Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH:25]([CH3:27])[CH3:26])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:28]([O:32][CH2:33]Cl)[CH2:29][CH2:30][CH3:31].O>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:33][O:32][CH2:28][CH2:29][CH2:30][CH3:31])[C:19](=[O:24])[N:18]([CH:25]([CH3:27])[CH3:26])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCOCCl
Reactant: CC(C)n1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(C(C)C)c1=O
Reaction time: 1 h

Procedure:
0.583 g (4.22 mmol) of potassium carbonate was added at 60° C. to a suspension of 0.75 g (2.64 mmol) of 7-benzyl-3-isopropylxanthine from stage a) in 20 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 0.42 g (3.43 mmol) of butoxymethyl chloride was then added dropwise and the mixture was stirred at 80° C. for 6 hours. A further 0.11 g (0.87 mmol) of butoxymethyl chloride was then added and the mixture was stirred again for 5 hours. 20 ml of water were then added, the mixture was extracted three times using 30 ml of methyl tert-butyl ether each time, and the combined organic phases were washed twice with 20 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, heptane/ethyl acetate (2/1).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]([CH:19]2[C:28]3[C:27](=[O:29])[CH2:26][CH:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:24][C:23]=3[NH:22][C:21]([CH3:36])=[C:20]2[C:37]#[N:38])[CH:16]=[C:15]([O:39][CH3:40])[C:3]=1[O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[S:61]1[CH:65]=[CH:64][CH:63]=[C:62]1[CH2:66][NH2:67]>ClCCl>[Br:1][C:2]1[CH:18]=[C:17]([CH:19]2[C:28]3[C:27](=[O:29])[CH2:26][CH:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:24][C:23]=3[NH:22][C:21]([CH3:36])=[C:20]2[C:37]#[N:38])[CH:16]=[C:15]([O:39][CH3:40])[C:3]=1[O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:67][CH2:66][C:62]1[S:61][CH:65]=[CH:64][CH:63]=1)=[O:10]
Reactant: COc1cc(C2C(C#N)=C(C)NC3=C2C(=O)CC(c2ccccc2)C3)cc(Br)c1OCc1cccc(C(=O)O)c1
Reactant: NCc1cccs1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2C(C#N)=C(C)NC3=C2C(=O)CC(c2ccccc2)C3)cc(Br)c1OCc1cccc(C(=O)NCc2cccs2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of step b (20 mg) in 2 mL of dichloromethane were added EDCI (7.0 mg), DIPEA (7 μL) and 2-thiophenemethylamine (4.1 μL) and the reaction mixture was stirred for 3 h. at room temperature. The reaction mixture was concentrated and the title compound was obtained after flash column chromatography (silica gel, heptane/ethyl acetate (1/4, v/v), Rf=0.78).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:39])[C:34]1[O:38][CH:37]=[CH:36][CH:35]=1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:39][CH2:33][C:34]2[O:38][CH:37]=[CH:36][CH:35]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NCc1ccco1
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4ccco4)ncnc32)[C@]1(C)F
Yield: 44.2 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.4 g, 0.86 mmol) in ethanol (about 5 ml) was added furfurylamine (about 0.96 ml, 10.38 mmol) and refluxed for about 30 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compounds Isomer A and B (0.20 g) as a colorless gummy mass. Yield: 44.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][S:7]([CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH3:11])(=[O:9])=[O:8].C([Li])CCC.[CH3:33][C:34]([CH3:36])=[O:35].FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][S:7]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:14][CH:13]=1)([C:34]([OH:35])([CH3:36])[CH3:33])[CH3:11])(=[O:9])=[O:8]
Reactant: COc1ccc(CNS(=O)(=O)C(C)c2ccc(C(C)(C)C)cc2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CNS(=O)(=O)C(C)(c2ccc(C(C)(C)C)cc2)C(C)(C)O)c(OC)c1
Reaction time: 0.17 h

Procedure:
