Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([C@H:17]([O:26]/[N:27]=[C:28](/[C:32]1[N:33]=[C:34]([NH:37][C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:35][CH:36]=1)\[C:29](O)=[O:30])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:57][CH:58]1[C:79](=[O:80])[N:60]2[C:61]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=3)=[O:68])=[C:62]([CH2:65][Cl:66])[CH2:63][S:64][C@H:59]12.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>>[CH:1]([O:14][C:15]([C@H:17]([O:26]/[N:27]=[C:28](/[C:32]1[N:33]=[C:34]([NH:37][C:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[S:35][CH:36]=1)\[C:29]([NH:57][CH:58]1[C:79](=[O:80])[N:60]2[C:61]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=3)=[O:68])=[C:62]([CH2:65][Cl:66])[CH2:63][S:64][C@H:59]12)=[O:30])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)/C(=N\O[C@@H](C(=O)OC(c1ccccc1)c1ccccc1)c1ccc(O)c(O)c1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N)C(=O)N23)cc1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(O)c(O)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 100.7 %

Procedure:
By using 4.57 g (6 mmol) of (Z)-2-[[(R)-α-benzhydryloxycarbonyl-3,4-dihydroxybenzyl]oxyimino]-2-(2-tritylaminothiazol-4-yl)acetic acid, 2.03 g (5 mmol) of p-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate, 1.39 ml (10 mmol) and 0.84 ml (6 mmol) of triethylamine and 0.75 ml (8 mmol) of phosphorus oxychloride, the treatment was conducted in the same manner as in Example 1 (A) to obtain 5.60 g (yield: 56%) of p-methoxybenzyl 7-[(Z)-2-[[(R)-α-benzhydryloxycarbonyl-3,4-dihydroxybenzyl]oxyimino]-2-(tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate as a foam-like solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:12][C:7]1[CH:6]=[C:5]([O:8][CH3:9])[C:4]([O:10][CH3:11])=[CH:3][C:2]=1[NH2:1]
Reactant: COc1ccc(N)cc1OC
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)c(Br)cc1OC
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
Following the procedure reported in JACS 1996, 118, 1028-1030, 4-aminoveratrole (3.06 g, 20.0 mmol) was dissolved in a mixture of dichloromethane (80 ml) and methanol (40 ml) at room temperature. Tetrabutylammonium tribromide (1.15 eq, 11.09 g) was added and the mixture was allowed to stir for 20 minutes. The mixture was extracted with saturated aqueous sodium sulfite solution. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 10:1 to 7:3 Hexanes/Ethyl Acetate) to give 2-Bromo-4,5-dimethoxy-aniline 1.403 g (30%) of a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[NH2:21][C@H:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:23][OH:24].CCN(C(C)C)C(C)C>CCCCO>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C@@H:22]([NH:21][C:2]2[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[N:7]=2)[CH2:23][OH:24])=[CH:30][CH:29]=1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 165 °C
Yield: 85.8 %

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method 28; 0.25 g, 0.84 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol (0.15 g, 0.97 mmol) and DIEA (0.16 ml, 0.92 mmol) in n-BuOH (3 ml) was heated in a sealed tube at 165° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:2) to give the title compound as a yellow solid (0.30 g, 87%). 1H NMR (400 MHz) δ 12.12, 12.10 & 11.61 (s, 1H), 10.94, 10.89 & 10.74 (s, 1H), 9.05, 8.82 & 8.73 (d, J=7.2 Hz, 1H), 8.13 & 8.11 (d, J=9.2 Hz, 1H), 7.45-7.32 (m, 2H), 7.20-7.10 (m, 2H), 6.32 & 6.07 (d, J=9.2 Hz, 1H), 5.90, 5.83 & 5.79 (s, 1H), 5.23, 5.12 & 4.78 (m, 2H), 4.71, 4.64 & 4.37 (m, 1H), 3.69 (m. 2H), 1.34 & 1.29 (d, J=6.0 Hz, 6H). MS: Calcd.: 416. Found: [M+H]+ 417.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=O)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].O>O1CCOCC1.C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[S:21])=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1ccccn1-c1ccc(I)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: S=c1ccccn1-c1ccc(I)cc1
Temperature: 80 °C

