Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24]>O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:25])=[O:24]
Reactant: CCCCCCCCO
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCC(=O)S(=O)(=O)c1ccccn1
Reaction time: 3 h
Yield: 99 %

Procedure:
To 3.0 mL of anhydrous triethylamine (23.04 mmol, 30 equiv.) at 0° C. was added 1-octanol (0.10 g 0.77 mmol, 1 equiv.) followed by the addition of 2-pyridylsulfonyl chloride in one portion. The mixture was kept at 0° C. for 3 hours followed by the addition of water (5 mL). The resulting mixture was extracted with diethyl ether (3×50 mL), then the organic extracts were combined and washed with aqueous NaHCO3 solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. Column chromatography (2% EtOAc/Hex) afforded 15 (99%): 1H NMR (CDCl3, 400 MHz) δ 8.68 (d, J=7.0 Hz, 1H, ArH), 7.94 (p, J=8.8 Hz, 2H, ArH), 7.54 (t, J=6.4 Hz, 1H, ArH), 4.26 (t, J=6.7 Hz, 2H, CH2OSO2R), 1.61 (p, J=7.9 Hz, 2H), 1.13 (m, 10H), 0.76 (t, J=7.0 Hz, 3H); MALDI-FTMS 294.1130 (C13H21NO3S+Na+ requires 294.1134).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:15][O:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)C>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Solvent: CCO
Product: CN1CCN(CC(O)COc2cccc3ccccc23)CC1
Yield: 61.3 %

Procedure:
To a solution of 2-((1-naphthyloxy)methyl)oxirane (50 mg, 0.25 mmol) in ethanol (0.50 mL) was added 4-methylpiperazine (33 μL, 0.30 mmol) at room temperature. The mixture was stirred under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give HUHS1008 (46 mg, 61%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1cccc(F)c1
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: CC(C)(C)c1cc2ncc(C#Cc3cccc(F)c3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=294.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-3-fluoro-benzene.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:13]([OH:24])=[CH:14][C:15]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:32][C:33]([F:39])([F:38])[S:34](Cl)(=[O:36])=[O:35]>CC(C)=O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[C:13]([O:24][S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])=[CH:14][C:15]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CN1CCc2cc(O)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCc2cc(OS(=O)(=O)C(F)(F)F)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To an ice bath cooled solution of D6 (340 mg, 0.82 mmol) in acetone (10 mL) was added triethylamine (0.29 mL, 2.1 mmol) followed by trifluoromethanesulfonyl chloride (0.13 mL, 1.2 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue partitioned between dichloromethane and saturated sodium bicarbonate. The organic layer was removed, dried (MgSO4) and evaporated to yield the title compound D7 as a solid (270 mg). MH+ 468. 1H NMR δ (CDCl3) 2.42 (3H, s), 2.55-2.70 (4H, m), 2.95-3.15 (4H, m), 7.09 (1H, s), 7.15-7.24 (2H, t), 7.93-8.04 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][OH:12].[C:13]([NH:20][CH2:21][C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].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>C(Cl)Cl>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][CH2:10][CH2:11][OH:12])=[C:2]([NH:1][C:22](=[O:23])[CH2:21][NH:20][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:7]=1
Reactant: Nc1cc(Br)ccc1NCCO
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cc(Br)ccc1NCCO
Yield: 107.1 %

Procedure:
2-(2-Amino-4-bromophenylamino)ethanol (700 mg, 3.03 mmol), N-Boc-glycine (639 mg, 3.65 mmol), HATU (1.39 g, 3.66 mmol) and i-Pr2NEt (785 mg, 1.0 mL, 6.09 mmol) were stirred in methylene chloride (20 mL) for 20 min. The mixture was purified by column chromatography eluting with methylene chloride and a 9:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 85% methylene chloride, to provide the title compound (1.26 g, quant) as a yellow oil: ESI MS m/z 388 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH:8]=[O:9])=[C:6]([F:14])[C:5]=1[F:15].O>CO>[Br:3][C:4]1[C:5]([F:15])=[C:6]([F:14])[C:7]([CH2:8][OH:9])=[C:10]([F:13])[C:11]=1[F:12]
Reactant: O=Cc1c(F)c(F)c(Br)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1c(F)c(F)c(Br)c(F)c1F