Under inert gas, 1.01 g of N-[2,4-dimethoxybenzyl]-1-(4-tert-butylphenyl)ethanesulfonamide were initially charged in 20 ml of THF and then, at a temperature of −75° C., 3.23 ml of a 1.6 N butyllithium solution in hexane were added dropwise and the mixture was stirred for 10 minutes. After the addition of 1.16 ml of acetone, the reaction mixture was stirred at constant temperature for 10 minutes. Subsequently, 0.45 ml of trifluoroacetic acid was added and the reaction solution was allowed to come to room temperature. After concentration by rotary evaporation, the crude product was purified using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (484 mg) with a molecular weight of 449.6 g/mol (C24H35NO5S).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[N:14][CH:15]=2)=[CH:6][CH:5]=1.Cl>CCO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccc(Cl)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cn1
Reaction time: 1 h

Procedure:
12.6 mL aqueous NaOH (1 M) was added at RT to a suspension of 1.200 g (4.200 mmol) ethyl (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-acrylate (Z34a) in 50 mL EtOH and the mixture was stirred for 1 h . 12.6 mL aqueous HCl (1 M) was added at 0° C. The precipitate formed was filtered off, washed with water and dried i. vac. at 100° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:26]1([N:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])[CH2:38][CH2:37]2)[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:46][CH2:45][CH2:44][CH2:43][CH2:42][N:39]2[CH2:40][CH2:41][N:36]([C:26]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)[CH2:37][CH2:38]2)=[O:11])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1CCN(c2cccc3c2CCCC3)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCCCN1CCN(c2cccc3c2CCCC3)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.6 g (11.1 mmol) 3-(3-pyridyl)-acrylic acid and 6.2 ml (44.3 mmol) TEA are suspended in 80 ml absolute dichloromethane and cooled to ca. 0° C. under moisture exclusion. 2.0 g (12.1 mmol) 81% HOBT and 2.3 g (12.1 mmol) EDC are added and the mixture is stirred for 30 min under ice cooling. 4.0 g (10.1 mmol) 4-[4-(5,6,7,8-tetrahydro-naphthalin-1-yl)-piperazin-1-yl]-butylamine are added and the mixture is stirred without cooling overnight at RT. Subsequently, the batch is washed twice with 25 ml 2M sodium hydroxide solution and 25 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically pre-purified over silica gel with CHCl3/CH3OH (95/5) and crystallized twice from acetonitrile (25 ml and 15 ml): Colorless crystals of MP. 108-109° C.; yield 2.7 g (64%).
Reaction SMILES: [CH3:1][C:2]([NH:25]C(=O)OC(C)(C)C)([CH3:24])[C:3](=[O:23])[NH:4][C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[C:17]3[C:18]4([CH2:21][O:22][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:20][CH2:19]4)=[CH:9][CH:10]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:24][C:2]([C:3]([NH:4][C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[C:17]3[C:18]4([CH2:21][O:22][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:20][CH2:19]4)=[CH:9][CH:10]=1)=[O:23])([CH3:1])[NH2:25]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of 1,1-dimethylethyl (1,1-dimethyl-2-oxo-2-{[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]amino}ethyl)carbamate (Intermediate 90, 50 mg) in dry dichloromethane (4 mL) at 0° C. TFA (1 ml, 12.98 mmol) was slowly added and the reaction mixture was stirred for 2 hours at the same temperature. The reaction was diluted with dichloromethane (10 ml) and an aqueous saturated solution of NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the organic layer was dried over sodium sulphate, filtered and evaporated affording the title compound (35 mg) as a colourless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=3)=[N:10][C:9]=2[N:8]([CH3:36])[C:7]1=[O:37].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1.O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:12]2[C:13]3[C:14](=[O:15])[N:6]([CH2:5][CH2:4][CH2:3][NH:2][S:39]([CH3:38])(=[O:41])=[O:40])[C:7](=[O:37])[N:8]([CH3:36])[C:9]=3[N:10]=[C:11]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:33])[F:35])[CH:26]=2)=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(CCCN)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCNS(C)(=O)=O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
