Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[C:19]1([NH2:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C>[C:13]1([C:6]2[CH:7]=[C:8]([C:10](=[O:12])[NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:9][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1sc(C(=O)O)cc1-c1ccccc1
Reactant: Nc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc(C(=O)Nc2ccccc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 174 (0.334 g, 1.273 mmol) in 6 mL DMF was added PhNH2 (0.128 ml, 1.401 mmol), followed by BOP (0.620 g, 1.401 mmol) and TEA (0.355 ml, 2.55 mmol). The mixture was stirred for 1 h at room temperature and then poured into water. The product was extracted with ethyl acetate twice and the combined organic phases were washed with water and brine. The solution was dried over sodium sulfate, filtered and evaporated in vacuo. The crude residue was purified by ISCO (24 g column, 0%-100% ethyl acetate in hexanes) to yield compound 175 (285 mg, 66%) a off-white solid.
Reaction SMILES: [NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)=[O:20].C([O-])(O)=O.[Na+]>ClCCl>[CH3:18][S:19]([N:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1)=[O:20]
Reactant: C1CCC2NCCCC2C1
Reactant: CS(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)N1CCCC2CCCCC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
A solution of decahydroquinoline (1.07 g, 7.68 mmol) in anhydrous dichloromethane (10 mL) was cooled to −15° C. The reaction mixture was treated with triethylamine (1.07 mL, 7.68 mmol) and methanesulfinyl chloride (800 mg, 8.11 mmol). After 1 hour, the reaction mixture was placed in a −40° C. freezer overnight. The reaction mixture was warmed to room temperature and treated with 5% aq. NaHCO3 (10 mL) and additional dichloromethane (10 mL) and was separated. The organic layer was washed with 3% aq. HCl (1×20 mL), 5% aq. NaHCO3 (2×20 mL), water (1×20 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2, ethyl acetate eluant) afforded the product as a yellow oil (1.2 g, 77%): 1H NMR (CDCl3, 600 MHz, δ) 3.41-2.70 (m, 4H), 2.52 (s, 1.3H, C1′-H), 2.51 (s, 0.4H, C1′-H), 2.49 (s, 1.3H, C1′-H), 1.75-1.26 (m, 12H); 13C NMR (CDCl3, 125 MHz, δ) 54.2, 49.2, 48.3, 47.8, 43.2, 42.6, 42.3, 41.6, 41.5, 41.4, 41.6, 41.5, 41.4, 39.0, 38.9, 38.84, 38.77, 35.6, 35.4, 34.0, 33.9, 33.1, 32.6, 32.5, 30.1, 30.0, 26.0, 25.7, 25.6; ESIMS m/z 224.2 (4, MNa+), 204.1 (5, 32S), 203.0 (13, 13C), 202.0 (base, MH+); ESIHRMS m/z 202.1260 (calculated for C10H20NOS 202.1260).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>ClCCl.O>[N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl isonipecotate (2.5 g, 15.9 mmol) in dichloromethane (80 mL) at 0° C. was treated with (BOC)2O (3.8 g, 17.3 mmol), warmed to room temperature, stirred for 2 hours, diluted with water, and extracted with dichloromethane. The combined extracts were washed sequentially with saturated sodium bicarbonate, 5% citric acid, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 258 (M+H)+.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[P:26]([O-:34])([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27]>>[P:26]([O:34][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOP(=O)([O-])OCC
Reactant: ON=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CCOP(=O)(OCC)OC1(N=O)CCCCC1

Procedure:
Diethyl 1-nitrosocyclohexyl phosphate was prepared from cyclohexanone oxime, lead tetraacetate and diethyl phosphate using conditions of General Method 3. 1H NMR (400 MHz, benzene-d6) δ 3.90-4.15 (3H, m), 1.24-1.78 (10H, m), 0.88-1.10 (7H, m)
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[O:15][N:14]=2)=O)=[C:8]([Cl:21])[C:7]([O:22][CH3:23])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:21][C:8]1[C:7]([O:22][CH3:23])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[O:15][N:14]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2cc(C(C)C)on2)c1Cl
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(O)cc(-c3cc(C(C)C)on3)nc2c1Cl