Procedure:
A mixture of 1-(4-iodophenyl)pyridin-2(1H)-one prepared above (0.760 g, 2.56 mmol), NaHCO3 (2.15 g, 25.6 mmol) and P2S5 (2.27 g, 10.2 mmol) in dioxane (20 mL) was heated at 80° C. overnight. After being cooled to room temperature, water and CH2Cl2 were added. The organic layer was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give 1-(4-iodophenyl)pyridine-2(1H)-thione as a solid (0.752 g). MS 313.8 (M+H).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)O
Yield: 85.6 %

Procedure:
2.0 g (4.66 mmoles) of Z-Glp-Leu-pyrrolidine are dissolved in 40 ml of methanol, 0.4 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, the oily residue is dissolved in ether, and the solution is allowed to stand at a cool place overnight. The separated crystals are filtered off to obtain 1.25 g (91%) of Glp-Leu-pyrrolidine; m.p.: 103°-104° C., Rf5 =0.65, [α]D25 =-31.6° (c=1%, in acetic acid). Analysis for amino acids: Glu=1.00 (1.0), Leu=1.00 (1.0).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.06 g, 4.86 mmol), 5-methyl-1H-pyrazol-3-amine (472.2 mg, 4.86 mmol) and sodium carbonate (2.06 g, 19.4 mmol) in 100 mL of EtOH was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude solid was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4), concentrated in vacuo, and purified by silica chromatography (EtOAc/hexanes: 1/1) to afford 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine; ESMS m/z 278.0 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH2:11][CH2:10]2.C(N(CC)CC)C.C(Cl)Cl>CN(C=O)C.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1=[N:5][CH2:4][CH2:3][CH2:2][CH:11]1[CH2:10]2
Reactant: NCCCBr
Reactant: O=C1CCc2cc(F)ccc21
Agent: [Ti+4]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc2c(c1)CC1CCCN=C21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Bromopropylamine (4.7 g. 21.7 mmole) and 5-Fluoro-1-indanone (2.5 g, 16.7 mmole) were dissolved in 50 ml DMF and the reaction was cooled to 0° C. Triethylamine (13.5 g, 133 mmole) was added. 20 ml DCM was also added to help with the stirring. Titanium chloride (1M in DCM, 15 ml) was then added and the ice bath was removed. The reaction was stirred at room temperature overnight. 200 ml ether was added and the reaction was filtered though a Celite cake. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in 200 ml ether and washed with brine (2×200 ml). The organic layer was dried over sodium sulfate and concentrated to dryness. 2.6 g Black oil was obtained and it was used in next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c12) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8](Cl)=[O:9])(=[O:3])[CH3:2].Cl.[C:23]([O:28][CH2:29][CH2:30][NH2:31])(=[O:27])[C:24]([CH3:26])=[CH2:25].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:23]([O:28][CH2:29][CH2:30][NH:31][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:13]([O:14][C:15](=[O:17])[CH3:16])=[C:12]([O:18][C:19](=[O:21])[CH3:20])[CH:11]=1)(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)OCCN
Reactant: CC(=O)Oc1cc(C(=O)Cl)cc(OC(C)=O)c1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCNC(=O)c1cc(OC(C)=O)c(OC(C)=O)c(OC(C)=O)c1
Reaction time: 0.5 h