1-(3-Aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.10 g, 0.19 mmol, example 357) and TEA (0.80 mL, 0.57 mmol) were combined in THF (1 mL). Methanesulfonyl chloride (0.30 mL, 0.38 mmol) was added and the reaction was stirred at room temperature for 3 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to an oil. The oil was purified using a 2000 micron preparative TLC plate eluted with 5% methanol/DCM. Target band was scraped off plate and eluted off silica gel with eluent to give N-(3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl)methanesulfonamide (0.045 g, 39% yield) as a tan solid. LCMS retention time=4.048 minutes and 99% purity, LCMS MH+ 602. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J=8 Hz), 7.45-7.48 (m, 1H), 7.39-7.43 (m, 5H), 7.31 (d, 1H, J=8 Hz), 6.96 (t, 1H), 5.43 (s, 2H), 3.91 (t, 2H, J=8 Hz), 3.29 (s, 3H), 2.96 (dd, 2H, J=4 Hz and 12 Hz), 2.87 (s, 3H), 1.69-1.79 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([N:12]1[CH2:20][CH2:19][CH2:18][C@H:13]1[C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=CC=CC=1.N[C@H](C(N1CCC[C@H]1C(OC)=O)=O)CCCCNC([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O.[F:49][C:50]([C:53]([OH:55])=[O:54])([F:52])[F:51]>>[NH2:1][C@H:2]([C:10]([N:12]1[CH2:20][CH2:19][CH2:18][C@H:13]1[C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:3][CH2:4][C:9](=[O:54])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[F:49][C:50]([C:53]([OH:55])=[O:54])([F:52])[F:51]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCC(=O)OCc1ccccc1

Procedure:
Instead of H-Phe-Pro-OMe (1 equivalent) and TEA (1 equivalent) in (b), (c) H-Lys(Z)-Pro-OMe trifluoroacetate (1 equivalent) and TEA (2 equivalents) were used to obtain (c') oleoyl-Lys(Z)-Pro-OMe (SUAM 1197) as an oil, and (d) H-Glu(Bzl)-Pro-OMe trifluoroacetate (1 equivalent) and TEA (2-equivalents) were used to obtain (d') oleoyl-Glu(Bzl)-Pro-OMe (SUAM 1196) as an oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]([O:11][CH3:12])=O)[CH2:4]1.[CH3:13][O:14]CCl.C(NC(C)C)(C)C.[NH4+].[Cl-]>ClCCl.O>[CH3:13][O:14][CH2:12][O:11][CH2:9][C@@H:5]1[CH2:6][CH2:7][CH2:8][C@H:3]([CH2:2][OH:1])[CH2:4]1
Reactant: COCCl
Reactant: COC(=O)[C@H]1CCC[C@@H](CO)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: ClCCl
Product: COCOC[C@@H]1CCC[C@H](CO)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
1.70 g of methyl cis-3-hydroxymethylcyclohexanecarboxylate are dissolved in 20 ml of dichloromethane, 1.60 g of methoxymethyl chloride and 2.60 g of diisopropylamine are added and the mixture is stirred at room temperature for 15 h. 50 ml of saturated NH4Cl solution and 50 ml of water are added to the solution, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried over magnesium sulfate and concentrated. This gives 2.0 g of methyl cis-3-methoxymethoxymethylcyclohexanecarboxylate as a yellow oil. This is dissolved in 50 ml of diethyl ether, 350 mg of LiAlH4 are added and the mixture is stirred at room temperature. After 2 h at 0° C., 5 ml of ethyl acetate, 40 ml of methyl tert-butyl ether and 3 g of MgSO4 are added. 15 ml of 10N KOH are then added dropwise. The suspension is stirred for 3 h and filtered through Celite and the filtrate is concentrated, which gives 1.65 g of (cis-3-methoxymethoxymethylcyclohexyl)methanol as a colorless oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[N:7][C:6]=1[CH2:26][CH:27]1[CH2:29][CH2:28]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:27]1([CH2:26][C:6]2[C:5]([CH2:4][OH:3])=[C:10]([C:11]([F:12])([F:13])[F:14])[CH:9]=[C:8]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=3)[N:7]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1CC1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1CC1CC1

Procedure:
In analogy to the procedure described in example 16 c], 2-cyclopropylmethyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-nicotinic acid ethyl ester was treated with lithium aluminium hydride to give the title compound as colorless crystals.