Procedure:
Compound 93d was synthesized from compound 92d as a white solid in quantitative yield, following the procedure as described for compound 43a.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](Cl)(=[O:20])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:9](=[O:20])([O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1ccccc1
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl alcohol was treated with phosgene or similar reagents, such as diphosgene or triphosgene, in the presence of a base, such as DIEA, at 0° C. for 30 min. The solvent was then removed via vacuum and the resulting intermediate carbonochloridate was dissolved in an organic solvent, such as DCM or EtOAc, and then treated with amine in the presence of base, such as Hunig's base or aqueous Na2CO3, to provide the desired carbamate. If required, hydrolysis under a basic condition, such as aqueous LiOH, was used to convert the carbamate to the final product. Alternatively, the benzyl alcohol was treated with 4-nitrophenyl carbonochloridate in the presence of base, such as pyridine, at 0° C. The reaction mixture was slowly warmed to room temperature where it was stirred overnight. After this time, the reaction was quenched with water. The organic layer washed with water and brine, dried over MgSO4 and concentrated in vacuum to provide the crude material. The crude material was purified by silica gel flash chromatography to afford the corresponding benzyl 4-nitrophenyl carbonate. The resulting benzyl 4-nitrophenyl carbonate was then treated with amine in the presence of a base, such as Hunig's base or aqueous Na2CO3, to get the desired carbamate. If required, hydrolysis under a basic condition, such as aqueous LiOH, was used to convert the carbamate to the final product.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[N:26]([CH2:29][CH3:30])=[C:27]=[O:28].O>C1COCC1>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:25]=[N:24][N:23]([C:27]([NH:26][CH2:29][CH3:30])=[O:28])[CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c2c1c(-c1cn[nH]c1)nn2-c1c(F)cccc1F
Reactant: CCN=C=O
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)n1cc(-c2nn(-c3c(F)cccc3F)c3c(Cl)cnc(OC)c23)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-1-(2,6-difluorophenyl)-4-methoxy-3-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (40 mg) obtained in Step A of Example 177 in THF (3 mL) was added isocyanatoethane (0.018 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (45 mg).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](OCC)=[O:5].[NH2:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:18][O:17][C:16]2=[O:28])=[CH:12][CH:11]=1.C(OCl)(C)(C)C.C(N(CC)CC)C.Cl>C1COCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[CH2:18][O:17][C:16](=[O:28])[N:15]([CH2:14][C:13]3[CH:29]=[C:30]4[C:10](=[CH:11][CH:12]=3)[NH:9][C:4](=[O:5])[CH:3]4[S:2][CH3:1])[N:20]=2)=[CH:22][CH:23]=1
Reactant: Nc1ccc(CN2N=C(c3ccc(Cl)cc3)COC2=O)cc1
Reactant: CCOC(=O)CSC
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSC1C(=O)Nc2ccc(CN3N=C(c4ccc(Cl)cc4)COC3=O)cc21
Temperature: -60 °C
Reaction time: 3 h