Temperature: 18 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Sodium borohydride (1.0 g) was added portionwise over a period of 30 minutes to a stirred solution of 4-bromo-2,3,5,6-tetrafluorobenzaldehyde (8.2 g) in methanol (80 cm3) whilst the temperature was maintained within the range from -5° C. to +5° C., after which the mixture was stirred for 2 hours at the ambient temperature (ca. 18° C.). The mixture was poured into water and the precipitated white solid collected by filtration, washed with water and air dried to yield 4-bromo-2,3,5,6-tetrafluorobenzyl alcohol (7.5 g), m.p. 60°-62° C.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.Cl.[C:19]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:19]1([N:29]2[CH2:34][CH2:33][N:32]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]3[N:9]=[C:10]4[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]4)=[CH:6][CH:7]=3)[CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2[nH]1
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a mixture of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (175 mg, 0.754 mmol) and 1-naphthalen-1-yl-piperazine hydrochloride (206 mg, 0.829 mmol) in DCE (4 mL) was added Et3N (0.23 mL, 1.66 mmol). The mixture was stirred for 10 min and NaBH(OAc)3 (224 mg, 1.06 mmol) was added as a powder. The reaction was stirred at room temperature for 2 h and then quenched with saturated NaHCO3. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated to give a white foam. Purification by liquid chromatography (5% MeOH/CH2Cl2) gave the title compound as a white foam (260 mg, 0.607 mmol, 80%). The foam was dissolved in a minimal amount of CH2Cl2 and Et2O was added. 1M HCl in Et2O (0.6 mL) was added and a white precipitate formed. The solid was collected by filtration, washed with Et2O and dried to give a white fluffy solid (257 mg). MS: APCI: M+1: 429.2 (Exact Mass: 428.22).
Reaction SMILES: [Cl:1][SiH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12]>>[Cl:1][Si:2]1([CH2:12][CH2:11][CH2:10][CH2:9][C:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C=CCCC(=O)OCc1ccccc1
Reactant: Cl[SiH]1CCCCC1
Product: O=C(CCCC[Si]1(Cl)CCCCC1)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a mixture of crude 1-chlorosilinane (0.35 g) and benzyl pent-4-enoate (0.50 g; 2.63 mmol) under argon was added two drops of Karstedt's catalyst solution (in xylenes; ˜2% Pt). The reaction vessel was sealed and the mixture was heated to 60° C. for 16 hours. The crude liquid was used without purification.
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH3:9])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].C(N(CC)CC)C.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>ClCCl>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([O:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])=[O:25])[CH:20]=1
Reactant: C/C=C(/C=C/CO)CC
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=C(C=CCOC(=O)c1cccnc1)CC
Temperature: 0 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
To a mixture of (E,E)-4-ethyl-2,4-hexadien-1-ol (2.0 g), triethylamine (8 ml), and dichloromethane (15 ml) at 0° C. was added nicotinic acid chloride hydrochloride (4.23 g). The solution was stirred at 0° C. for 1.5 hours and at room temperature for 14 hours. The reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (chloroform) to give 4-ethyl-2,4-hexadien-1-yl 3-pyridinecarboxylate (3.3 g) as an oil.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:9][CH:8]=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC=C(c1ccccc1)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC=C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 1,1-diphenyl-1-propene (17.0 g, 0.10 mol), carbon tetrachloride (100 ml), benzoylperoxide (0.2 g) and N-bromosuccinimide (17.8 g, 0.10 mol) was heated at reflux temperature for 18 h. The reaction mixture was allowed to cool to room temperature, filtered and the solvent was evaporated in vacuo to give 3-bromo-1 1-diphenyl-1-propene in a quantitative yield.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Ca+2:5].[C:6]([O-:9])(=[O:8])[CH3:7].[CH:10]([CH:22]1[CH2:27][C:26](=[O:28])[O:25][C:23]1=O)=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC>O.C(O)(C)C>[C:26]([O:25][CH:23]=[CH:22][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:28])[CH2:27][CH2:2][C:1]([O-:4])=[O:3].[Ca+2:5].[CH:23]([O:25][C:26](=[O:28])[CH2:27][CH2:7][C:6]([O-:9])=[O:8])=[CH:22][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Agent: [Ca+2]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCC=COC(=O)CCC(=O)[O-]
