Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3](=[O:24])[NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[NH:16]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:16][C:6]1[CH:7]=[CH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:10][C:5]=1[NH:4][C:3](=[O:24])[N:2]([CH3:1])[CH3:25]
Reactant: CN(C)C(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of tert-butyl (2-(3,3-dimethylureido)-4-(thiophen-2-yl)phenyl)carbamate (115 mg, 0.32 mmol) in dichloromethane (5 mL) was added TFA (2 mL) at 0° C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was concentrated. The crude residue was diluted with ethyl acetate (30 mL) and washed with a saturated aqueous solution of sodium bicarbonate, then water (20 mL), dried over sodium sulfate, filtered and concentrated. The obtained residue was washed with hexane (2 mL) to afford 3-(2-amino-5-(thiophen-2-yl)phenyl)-1,1-dimethylurea (65 mg, 83% yield). ESI+ MS: m/z 262 ([M]+). 1H NMR (500 MHz, d6-DMSO): δ7.68 (s, 1H), 7.34 (d, J=5.0, 1H), 7.29 (d, J=2.0, 1H), 7.19 (dd, J=4.5, 2.0, 2H), 7.04 (m, 1H), 6.73 (d, J=8.5, 1H), 5.00 (s, 2H), 2.93 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:17])=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[OH:18].[CH3:19][O:20][CH2:21]Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:17])=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[O:18][CH2:19][O:20][CH3:21]
Reactant: CCCc1cc2cc(OC)c(F)cc2c(O)c1Br
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2cc(OC)c(F)cc2c(OCOC)c1Br
Yield: 83 %

Procedure:
2-Bromo-7-fluoro-6-(methyloxy)-3-propyl-1-naphthalenol (134) (0.52 g, 1.66 mmol) was treated with chloromethyl methyl ether in the presence of diisopropylethylamine in THF to give 0.49 g (83%) of the title compound (135) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.01 (t, J=7.3 Hz, 3H), 1.65-1.75 (m, 2H), 2.83 (t, J=7.8 Hz, 2H), 3.72 (s, 3H), 3.98 (s, 3H), 5.21 (s, 2H), 7.10 (d, J=8.3 Hz, 1H), 7.37 (s, 1H), 7.76 (d, J=12.4 Hz, 1H). LCMS (ESI): m/z 379 (M+Na)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=2)=[C:7]([CH3:20])[CH:6]=1)(=[O:3])[CH3:2].[CH3:21][N:22]1[CH2:27][CH2:26][C:25]2([C:38]3[C:30](=[CH:31][C:32]4[CH2:33][CH2:34][NH:35][C:36]=4[CH:37]=3)[O:29][CH2:28]2)[CH2:24][CH2:23]1.C(Cl)(=O)C(Cl)=O>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([N:35]3[C:36]4[CH:37]=[C:38]5[C:25]6([CH2:28][O:29][C:30]5=[CH:31][C:32]=4[CH2:33][CH2:34]3)[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]6)=[O:19])=[CH:15][CH:16]=2)=[C:7]([CH3:20])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Agent: O=C(Cl)C(=O)Cl
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1

Procedure:
The title compound was prepared from 4'-acetamido-2'-methylbiphenyl-4-carboxylic acid (D47) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) following a similar procedure to Example 1 using oxalyl chloride in place of thionyl chloride, as a yellow oil (43%). This was converted to its oxalate salt which crystallised as a white solid from acetone.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]=2[CH:14]=1)(=[O:3])[CH3:2].[BrH:15].BrBr>C(O)(=O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]=2[CH:14]=1)=[O:3]
Reactant: Br
Reactant: CC(=O)c1ccc2c(c1)CCS2(=O)=O
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc2c(c1)CCS2(=O)=O
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 5-acetyl-2,3-dihydrobenzothiophene-1,1-dioxide (8 g, 38.1 mmol) (obtained in preparation 17) dissolved in acetic acid (45 ml) under argon atmosphere, aqueous HBr (0.5 ml, 47%), bromine (5.84 g, 36.54 mmol) was added slowly at 15°-20° C. and the reaction mixture was stirred for about 0.5 h. Additional quantity of bromine (4.84 g) was slowly added and the stirring continued for further 10 h at 25°-30° C. Argon atmosphere was removed and the reaction mixture was kept open in the wave of blowing air in the fuming cup board to eliminate free bromine. The solid separated was filtered and washed with acetic acid (2×10 ml) followed by pet. ether to yield the title compound (10 g, 91%). mp. 68°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21]COC)=[C:5]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][O:14][C:15]3=[O:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>CO>[OH:21][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][O:14][C:15]2=[O:20]
Reactant: COCOc1c(-c2cccc3c2COC3=O)ccc(OC)c1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2cccc3c2COC3=O)c(O)c1OC
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 4-(3,4-dimethoxy-2-(methoxymethoxy)phenyl)isobenzofuran-1(3H)-one (1.3 g, 3.9 mmol) in methanol (15 mL) at 0° C., was added concentrated hydrochloride acid (3 mL) and the resultant reaction mixture was stirred at 50° C. for 15 min. The reaction mixture was concentrated under reduced pressure and basified with aq. sodium bicarbonate solution extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure and purification. The resulting residue purified by washings with pentane to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C=O)C.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:19])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(Cl)c(Cl)c1
Temperature: 75 °C

