 ml) and tetrahydrofuran (15 ml) and the mixture was then treated with crushed sodium hydroxide (0.402 g, 10.05 mmol) for 20 minutes under argon. At this stage acetic acid (0.575 ml, 10.05 mmol) and cyclopentanone (0.889 ml, 10.05 mmol) were added to the mixture. After stirring for 10-15 minutes the mixture was cooled to 0° C. in an ice-bath and treated with sodium borohydride pellets (0.380 g, 10.05 mmol). The mixture was stirred for 3 hrs under argon and allowed to warm to room temperature. Once the mixture had reached room temperature the methanol was evaporated off and the residue was diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (˜25 ml). The organic layer was separated and the aqueous layer was back-extracted with more dichloromethane (2×20 ml). The combined organic layers were concentrated in vacuo to give an oil. The oil was dissolved in toluene (10 ml) and heated at reflux overnight. The solvent was then evaporated and the resulting residue was purified by flash-silica column chromatography, eluting with a gradient of 0-10% methanol in dichloromethane, to give crude methyl 1-cyclopentyl-5-oxoprolinate which was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:34]#[C:35][CH2:36][CH3:37])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([C:34]#[C:35][CH2:36][CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCC#C[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC#C[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 18 h
Yield: 57.3 %

Procedure:
To a stirred solution of 24.3 (0.050 g, 0.10 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting mixture was stirred for 18 hours. The resulting mixture was then concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 24 (28 mg, 57% yield) as a colorless oil. MS ESI (neg.) m/e: 487.1 (M−H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[N:26][CH:27]=1>C1(C)C=CC=CC=1.CCO.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[CH:27][N:26]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Fc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccc(OC(F)(F)F)cc2)cn1
Temperature: 86.5 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A stirred mixture of 4-(trifluoromethoxy)phenylboronic acid (1.55 g, 7.53 mmol) and Pd(dppf)Cl2 (367 mg, 0.502 mmol) in toluene (50 mL) and EtOH (25 mL) was degassed for 15 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (12.5 mL, 25.0 mmol) was added by syringe and the stirred mixture was again degassed for 15 min, and then N2 was added, followed by 5-bromo-2-fluoropyridine (91) (0.53 mL, 5.15 mmol). The resulting mixture was stirred at 85-88° C. for 3 h, and then cooled, diluted with aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (4×100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-10% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 10-20% CH2Cl2/petroleum ether gave 2-fluoro-5-[4-(trifluoromethoxy)phenyl]pyridine (92) (1.32 g, 100%) as a white solid: mp (CH2Cl2/petroleum ether) 58-60° C.; 1H NMR (CDCl3) δ 8.40 (d, J=2.5 Hz, 1H), 7.94 (ddd, J=8.4, 7.6, 2.6 Hz, 1H), 7.55 (dt, J=8.8, 2.5 Hz, 2 ft), 7.33 (br d, J=8.0 Hz, 2H), 7.02 (dd, J=8.5, 3.0 Hz, 1H); HRESIMS calcd for C12H8F4NO m/z (MH+) 258.0537. found 258.0531.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>C(#N)C>[C:3]1([C:9]([CH3:13])([CH3:12])[CH2:10][O:11][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][F:14])=[CH:25][CH:24]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FCCOc1ccc(CCl)cc1
Reactant: CC(C)(CO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(COCc1ccc(OCCF)cc1)c1ccccc1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
Sodium hydride (1.4 g; 60% in oil) was added to 20 ml of dry acetonitrile, and a solution of 4.4 g of 2-phenyl-2-methylpropyl alcohol in 10 ml of acetonitrile was added dropwise at 50° C. The mixture was heated under reflux for 30 minutes, and a solution of 5.4 g of 4-(2-fluoroethoxy)benzyl chloride in 10 ml of acetonitrile was added dropwise over 10 minutes. The mixture was further heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (180 g) column chromatography (developing solvent: a 2:1 mixture of toluene and n-hexane) to give 6.5 g of 4-(2-fluoroethoxy)benzyl 2-phenyl-2-methylpropyl ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]=[C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10]2)[CH:2]=1.ON1C(=O)C2C=CC=CC=2N=N1.Cl.[CH3:38][O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH2:44][S:45][CH3:46])[NH2:42].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O.C(N(CC)CC)C>[CH3:38][O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH2:44][S:45][CH3:46])[NH:42][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:10][C:11]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)C1=C(Oc2ccccc2)CC(=COc2cccnc2)C=C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COc2cccnc2)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To a solution in DMF (3 mL) of 4-(3-pyridyloxymethylene)-2-phenoxybenzoic acid (321 mg), prepared as in Example 157F, was added 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (345 mg, 1.5 mmol) followed by methionine methyl ester hydrochloride (300 mg, 1.5 mmol), ethyl dimethylaminopropyl carbodiimide hydrochloride (288 mg, 1.5 mmol), and triethylamine (280 mg). The reaction mixture was stirred for 15 hours at ambient temperature. The reaction mixture was diluted with water and extracted with toluene. The toluene solution was washed with, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (75% ethyl acetate-hexanes) gave [4-(3-pyridyloxymethyl)-2-phenoxybenzoyl]methionine methyl ester (425 mg, 98%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C@@H:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][S:21]([OH:24])(=[O:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14](F)[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[Cl:29]C1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.FC1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.C(O)(C(F)(F)F)=O>C(#N)C.O>[Cl:29][C:14]1[CH:15]=[C:16]2[C:8]([C:5]3[N:4]=[C:3]([NH:18][C@@H:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][S:21]([OH:24])(=[O:23])=[O:22])[C:2]([F:1])=[CH:7][N:6]=3)=[CH:9][NH:10][C:11]2=[N:12][CH:13]=1
Reactant: CC(C)(C)[C@@H](CS(=O)(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[C@@H](CS(=O)(=O)O)Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F