Procedure:
Ethyl (methylsulphanyl)acetate (27.31 mmoles) is added dropwise to a solution of the compound obtained in Step E (23.75 mmoles) in THF (200 ml) at −60° C. under a nitrogen atmosphere. tBuOCl− (27.31 mmoles) is added dropwise to the reaction mixture over 20 minutes, keeping the temperature between −60° C. and −55° C. After stirring for 3 hours at −60° C., triethylamine (29.68 mmoles) is added dropwise. The reaction mixture is brought to ambient temperature; aqueous 3M HCl solution (340 ml) is then added and stirring is carried out for a further 2 hours. The organic phase is evaporated and the aqueous suspension is extracted with DCM. The organic phases are combined, then washed with 2M HCl solution and then with saturated NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue is triturated in ethyl ether, filtered and dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: C([C:3]1[C:4]([F:27])=[C:5]([C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]=[C:7]([F:18])[C:8]=1[CH:9]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10]1)C>C(OC(=O)C)(=O)C>[O:15]1[C:11]2([CH2:16][CH2:17][CH:9]([C:8]3[C:7]([F:18])=[CH:6][C:5]([C:19](=[O:26])[C:20](=[CH:13][O:12][CH2:11][CH3:10])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([F:27])[CH:3]=3)[CH2:10]2)[O:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2CCC3(C2)OCCO3)c(CC)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCC3(C2)OCCO3)cc1F

Procedure:
A solution of 35.4 g (0.1 mol) of ethyl 2,5-difluoro-4-(1,4-dioxaspiro[4.4]non-7-yl)-β-oxobenzenepropanoic acid, ethyl ester 22.2 g (0.15 mol) triethyl orthoformate and 150 ml of acetic anhydride was heated at reflux for 4 hours. The solvent was removed in vacuo and the residue was triturated with ethanol and toluene (150 ml ea) which was also removed in vacuo, then high vacuo at 50°. The residue was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[N:10]3[C:14]([CH2:15][NH:16][CH2:17][C:8]=2[CH:7]=1)=[N:13][N:12]=[C:11]3[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1>>[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[N:10]3[C:14]([CH2:15][N:16]([C:1](=[O:3])[CH3:2])[CH2:17][C:8]=2[CH:7]=1)=[N:13][N:12]=[C:11]3[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[CH:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Reactant: CC(=O)Cl
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Yield: 37 %

Procedure:
The title compound was prepared from acetyl chloride and the amine of example 12, in 37% yield, using the procedure described in example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1OC2C=CC=CC=2N=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOC(C)=O>[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1[O:8][C:7]2[C:6]([CH3:9])=[CH:5][CH:4]=[CH:3][C:2]=2[N:1]=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)c1nc2ccccc2o1
Reactant: Cc1cccc(N)c1O
Solvent: CCOC(C)=O
Product: Cc1cccc2nc(C(O)[C@H](C)NC(=O)OCc3ccccc3)oc12
Yield: 57 %

Procedure:
This material was prepared as a 1:1 mixture of isomers in 57% yield from the above cyanohydrin (609 mg, 2.60 mmol) and 6-amino-o-cresol (330 mg, 2.60 mmol) using the procedure described above for compound 16. An analytical sample (1.2:1 mixture of isomers) was obtained by flash chromatography (30% EtOAc in hexanes). oil; IR (neat) υ 1705 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.50 (m, 1H), 7.35-7.10 (m, 7H), 5.50 and 5.38 (2×d, J=8.9 and 8.3 Hz, 1H), 5.15-4.90 (m, 3H), 4.41 (s, 1H), 2.36 (5, 3H), 1.35 and 1.14 (2×d, J=6.7 and 7.0 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3) δ 165.41, 164.85, 156.29, 156.12, 150.14, 139.67, 136.28, 128.50, 128.39, 128.13, 127.97, 127.84, 126.36, 126.31, 124.59, 124.51, 121.54, 117.28, 117.12, 70.99, 70.56, 66.96, 66.71, 50.42, 50.25, 17.41, 15.26, 15.08; FAB MS m/z: 341 (MH+); HRMS calcd for C19H21N2O4 (MH+) 341.1501, found: 341.1490; Anal (C19H20N2O4) C, H, N.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([C:10]([O:12]CC)=O)=[CH:7][CH:6]=1)[CH3:3].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([C:10]([NH:17][CH2:16][CH2:15][NH2:18])=[O:12])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CCOC(=O)c1ccc(CN(C)C)o1
Reactant: NCCN
Product: CN(C)Cc1ccc(C(=O)NCCN)o1
Temperature: 80 °C
Yield: 104.6 %