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 113.2 %

Procedure:
A solution of 313.5 g (1.98 mol) calcium acetate in 1000 ml water was added to a solution of 570 g (1.98 mol) dodecenyl succinic anhydride in 1000 ml isopropanol. The mixture was then heated to 90° C., left at that temperature for 1.5 h and then concentrated in a water jet vacuum. The residue was dried in vacuo in a drying cabinet at 100° C. 680 g of the calcium soap were obtained in the form of a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N+:3]=1[CH2:9][C:10]([O:12]CC)=O.[Br-].C[O-].[Na+]>CO.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH2:9][C:10](=[O:12])[N:1]=2)[CH:4]=1
Reactant: CCOC(=O)C[n+]1cc(Br)ccc1N
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CN2C=C(Br)C=CC2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3 %

Procedure:
To a solution of 2-Amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium; bromide (2.86 g, 8.4 mmol) in methanol (30 mL) was added sodium methoxide (25 wt %, 2.5 mL, 10.1 mmol). The reaction mixture was stirred at room temperature overnight under argon. The reaction mixture was diluted with water and then extracted three times with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, evaporated to yield a tan solid. The crude material was purified by column chromatography eluting with 3, 5, and 10% methanol/dichloromethane. The product was obtained as a brown solid (56 mg, 3%). 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.67 (dd, J=1.6, 9.5 Hz, 1H), 7.07 (d, J=9.5 Hz, 1H), 4.52 (s, 2H); MS (m/e): 215 (MH+); HRMS: calc'd MH+ for C7H5BrN2O 212.9672. Found 212.9664.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][CH:11]([CH2:16][CH:17]=[CH2:18])[C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH2:19]([O:22][C:23]1([CH3:52])[CH2:28][CH2:27][N:26]([C:29]2[N:34]3[N:35]=[C:36]([CH2:38]I)[CH:37]=[C:33]3[N:32]=[C:31]([CH3:40])[C:30]=2[C@H:41]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:25][CH2:24]1)[CH:20]=[CH2:21].[H-].[Na+]>CN(C=O)C>[C:48]([O:47][C@@H:41]([C:30]1[C:31]([CH3:40])=[N:32][C:33]2[N:34]([N:35]=[C:36]([CH2:38][O:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:10][CH:11]([CH2:16][CH:17]=[CH2:18])[C:12]([F:13])([F:14])[F:15])[CH:37]=2)[C:29]=1[N:26]1[CH2:25][CH2:24][C:23]([CH3:52])([O:22][CH2:19][CH:20]=[CH2:21])[CH2:28][CH2:27]1)[C:42]([O:44][CH2:45][CH3:46])=[O:43])([CH3:51])([CH3:49])[CH3:50]
Reactant: C=CCC(Oc1cc(F)ccc1CO)C(F)(F)F
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(F)cc4OC(CC=C)C(F)(F)F)nn23)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(4-Fluoro-2-((1,1,1-trifluoropent-4-en-2-yl)oxy)phenyl)methanol (66 mg, 0.25 mmol) and (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (145 mg, 0.25 mmol) were dissolved in 1 mL of DMF at 0° C. and 60% (mineral oil) NaH (10 mg, 0.25 mmol) added. The resulting mixture was stirred at 0° C. for 3 hours then quenched with 1N HCl. The mixture was extracted with ethyl acetate. The organic fractions were combined and dried over Na2SO4, filtered and the solvent removed to yield the crude product which was used in the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25].O>CN(C)C=O>[CH3:22][C:23]([CH3:28])([CH3:27])[C:24]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)n1ccc2cc(C(=O)OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