Procedure:
Sulfonic acid, 10, was synthesized in a manner similar to Compound 11, using 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine instead of boronate ester, 7a, as the starting material: 1H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd, J=9.2, 2.6 Hz, 1H), 8.22 (d, J=5.7 Hz, 1H), 8.13 (s, 1H), 5.16 (d, J=4.1 Hz, 1H), 3.46-3.33 (m, 2H), 1.10 (d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 412.19 (M+H) retention time=1.91 minutes.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][C:11](=[O:46])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[N:24]([CH:25]=2)[N:23]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][CH:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH2:34][CH2:33]4)=[CH:28][CH:27]=2)[S:21]3)=[CH:14][CH:13]=1)C.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH3:45][O:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][CH:35]1[CH2:34][CH2:33][N:32]([C:29]2[CH:28]=[CH:27][C:26]([C:22]3[S:21][C:20]4=[N:19][C:18]([C:15]5[CH:14]=[CH:13][C:12]([C:11]([OH:46])=[O:10])=[CH:17][CH:16]=5)=[CH:25][N:24]4[N:23]=3)=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: CCOC(=O)c1ccc(-c2cn3nc(-c4ccc(N5CCC(OCCCCCOC)CC5)cc4)sc3n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COCCCCCOC1CCN(c2ccc(-c3nn4cc(-c5ccc(C(=O)O)cc5)nc4s3)cc2)CC1
Yield: 81.1 %

Procedure:
To a solution of 4-[2-[4-[4-(5-methoxypentyloxy)-piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (2.01 g) in a mixture of methanol (40 ml) and tetrahydrofuran (20 ml) was added 4N-NaOH (20 ml), and the mixture was refluxed for 6 hours. The reaction mixture was cooled, poured into water (200 ml) and adjusted to pH 2 with conc. HCl. The resulting precipitate was collected by filtration, washed in turn with water, isopropyl alcohol (30 ml) and IPE (50 ml) to give 4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]-imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (1.28 g).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3B3OC(C)(C)C(C)(C)O3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:43]1[S:44][CH:45]=[C:46]([Br:48])[N:47]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:43]3[S:44][CH:45]=[C:46]([Br:48])[N:47]=3)[C@H:14]2[CH3:39])[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=1
Reactant: Brc1csc(Br)n1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
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: COCCOC
Solvent: CCO
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(Br)cs1
Temperature: 100 °C

Procedure:
In a tube were placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (59 mg, 0.099 mmol), 2,4-dibromothiazole (60 mg, 0.247 mmol), DME (420 μL), EtOH (140 μL), and 1M Na2CO3 (296 μL, 0.296 mmol). The mixture was degassed with N2 and then Pd(PPh3)4 (5.7 mg, 4.94×10−3 mmol) was added. The mixture was degassed with N2 again, and then the tube was sealed, and the reaction was heated at 100° C. for 90 minutes. The reaction was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with water and brine (10 mL) each, dried over Na2SO4, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-bromo-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.33 (25% EtOAc/hexanes). LCMS=635.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89 (bs, 2H), 7.78 (s, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.68 (dd, J=8.1, 1.0 Hz, 1H), 7.41 (s, 1H), 5.66 (d, J=8.0 Hz, 1H), 5.02 (d, J=15.8 Hz, 1H), 4.84 (d, J=15.8 Hz, 1H), 4.20 (m, 1H), 0.78 (d, J=6.7 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(Cl)Cl>[C:21]([N:28]1[CH2:29][CH2:30][N:31]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:32][CH2:33]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: OC(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 48 h