Reaction SMILES: [C:1]([CH:8]([NH2:14])[CH2:9][O:10][CH2:11][CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].C(O)(C)(C)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].Cl>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:13][CH2:12][CH2:11][O:10][CH2:9][CH:8]([NH2:14])[C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)C(N)COCCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCOC(=O)COCCOCC(N)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 2-(2-Boc-aminoethoxy)-ethanol (4.5 g, 24.39 mmol) in toluene (100 mL) was added 1.0 M potassium t-butoxide in t-butanol (36.6 □L, 36.6 mmol) between −10 to −20° C. for 1.5 hrs and followed by addition of ethyl bromoacetate (8.15 g, 48.78 mmol). The resulting mixture was stirred for 3 hrs at a temperature between −10 to −20° C., followed by the addition of 0.25 N HCl (50 mL). The organic layer was separated and dried over anhydrous MgSO4. The solvent was removed and the residue purified using silica gel column chromatography (30 to 50% ethylacetate in hexane) to give [2-(2-Boc-aminoethoxy)-ethoxy]-acetic acid ethyl ester (4.0 g, 15.36 mmol, 63%). 1H NMR (300 MHz, CDCl3) δ 5.20 (s, 1H), 4.22 (q, 2H, J=7.29 Hz), 4.14 (s, 2H), 3.66-3.75 (m, 4H), 3.55 (m, 2H), 3.31 (m, 2H), 1.44 (s, 9H), 1.29 (t, 3H, J=7.29 Hz); 13C NMR (67.8 MHz, CDCl3δ170.02, 155.72, 78.68, 70.52, 69.94, 68.29, 60.44, 40.04, 28.06, 13.85.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12](COCC[Si](C)(C)C)[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH:27]=2)[CH:3]=1.CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH:27]=2)[CH:3]=1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (0.95 g, 1.80 mmol) (prepared in the previous step) in 10 mL of DCM was added 0.4 mL of EtOH and 10 mL of TFA and the mixture stirred for 1 h at RT. The mixture was concentrated and triturated with Et2O to give 0.68 g (95%) of a white solid: 1H-NMR (400 MHz, CDCl3): δ 11.23 (br s, 1H), 9.52 (br s, 1H), 8.27 (d, J=8.7 Hz, 1H), 7.72 (s, 1H), 7.41 (dd, J=2.3, 8.7 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 5.82 (m, 1H), 2.28 (m, 2H), 2.10 (m, 2H), 1.58 (m, 2H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C19H19BrN4O, 399.1 (M+H). found 399.0.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](Br)=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:23]=[O:24].OP(O)(O)=O>C1COCC1.C1(C)C(C)=CC=CC=1>[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:23][OH:24])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=O
Reactant: Brc1nn(Cc2ccccc2)c2ccccc12
Agent: CC(C)[Mg]Cl
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: OCc1nn(Cc2ccccc2)c2ccccc12
Temperature: -10 °C
Yield: 34 %

Procedure:
A solution of 2M i-PrMgCl in THF (69 mL, 138 mmol, 4.0 eq.) was added to a suitably thoroughly dried flask maintained under a nitrogen atmosphere. The solution was cooled to approximately −10° C. A solution of 1-benzyl-3-bromo-1H-indazole (10 g, 34.8 mmol, 1.0 eq.) in anhydrous THF (40 mL) was added over approximately one hour keeping the temperature constant. The reaction mixture was kept stirred for at least 6 hours, and a yellow suspension was obtained. Gaseous formaldehyde (generated by heating a suspension of 16.7 g of paraformaldehyde in 60 mL of xylene at approximately 115° C.) was passed over this for approximately two hours at a temperature of below 0° C. When the reaction was complete, dilute H3PO4 was added and the excess of re-polymerised paraformaldehyde was removed by filtration. Me-THF (60 mL) was added to the mixture and the phases were separated. The organic phase was washed with a dilute solution of NaHCO3. After concentration of the organic phase an oily residue containing the product was obtained. Subsequent purification of the crude product by silica gel chromatography yielded 2.8 g of white solid (yield: 34%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][OH:18])=[O:14].ClC(Cl)(Cl)C(=N)O[CH2:34][CH:35]=[CH2:36].FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][O:18][CH2:36][CH:35]=[CH2:34])=[O:14]
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesulfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95°-97° C.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1.S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[F:22][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([C:20]([OH:25])=[O:21])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a stirring solution of 4-(difluoromethoxy)-8-nitrodibenzo[b,d]furan-1-carbaldehyde (6.5 g, 0.021 mol) and sulphamic acid (3.7 g, 0.038 mol) in acetone (25 mL) was added sodium chlorite (3.0 g, 0.033 mol) in water (25 mL) dropwise at 5-10° C. After 15 minutes, the reaction slurry was allowed to stir at room temperature for 17 hours. The reaction slurry was poured into ice-cold water and filtered. The solid obtained was washed with hexane and dried. Yield—81.9%. 1H-NMR (DMSO-d6) δ: 7.44-7.64-7.80 (t, 2H), 8.09-8.16 (m, 2H), 8.53-8.55 (m, 1H), 9.80 (d, 1H), 13.75 (s, 1H); HPLC (purity): 87.6%; Mass calculated for C14H7F2NO6-323.2, observed—322.0; Rf—0.25 (Ethyl acetate:Hexane (1:1).