Procedure:
A mixture consisting of 49.0 g (248 mmol) of ethyl 5-(dimethylaminomethyl)-2-furancarboxylate and 150 g (2.496 mol) of anhydrous ethylenediamine was heated at 80° C. for 2 hours. After cooling, the excess ethylenediamine was distilled off under reduced pressure to give 54.8 g (98.0%) of 5-(dimethylaminomethyl)-N-(2-aminoethyl)-2-furancarboxamide (Compound a) as light yellow oil.
Reaction SMILES: C1(S[CH:8]=[CH:9][C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:11])C=CC=CC=1.C(OC1C=CC(C2C=CC=CC=2)=CC=1)(=O)C#C.[CH2:42]([OH:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([O:49][CH:8]=[CH:9][C:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)=[O:11])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: OCc1ccccc1
Reactant: O=C(C=CSc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Agent: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Product: O=C(C=COCc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Yield: 94 %

Procedure:
The compound 7 was prepared according to the method described for compound 4 employing compound 1 (300 mg, 1.34 mmol) and benzylalcohol (161 mg, 1.48 mmol) to give white solid compound 7 (419 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 5.00 (s, 2H), 5.53 (d, J=12.5 Hz, 1H), 7.18 (d, J=8.2 Hz, 2H), 7.39 (m, 8H), 7.57 (t, J=4.8 Hz, 4H), 7.88 (d, J=12.5 Hz, 1H). HRMS ESI (m/z): Calculated for C22H18O3 ([M+H]+): 331.1256. found: 331.133.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10]N>CO.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][CH3:10]
Reactant: NCc1ccccc1Br
Reactant: CN
Solvent: CO
Solvent: ClCCl
Product: CNCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-bromobenzylamine (9 g, 36.1 mmol) in MeOH (60 ml) was added dropwise over 30 min. to a solution of methylamine in MeOH (200 mL of a 2.0 M solution, 0.4 mol). The resulting solution was stirred at rt for 2 h and concentrated. The residue obtained was dissolved in DCM (100 mL) and successively washed with saturated aqueous sodium carbonate, dried over sodium sulphate, and concentrated. The resulting oil was distilled to afford the title compound (7 g, 95%) as a colorless oil (b.p. 110° C. at 0.1 mm Hg, LC/MS retention time=1.22 min.; M+=201.92 Column: Phenominex 4.6 mm×50 mm. Solvent A=10% MeOH, 90% H2O, 10 mM NH4Ac; Solvent B=90% MeOH, 10% H2O, 10 nM NH4Ac, Flow rate: 4 mL/min, Gradient: 0% B-100% B 4 min.).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(#N)C>[CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CCOC(=O)CBr
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCNC2)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)NC)C(C)(C)C)C1
Temperature: 60 °C
Yield: 57 %

Procedure:
A mixture of intermediate 84 (0.39 g), DIEA (0.35 mL) and ethyl bromoacetate (0.22 mL) in acetonitrile was heated at 60° C. for 1.5 h. After evaporation of MeCN, the residue was extracted between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography with 70% to 90% EtOAc/Hex to give compound 83 (0.27 g, 57%). LCMS (+ESI) m/z=510.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[C:23](Br)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:36]([Sn:40](Cl)([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH3:39]>O1CCCC1>[C:1]([O:5][C:6](=[O:30])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[C:23]([Sn:40]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:24][N:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(Br)n2ccnc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2nccn12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.8 %