Procedure:
To a well stirred suspension of 5,6-dichloronicotinic acid 5 (600 g, 3.125 mole, Sigma-Aldrich) and DMF (20.0 mL) in dichloroethane (1.2 L) was added drop wise with stirring thionyl chloride (743.56 g, 6.25 mole). The reaction mixture was set up for heating with reflux, fitted with a gas trap filled with saturated aqueous sodium bicarbonate and heated at a temperature of 75° C. until the reaction mixture formed a clear solution, about 3 h. LC/MS of a sample quenched in methanol showed only the presence of the methyl ester. The reaction mixture was cooled to a temperature of about 25° C. and concentrated under reduced pressure to provide 5,6-dichloronicotinoyl chloride 6 as a thick paste.
Reaction SMILES: B.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9].CO.Cl>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH2:8][OH:9])[CH:11]=1
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
Borane (10.80 mL of a 1M solution in THF, 10.80 mmol) was added to a cooled solution of 5-bromo-2-methyl-benzoic acid (116 mg, 0.54 mmol) in THF (15 mL), under nitrogen, at 0° C. (ice water bath) and the resulting mixture allowed to warm to rt overnight. The mixture was then treated with MeOH (10 mL) followed by aqueous HCl (2M, 20 mL) and the mixture stirred for about 15 minutes, concentrated under vacuum and then partitioned with EtOAc. The organic layer was washed with aqueous HCl (2M), water and brine, dried (MgSO4), filtered and reduced to give the title compound as a colourless oil (90 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:17]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH2:9][C:10]1[N:17]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:15]([Br:1])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2ccco2)nc1N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)c(-c2ccco2)nc1N
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
N-Bromosuccinimide (3.5 g, 19.7 mmol) was added to a solution (60 ml) of 2-amino-6-(2-furyl)nicotinonitrile (4.0 g, 21.6 mmol) in N,N-dimethylformamide in a nitrogen atmosphere at 1 to 2° C., followed by stirring as it was. After 30 minutes, the reaction solution was diluted with ethyl acetate and an aqueous saturated solution of potassium carbonate. The organic layer was washed with an aqueous saturated solution of potassium carbonate and an aqueous saturated solution of ammonium chloride, then dried over anhydrous sodium sulfate and concentrated. Methanol was added to the residue, and the resulting solid was collected by filtration and washed with methanol, to give the title compound (3.02 g, 53%) as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)C>[C:33]1([NH:39][C:40]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)[N:3]=2)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc(Br)nc(Oc2cccc(OC(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(Oc2cccc(OC(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
1.0 g (0.0027 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethoxy)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. The obtained solution was cooled in a dry ice-acetone bath in an argon atmosphere and mixed with 2.6 ml of a 1.6M-hexane solution of BuLi (0.0027×1.5 mol), followed by stirring for about 10 minutes. After 0.74 g (0.0027×2.3 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about 45 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The obtained fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11](=[CH:17][N:18](C)C)[C:12]2=O)[CH2:9]1)C1C=CC=CC=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27]N>>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[N:18]=[CH:17][C:11]2[CH:10]3[CH2:15][CH:13]([CH2:14][NH:8][CH2:9]3)[C:12]1=2
Reactant: NNc1ccccn1
Reactant: CN(C)C=C1C(=O)C2CC1CN(Cc1ccccc1)C2
Product: c1ccc(-n2ncc3c2C2CNCC3C2)nc1