Procedure:
To a stirring solution of bis(4-bromophenyl)methanol (0.060 mmol) in CH2Cl2 (0.3 mL) was added thionyl chloride (40 μL, 0.60 mmol) and the reaction mixture was stirred for 48 h. The reaction was evaporated to dryness under a stream of N2 and the crude product redissolved in acetonitrile (1.0 mL). 1-Boc-piperazine (22.3 mg, 0.12 mmol) was added and the reaction mixture was refluxed for 4 h. The reaction mixture was concentrated under reduced pressure, redissolved in CH2Cl2 and passed through a short pad of SiO2, providing the 1-Boc-4-diphenylmethylpiperazine.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([Sn](CCCC)(CCCC)[C:18]1[N:19]=[CH:20][S:21][CH:22]=1)CCC.O.CCOC(C)=O>C1COCC1.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>[S:21]1[CH:22]=[C:18]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=[CH:20]1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(-c2cscn2)c1
Temperature: 75 °C

Procedure:
A mixture of commercially available ethyl 3-iodobenzoate (650 mg; 2.35 mmol), 4-(tributylstannyl)thiazole (894 mg; 2.39 mmol), and PdCl2(PPh3)2 (165 mg; 0.23 mmol) in anh. THF (20 ml) was heated to 75° C., under nitrogen, for 17 h. Water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded ethyl 3-(thiazol-4-yl)benzoate as a yellow oil. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 233.94 g/mol.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:9]=1)(C)(C)C.C(C1NC=CN=1)(C1[NH:25]C=CN=1)=O.N>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([C:10]2[CH:9]=[C:8]([CH2:7][C:6]([NH2:25])=[O:5])[CH:13]=[CH:12][N:11]=2)[CH2:15][CH2:16]1
Reactant: CN1CCN(c2cc(CC(=O)OC(C)(C)C)ccn2)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2cc(CC(N)=O)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[2-(4-Methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid tert-butyl ester (95 mg, 0.33 mmol) is dissolved in a mixture of TFA and CH2Cl2 (5 ml/5 ml) and stirred at RT. After 1 h at RT, TLC analysis indicated complete conversion of starting material. The solvent is removed by rotary evaporation, and replaced by dry DMF (1.5 ml). Under an atmosphere of argon, carbonyl diimidazole (58 mg, 0.36 mmol) is added. After 20 minutes at RT, TLC analysis indicated complete conversion of the carboxylic acid. An aqueous solution of ammonia (25%, 6 ml) is added at RT. After 15 minutes at RT, solvents are removed under high vacuum. The residue is dissolved in CH2Cl2/MeOH (9:1) and purified by FCC (CH2Cl2/MeOH, slow gradient from 95:5 to 40:60) to yield the title compound. 1H NMR (d4-MeOD, 400 MHz): δ 2.35 (s, 3H), 2.56 (m, 4H), 3.46 (s, 2H), 3.54 (m, 4H), 6.66 (d, J=6 Hz, 1H), 6.78 (s, 1H), 8.02 (d, J=6 Hz, 1H). ES+−MS: 235.3 [M+H]+.
Reaction SMILES: [N+](CC)([O-])=O.C(N)(C)C.C=O.[N+:12]([C:15]([CH3:26])([CH2:21][NH:22][CH:23]([CH3:25])[CH3:24])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])([O-])=O>CC(O)C>[NH2:12][C:15]([CH3:26])([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:21][NH:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)NCC(C)(CNC(C)C)[N+](=O)[O-]
Agent: C=O
Solvent: CC[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CC(C)N
Product: CC(C)NCC(C)(N)CNC(C)C
Reaction time: 4 h

Procedure:
In a manner analogous to that described hereinabove, 1 mol of nitroethane is added slowly to 2 mols of isopropylamine to form the salt intermediate, and thereafter 2 mols of paraformaldehyde are slowly added to the salt with stirring which is continued for 4 hr. The conversion of the nitroethane to 2-nitro-2-methyl-1,3-di(isopropylamino)propane is in excess of 90 mol %. The reaction mixture is then diluted with 250 ml of i-PrOH and hydrogenated in a manner analogous to that described hereinabove, to yield 2-amino-2-methyl-1,3-di(isopropylamino)propane the conversion of which is in excess of 90 mol % based on the nitroethane charged.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:4]=1[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[N:7]=1.Cl.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.[OH-].[Na+].O.CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][CH2:34][NH:35][C:11]([C:8]1[N:7]=[C:6]([CH2:5][C:4]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:3]=2[O:2][CH3:1])[O:10][N:9]=1)=[O:13]
Reactant: CCOC(=O)c1noc(Cc2cc(OC)ccc2OC)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc(OC)c(Cc2nc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)no2)c1
Yield: 36.1 %

Procedure:
This compound was prepared according to method F with ethyl 5-(2,5-dimethoxybenzyl)-1,2,4-oxadiazole-3-carboxylate (0.126 g; 0.433 mmol) in methanol (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.069 g (36%) of the N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,5-dimethoxybenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.