Procedure:
3,4,5-Triacetoxybenzoyl chloride (0.050 mol) was dissolved in 100 mL CH2Cl2 at 0° C. To this was added 2-aminoethyl methacrylate hydrochloride (8.28 g, 0.050 mol), followed by dropwise addition of triethylamine (14.63 mL, 0.105 mol). After 30 min, 100 mL 1N HCl was added with vigorous stirring. The organic layer was isolated, washed with saturated NaHCO3 and 50 mL 1N HCl, dried over MgSO4, and evaporated to give an oil, which crystallized rapidly after the addition of 50 mL diethyl ether. The product was isolated by filtration and vacuum dried. Yield, 17.97 g as a white solid, 88%. 1H NMR (300 MHz, CDCl3), δ1.92 (s, 3H), 2.26 (s, 6H), 2.27 (s, 3H), 3.68 (m, 2H), 4.30 (t, 2H), 5.58 (m, 1H), 6.11 (s, 1H), 6.66 (t, broad, 1H), 7.51 (s, 2H). Anal., calcd for C19H21N1O9C 56.02, H 5.20, N 3.44, found C 55.99, H 5.15, N 3.50.
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:18][C:19]([F:24])([F:23])[C:20]([NH2:22])=[NH:21]>C(Cl)(Cl)Cl.CO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:2]2[NH:22][C:20]([C:19]([F:24])([F:23])[F:18])=[N:21][C:3]=2[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)C(Br)c1ccc(F)cc1
Reactant: N=C(N)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2[nH]c(C(F)(F)F)nc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 33.7 %

Procedure:
A mixture containing impure 2-bromo-2-(4-fluorophenyl)-1-phenyl-ethanone (13.07 g) and trifluoroacetamidine (5.00 g) was heated at 60° under nitrogen and with stirring for 19 h. More trifluoroacetamidine (2.00 g) was added and after a further 3 h the mixture was allowed to cool to room temperature and dissolved in chloroform/methanol before purifying by FCC eluting with System A (1:9) to give the title compound (4.60 g) as a pale yellow solid. δ (DMSO-d6) 7.16 and 7.2-7.6 (t, J 9 Hz and m, aromatic protons), 13.90 (bs, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[N:62]1([CH2:68][CH2:69][CH2:70][O:71][C:72]2[CH:80]=[CH:79][CH:78]=[C:77]3[C:73]=2[CH2:74][NH:75][CH2:76]3)[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([N:75]1[CH2:74][C:73]2[C:77](=[CH:78][CH:79]=[CH:80][C:72]=2[O:71][CH2:70][CH2:69][CH2:68][N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)[CH2:76]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1cc2c(c(OCCCN3CCOCC3)c1)CNC2
Reactant: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A solution of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (210 mg, 0.56 mmol) and diisopropylethylamine (0.25 mL, 1.4 mmol) in DCM (5 mL) was treated with bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (287 mg, 0.62 mmol). After 1 hour a solution of 4-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-isoindole (0.56 mmol, assuming a quantitative yield from the preceding step (C18)) in DCM (5 mL) was added. After 4 hours the mixture was diluted with ethyl acetate and washed with water, 1N sodium hydroxide solution and brine. The organic phase was dried (MgSO4) and concentrated to give a residue which was absorbed onto an SCX column. This was washed with 10% methanol/DCM then the product was eluted with 25% 2M methanolic ammonia/DCM) to afford an impure sample of the intermediate (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-[4-(3-morpholin-4-yl-propoxy)-1,3-dihydro-isoindol-2-yl]-methanone.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH:9]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:11][CH2:10]1.C([Li])CCC.[CH3:21][O:22][CH2:23]Cl.Cl>C1COCC1>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][CH2:23][C:9]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:11][CH2:10]1
Reactant: NS(=O)(=O)C1CC1
Reactant: COCCl
Agent: CC(C)(C)NC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC1(S(N)(=O)=O)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of cyclopropylsulfonylamine tert-butyl carbamate (1.0 g, 4.5 mmol) dissolved in THF (30 mL) cooled to −78° C., was added n-butyl lithium (6.4 mL, 10.2 mmol, 1.6M in hexane) and the reaction mixture was stirred for 1 hour. To this solution was added a neat solution of chloromethyl methyl ether (0.40 mL, 5.24 mmol), and the mixture was slowly allowed to warm to room temperature overnight. The solution pH was adjusted to 3 using 1N aqueous HCl and was then extracted with ethyl acetate (4×50 mL portions). The combined extracts were dried (MgSO4), filtered, and concentrated to afford 1-methoxymethylcyclopropylsulfonylamine tert-butylcarbamate, as a waxy solid (1.20 g, 100%) which was taken directly into the next reaction without further purification: 1H NMR (CDCl3) δ 1.03 (m, 2H), 1.52 (s, 9H), 1.66 (m, 2H), 3.38 (s, 3H), 3.68 (s, 2H), 7.54 (s, 1H); 13C NMR (CDCl3) δ 11.37, 28.29, 40.38, 58.94, 73.43, 83.61, 149.57.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[OH:27][C:24]1([CH3:26])[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][C:29]([CH3:28])=[N:34][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(C)(O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine to afford an off-white solid. HPLC (Condition 4) tR=4.75 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=460.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 3H) 2.68 (s, 3H) 3.58 (s, 4H) 5.47 (s, 1H) 7.26-7.40 (m, 2H) 7.77-7.92 (m, 2H) 8.04 (d, J=2.35 Hz, 1H) 8.67-8.82 (m, 3H) 10.19 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])[CH:5]=[C:4]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=2)[C:3]=1[CH3:41].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:50]1(B(O)O)[CH2:52][CH2:51]1.C1(C)C=CC=CC=1>O>[CH:50]1([C:2]2[CH:7]=[C:6]([C:8]3([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]3[O:11][C:12](=[O:14])[CH3:13])[OH:9])[CH:5]=[C:4]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([CH2:39][CH3:40])=[CH:37][CH:38]=3)[C:3]=2[CH3:41])[CH2:52][CH2:51]1
Reactant: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(Br)c2C)cc1
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(C3CC3)c2C)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A flask charged with 1-bromo-3-(4-ethylbenzyl)-2-methyl-5-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzene (0.30 g), potassium phosphate (0.38 g), cyclopropylboronic acid (50 mg), toluene (2 mL) and water (1 mL) is flushed with Ar for 5 min. Then, palladium acetate (11 mg) and tricyclohexylphosphonium tetrafluoroborate (36 mg) are added. The flask is tightly sealed and the mixture is stirred at 100° C. overnight. After cooling to room temperature, the mixture is diluted with water and ethyl acetate and treated with charcoal. After filtration, the organic layer is separated, washed with brine and dried (magnesium sulphate). The solvent is removed under reduced pressure and the resulting crude product is submitted to deacetylation without further purification.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17]([N:9]1[C:10](=[O:12])[CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:13])=[O:18]
Reactant: Cc1cccc(C)c1C(=O)Cl
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Solvent: c1ccncc1
Product: Cc1cccc(C)c1C(=O)N1C(=O)CN(c2ccccc2)C1=O
Yield: 6.3 %