Procedure:
To a cooled (−78° C.) solution of (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (2.55 g, 5.38 mmol) in tetrahydrofuran (20 mL) is added isopropylmagnesium chloride (0.829 g, 8.06 mmol). After stirring for 5 min tributyltin chloride (2.97 g, 9.14 mmol) is added and the reaction is stirred at −78 ° C. for 10 min before being allowed to warm to room temperature. After stirring at room temperature for 30 min, the mixture is concentrated. The residue is purified by silica gel flash column chromatography eluting with 5:1 petroleum ether-ethyl acetate followed by 1:1 petroleum ether-ethyl acetate to afford the product as yellow solid (2.35 g, 64%).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[C:22]([S:24]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[CH3:33])(C)(C)C>CCCCC.C(OCC)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:34])=[O:5])=[C:10]([C:16]#[C:17][C:18]2[CH:23]=[C:22]([S:24]([N:27]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH3:28])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[CH3:33])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N(C)CC(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)O
Yield: 77 %

Procedure:
Following the general method as outlined in Example 15, starting from tert-butyl{4-chloro-2-[(5-{[isobutyl(methyl)amino]sulfonyl}-2-methylphenyl)ethynyl]phenoxy}acetate (Intermediate 160), the title compound was obtained as a beige solid in 77% yield after tituration in pentane/diethyl ether.
Reaction SMILES: [N:1]1([CH2:6]N2C3C=CC=CC=3N=C2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18](=[O:30])[C:19]1[CH:24]=[C:23]([CH2:25]Br)[CH:22]=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]>CN(C)C=O.[Zn]>[CH3:16][O:17][C:18](=[O:30])[C:19]1[CH:24]=[C:23]([CH2:25][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:22]=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]
Reactant: c1ccc2c(c1)ncn2CN1CCCC1
Reactant: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CCN2CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of zinc powder (1.05 g, 16.05 mmol) and 1-pyrrolidin-1-ylmethyl-1H-benzoimidazole (2.95 g, 14.59 mmol) in N,N-dimethyl formamide (40 mL) under a nitrogen atmosphere was added 5-bromomethyl-2-nitro-benzoic acid methyl ester (4.0 g, 14.59 mmol). The reaction mixture was stirred at room temperature for 24 hours, then quenched at 0° C. with an ice-cold 25% aqueous solution of ammonium hydroxide (108 mL). The stirring was continued until most of the solid had dissolved. Undissolved solid was filtered off and the filtrate was extracted with diethyl ether. The combined organic layers were washed with 1 N aqueous sodium hydroxide, then water, and were dried over anhydrous sodium sulfate and concentrated under high vacuum to give 2-nitro-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid methyl ester as an orange oil. Yield: 1.3 g (32%). The crude material was used for the next step without further purification.
Reaction SMILES: II.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:14])C=CC=1)=O.O=C([C@H](CC1C=C(O)C(O)=CC=1)N)O.[CH2:38]([O:40][C:41](=[O:74])[C@H:42]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[C:54]([O:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH:53]=1)[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH3:39]>ClCCl>[CH2:38]([O:40][C:41](=[O:74])[C@H:42]([CH2:51][C:52]1[C:57]([I:14])=[CH:56][C:55]([O:58][C:59]([O:61][C:62]([CH3:63])([CH3:64])[CH3:65])=[O:60])=[C:54]([O:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH:53]=1)[NH:43][C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH3:39]
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)c1)NC(=O)OC(C)(C)C
Agent: II
Agent: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1I)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
Iodine (7.4 mmol) and bis(trifluoroacetoxy)iodobenzene (8.16 mmol) were added to a solution of the tri-boc protected dopa analog 14 (5.7 mmol) in anhydrous dichloromethane (60 mL) under argon. (t-Boc, or Boc, stands for (t)ert-(B)ut(O)xy(c)arbonyl.) The reaction mixture was stirred at room temperature for 40 min and then quenched with a saturated solution of sodium thiosulfate. The organic layer was washed with water (3×10 mL), dried with anhydrous sodium sulfate, filtered and evaporated in rotary evaporator. The product was purified by silica gel column chromatography using 15-20% ethyl acetate in hexane as the mobile phase to give the iodo analog, N-(tert-butoxycarbonyl)-3,4-di(tert-butoxycarbonyloxy)-6-iodo-L-phenylalanine ethyl ester 15, as white foam in 77% yield.