Procedure:
Following the method described in Example 14, 3-benzyl-7-dimethylaminomethylene-3-aza-bicyclo[3.2.1]octan-6-one and 2-pyridyl hydrazine were converted to the title compound in 7.6% overall yield. APCl MS m/z 227.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:18][CH:17]=3)[C:11]2=[O:33])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O>CO>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:10]([CH2:9][C:8]3[CH:34]=[CH:35][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)[C:11]2=[O:33])=[CH:21][CH:20]=1
Reactant: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(N4C(=O)c5ccccc5C4=O)cc3)C2=O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(N)cc3)C2=O)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-{4-[3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-ylmethyl]phenyl}isoindol-1,3-dione (E) (654 mg, 1.4 mmol) in MeOH (30 mL) hydrazine hydrate was added as a 0.8 M solution in MeOH (10 mL, 8 mmol) with stirring at RT. The reaction mixture was stirred for 90 min at RT and then H2O (50 mL) was added. The solvent was removed in vacuo and the residue was extracted with EtOAc (3×20 mL). The combined organic phases were dried over Na2SO4 and the solvent again removed in vacuo. There were obtained 430 g (91% of theory) of the desired product 1-(4-aminobenzyl)-3-(4-tert-butylbenzyl)-imidazolidin-2-one (F).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([SH:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>[OH-].[Na+]>[CH2:12]([S:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCS
Reactant: O=C(O)CCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCSCCCCCCCC(=O)O
Temperature: 100 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
At room temperature, a commercially available reagent of 8-bromo-octanoic acid (97% content, 1.74 g, 7.56 mmol) was dissolved in an aqueous solution (15 mL) of 18% sodium hydroxide, and a commercially available reagent of heptane-1-thiol (1.0 g, 7.56 mmol) was added dropwise. The mixture was then warmed to 100° C., and stirred for 2.0 hours while maintaining the temperature at 100° C. The mixture was cooled to room temperature, and then neutralized to pH 6.0 with concentrated hydrochloric acid. After filtration, solid was washed with dichloromethane, and the filtrate was extracted. The aqueous layer was then washed with ethyl acetate. To the organic layer was added 150 mL of ethyl acetate and the organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. After the solvent was distilled off, the filtrate was dried under reduced pressure to obtain 8-heptylsulfanyl-octanoic acid (No. 6804237; 2.04 g, 98% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)cn1
Temperature: 23 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
2-Chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After stirring at 23° C. for 6 hours, the reaction mixture was diluted with water, adjusted to pH 7 with saturated aqueous NaH2PO4, and extracted with dichloromethane. The organic extract was dried over Na2SO4 filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with CH2Cl2) to provide the title compound as a white solid (3.44 g, 79%). mp<50° C.; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6H), 5.19 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH2:11][OH:12]>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)CO
Reactant: Nc1cc(Cl)cnc1N
Product: OCc1nc2cc(Cl)cnc2[nH]1