Sodium hydride (53 mg) was added to a solution of benzyl 1H-indole-5-carboxylate (276 mg) in N,N-dimethylformamide (2 ml) with ice cooling, and the mixture was stirred for 30 minutes. 2,2-Dimethylpropionyl chloride (162 mg) was added thereto, and the mixture was stirred for 2 hours. Water was added thereto, and the aqueous phase was neutralized, extracted with dichloromethane, and the extract was dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure to give benzyl 1-(2,2-dimethylpropionyl)-1H-indole-5-carboxylate (320 mg, Y.:87%) as pale orange crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=[O:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Cc1cnc(-c2ccnc(F)c2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cnc(-c2ccnc(F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)acetate 205-5 (248 mg, 0.81 mmol) and TFA (0.8 mL) in DCM (0.8 mL) was stirred at room temperature for 3 hours. The solution was adjusted to pH around 12 by Na2CO3 and extracted with dichloromethane. The aqueous phase was acidified to pH 3 by 1N HCl aqueous solution and stirred for 15 minutes. The solvents were evaporated and the remaining solid was extracted with 20% methanol in ethyl acetate and filtered to remove the insoluble. The filtrate was concentrated to dryness by rotary evaporation to give 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)acetic acid 205-6, which was used directly for next step. MS m/z 251.1 (M+1).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[CH:25]1([CH2:30][C@H:31]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)[C:32](Cl)=[O:33])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:32](=[O:33])[C@@H:31]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)[CH2:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
In a round bottom flask was placed 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 86 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (prepared as in Example 102, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes) afforded (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (128 mg, 77%) as a white foam: [α]30589=−74.3° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C25H37N3O2SiCl2 (M+H)+ 510.2105, observed 510.2105; 1H NMR (300 MHz, DMSO-d6) δ −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.10 (m, 2H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.05 (m, 1H, CH), 3.81 (m, 1H, ArCHCO), 3.84 (t, J=5.4 Hz, 2H, OCH2), 4.04 (t, J=5.4 Hz, 2 H, NCH2), 6.40 (d, J=2.3 Hz, 1H, Ar), 7.34 (dd, Jm=2.1 Hz, Jo=8.3 Hz, 1H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.58 (d, Jo=8.3 Hz, 1H, Ar), 7.59 (d, Jm=2.1 Hz, 1H, Ar), 10.68 (s, 1H, NH).
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.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:17][CH:16]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
To a solution of ethyl 4-aminobenzoate (10 g) and 4-(dimethylamino)benzaldehyde (9.0 g) in methylene chloride (200 mL) is added sodium triacetoxyborohydride (18.9 g) and acetic acid (3.47 mL) under ice-cooling, and the mixture is stirred at room temperature for 2 days. To the reaction mixture is added a saturated sodium hydrogencarbonate solution and extracted with chloroform (×2). The extract is concentrated in vacuo and the residue is triturated in n-hexane/ethyl acetate to give ethyl 4-[4-(dimethylamino)benzylamino]benzoate (11.6 g, yield; 64%) as powder. MS (APCI) m/z; 299 [M+H]+
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[C:56]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:55][CH:54]=[CH:53][N:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[C:56]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)=[CH:55][CH:54]=[CH:53][N:52]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ncccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.013 g of product in 54% yield: LCMS (ESI) m/z 389 (MH+).
Reaction SMILES: C[O-].[Na+].[Si:4]([N:11]1[CH:14]([CH2:15][CH2:16][O:17]C(=O)C(F)(F)F)[CH:13]([N:24]=[N+:25]=[N-:26])[C:12]1=[O:27])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].C(O)(=O)C>CO>[Si:4]([N:11]1[CH:14]([CH2:15][CH2:16][OH:17])[CH:13]([N:24]=[N+:25]=[N-:26])[C:12]1=[O:27])([C:7]([CH3:9])([CH3:10])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium methoxide (0.02 mol) in methanol (20 ml) is added to an ice-cold solution of N-(t-butyldimethylsilyl)-3-azido-4-(2-trifluoroacetoxyethyl)-azetidin-2-one (0.1 mol) in methanol (100 ml). After stirring in the cold for 10 min, the solution is treated with acetic acid (2 ml) and concentrated under vacuum. The resdue is taken up in ethyl acetate, washed with water, 5% sodium bicarbonate solution, and brine, dried, and evaporated. The residue is chromatographed on silica gel to give N-(t-butyldimethylsilyl)-3-azido-4-(2-hydroxyethyl)-azetidin-2-one.