Procedure:
In 30 ml of pyridine, were dissolved 1.1 g (6.25 mmol) of 1-phenyl-imidazolidin-2,4-dione and 1.12 g (6.65 mmol) of 2,6-dimethylbenzoyl chloride to conduct a reaction at 60° C. for 3 hours. After completion of the reaction, pyridine was distilled off under reduced pressure, and the resultant residue was subjected to extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and with saturated saline. The thus-washed organic layer was then dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resultant residue was purified by column chromatography on silica gel (developing solvent: n-hexane/ ethyl acetate) and subjected to crystallization from n-hexane/ethyl acetate to obtain 122 mg (yield: 5.8%) of the title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22](OC(N1CCN(C(=O)C2C=CC(CN3CCOCC3)=CC=2)CC1)=O)([CH3:25])(C)[CH3:23].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:25]1([N:19]2[CH2:18][CH2:17][N:16]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:13][CH:12]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:22][CH2:23]1
Reactant: O=C(c1ccc(CN2CCOCC2)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
(4-Morpholin-4-ylmethyl-phenyl)-piperazin-1-yl-methanone. A solution of 4-(4-morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic acid tert -butyl ester (1.163 g) in CH2Cl2 (10 mL) was treated with TFA (˜4 mL). After 30 min, additional TFA (5 mL) was added, and the mixture was stirred for a further 2 h. The mixture was diluted with diluted with satd. aq. NaHCO3 and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to give the title compound (0.255 g, 30%). MS (ESI): mass calcd. for C16H23N3O2, 289.18; m/z found, 290.4 [M+H]+. 1H NMR (CDCl3): 7.41-7.35 (m, 4H), 3.95-3.70 (m, 6H), 3.52 (s, 2H), 3.09-2.80 (m, 6H), 2.49-2.42 (m, 4H).