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 7.67 g of 5-chloro-2,3-diaminopyridine (prepared as described in Preparation 62) and 18.6 g of glycolic acid were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 8.83 g of the title compound, melting at 209-211° C.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[C:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:22][CH:23]=1>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[C:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]2[O:9][N:8]=[C:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=23)[CH2:20][CH:19]=1
Reactant: CCOC(=O)CCCN1CC=C(c2cccc(Cl)c2Cl)CC1
Reactant: ON=C1CCCCCC1
Product: Clc1cccc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)c1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(2,3-dichlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(2,3-dichlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([NH:28][C:29]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:30])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:39])[CH:4]=1)#[N:2].[H-].[Na+].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([NH:28][C:29]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:30])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:39])[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4ccc(NC(=O)OCc5ccccc5)cc4c3)C2=O)cs1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(CN2CC[C@H](N(Cc3ccccc3)S(=O)(=O)c3ccc4ccc(NC(=O)OCc5ccccc5)cc4c3)C2=O)cs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
N-Cbz-7-aminonaphthalene-2-sulfonic acid-[1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.56 g, 1.01 mmol) is dissolved in 10 mL of DMF and cooled to 0° C. Sodium hydride (42 mg of a 60% dispersion in mineral oil, 1.06 mmol) is added and the solution is stirred for 20 minutes. To the mixture is added benzyl bromide (0.18 g, 1.06 mmol). The reaction mixture is stirred at 0° C. for 20 minutes and then at room temperature for 1.5 hours. The solution is poured into a separatory funnel and diluted with 100 mL of EtOAc. The organic layer is washed with water, 1 N HCl and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude residue is purified by column chromatography eluting with a gradient of 25% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to give the title compound (0.34 g, 0.53 mmol) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]([OH:22])=O)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[N:5]2[C:10]=1[CH:9]=[CH:8][N:7]=[CH:6]2.[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH2:31])[CH2:26][O:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH:31][C:20]([C:3]2[C:2]([Cl:1])=[C:10]3[CH:9]=[CH:8][N:7]=[CH:6][N:5]3[C:4]=2[NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[O:22])[CH2:26][O:25]1
Reactant: O=C(O)c1c(Cl)c2ccncn2c1Nc1ccc(I)cc1F
Reactant: CC1(C)OC[C@H](CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CONC(=O)c2c(Cl)c3ccncn3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
5-Chloro-7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (145 mg, 0.34 mmol), O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (50 mg, 0.34 mmol), HOBt (50 mg, 0.37 mmol), EDCI hydrochloride (71 mg, 0.37 mmol) and DIPEA (63 μL, 0.37 mmol) were dissolved in DMF (3 mL). The reaction was stirred at room temperature for 3 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 25-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (57 mg, 25%). LCMS (Method B): RT=3.63 min, M+H+=561.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5](=[O:18])[CH:6]=[C:7]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][CH3:9].C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C>>[CH3:1][O:2][C:3](=[O:19])[C:4](=[N+:29]=[N-:30])[C:5](=[O:18])[CH2:6][CH:7]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:8]=[CH2:9]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCC(=CC(=O)CC(=O)OC)OCc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(CC(=O)C(=[N+]=[N-])C(=O)OC)OCc1ccccc1
Yield: 98.1 %

Procedure:
In accordance with the process of Preparation 1, 5-benzyloxy-3-oxo-heptenoic acid methyl ester (1.07 g; 4.1 mmol), p-toluene-sulfonyl azide (810 mg; 4.1 mmol) and triethylamine (450 mg; 4.5 mmol) were used as starting materials to obtain 1.16 g of 5-benzyloxy-2-diazo-3-oxo-6-heptenoic acid methyl ester as a yellow oily product.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26](F)=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][CH:33]([CH3:35])[O-:34].[Na+]>CC(O)C>[Si:1]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:34][CH:33]([CH3:35])[CH3:32])=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(-c3cnc(-c4ccc(F)c(C#N)c4)s3)cccc21
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@@H]4O[Si](C)(C)C(C)(C)C)s2)cc1C#N
Temperature: 60 °C
Yield: 123.1 %

Procedure:
Prepared using General Procedure 2. To a solution of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-fluorobenzonitrile (116 mg, 0.25 mmol) in IPA (2 mL) was added sodium isopropoxide (21.1 mg, 0.25 mmol). The reaction mixture was heated at 60° C. for 2 h. Upon cooling, the solvent was evaporated and the product was purified by a silica gel column chromatography (EA/hexanes) to afford 151 mg (88%) of (S)-5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxy-benzonitrile LCMS-ESI (m/z) calculated for C28H34N2O2SSi: 490.7, found 491.1 [M+H]+, tR=6.81 min (Method 1).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[C:17](=[O:19])=[O:18].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:17]([OH:19])=[O:18]
Reactant: CC(C)CCCCCCCCCCCBr
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
Magnesium (1.5 g) was added to a solution of 1-bromo-12-methyltridecane (15.0 g) in tetrahydrofuran (200 ml). The mixture was refluxed for 10 minutes under nitrogen atmosphere and stirred for 1 hour at room temperature. A solid of carbon dioxide (50 g) was added to the mixture. To the mixture was added a mixture of 1% hydrochloric acid (300 ml) and ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on a silica gel column eluting with chloroform to give 13-methyltetradecanoic acid as an oil (7.54 g).