Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([CH2:12][OH:13])[C@@H:9]([OH:14])[C@H:8]([OH:15])[C@H:6]2[N:7]=1.[H-].[Na+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH2:25]([O:14][C@@H:9]1[C@@H:10]([CH2:12][O:13][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[O:11][C@H:5]2[C@H:6]([N:7]=[C:3]([N:2]([CH3:16])[CH3:1])[S:4]2)[C@H:8]1[O:15][CH2:25][C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 7 (100 g, 0.4 mol) in DMF (600 mL) was treated with NaH (110 g, 3.2 mol, 70% dispersed by mineral oil) at 0° C. for 30 min, followed by the addition of BnBr (410 g, 2.4 mol) dropwise. After kept additional 2 hours at room temperature, the mixture was poured into ice-water (1.5 kg) slowly and extracted with ethyl acetate (3×500 mL). The organic layers were combined, washed with brine (3×300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 10%-30% ethyl acetate in petroleum ether to afford 92 (166 g, 80%) as a yellow oil; (ES, m/z) [M+H]+ 519.0; 1H NMR (300 MHz, CDCl3) δ 7.26-7.48 (m, 15H), 6.40 (d, J=6.6 Hz, 1H), 4.54-4.86 (m, 6H), 4.41 (d, J=4.8 Hz, 1H), 4.17-4.18 (m, 1H), 3.60-3.79 (m, 4H), 3.12 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[NH2:12][O:13][CH2:14][CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 40(f), 0.18 ml of 4'-chloroacetophenone was reacted with 400 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was mixed with a mixture of diethyl ether, diisopropyl ether and hexane, and the mixture was then stirred. The resulting precipitate was collected by filtration, to give 360 mg of the title compound, melting at 118°-119° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[F:16][C:17]1[CH:18]=[C:19]([CH:23]([NH2:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH:20]=[CH:21][CH:22]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:34][CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1cccc(F)c1)c1cccc(C(F)(F)F)c1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1cccc(F)c1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(3-fluoro-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine hydrochloride (example 4.10).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH:16][C:17]([NH2:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28].CNCCNC>[Cu]I.O1CCOCC1>[CH2:9]([NH:16][C:17]([NH:19][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: COc1ccccc1Br
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccccc1NC(=O)NCc1ccccc1
Temperature: 80 °C
Reaction time: 26 h
Yield: 67.1 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 0.10 equiv), K3PO4 (425 mg, 2.0 mmol, 2.0 equiv), benzylurea (225 mg, 1.5 mmol, 1.5 equiv), 2-bromoanisole (125 μL, 1.0 mmol, 1.0 equiv), N,N′-dimethylethylendiamine (22 μL, 0.20 mmol, 0.20 equiv) and dry dioxane (1.0 mL), filled with nitrogen. The test tube was sealed and the reaction mixture was stirred at 80° C. for 26 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel, eluting with ethyl acetate. The filtrate was concentrated in vacuo. The solid residue was dissolved in ˜2 mL DMF. Purification of the residue by flash chromatography on silica gel (2×20 cm; hexane:ethyl acetate 2:1) provided 172 mg (67% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]2[C:22]([C:23]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:15]1[C:13]([O:12][CH3:11])=[O:14]
Reactant: COC(=O)Cc1c(C(=O)OC)[nH]c2ccccc12
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1c(C(=O)OC)n(Cc2ccc(Cl)c(Cl)c2)c2ccccc12
Temperature: 80 °C
Yield: 65.1 %

Procedure:
3,4-Dichlorobenzyl chloride (8.2 g) was added to a stirred solution of methyl 2-methoxycarbonyl-3-indoleacetate (6.5 g) and potassium carbonate (8.36 g) in acetonitrile (200 ml) under an atmosphere of argon. The reaction was heated to 80° C. for 24 hours. The reaction was concentrated in vacuo and partitioned between ethyl acetate and water. Combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography using 25% ethyl acetate:iso-hexane as eluent to give the product as a white solid (6.95 g, 65%), NMR d (CD3SOCD3) 3.60 (s, 3H), 3.77 (s, 3H), 4.13 (s, 2H), 5.89 (s, 2H), 6.89 (dd, 1H), 7.16 (t, 1H), 7.27 (d, 1H), 7.34 (t, 1H), 7.52 (d, 1H), 7.57 (d, 1H), 7.78 (d, 1H); M/z (+) 406 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:31])=[C:16]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:33])[CH3:32])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:34]I.O>CN(C)C=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:31])=[C:16]([N:21]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[CH3:34])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:33])[CH3:32])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: COc1ccc(CNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(C)c2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Sodium hydride (a 60% dispersion in liquid paraffin, 598.8 mg, 14.97 mmol) was washed twice with hexane and then suspended to N,N-dimethylformamide (10 ml). To this suspension was gradually added a solution of 3-(4-isopropylphenyl)-N-(4-methoxybenzyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (998.9 mg, 2.25 mmol) in N,N-dimethylformamide (30 ml) and the reaction mixture was stirred at 60° C. for 30 minutes. To this mixture was added methyl iodide (2.19 g, 15.45 mmol) and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was cooled down to room temperature and water was added to the solution. The product was extracted with ethyl acetate. The extracts were dried on magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 10:1) to obtain the title compound (69% yield) as an oily mixture of rotamers.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[F:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([NH2:23])=[CH:16]2.C([O:26][C:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:40][CH:39]3[CH2:41][CH2:42][CH:36]([CH2:37][CH2:38]3)[CH2:35]2)=[CH:30][CH:29]=1)C>ClCCCl.ClCCl.CO>[CH:39]12[CH2:38][CH2:37][CH:36]([CH2:42][CH2:41]1)[CH2:35][N:34]([C:31]1[CH:30]=[CH:29][C:28]([C:27]([NH:23][C:17]3[CH:18]=[N:19][C:20]4[C:15]([CH:16]=3)=[CH:14][C:13]([F:12])=[CH:22][CH:21]=4)=[O:26])=[CH:33][CH:32]=1)[CH2:40]2
Reactant: CCOC(=O)c1ccc(N2CC3CCC(CC3)C2)cc1
Reactant: Nc1cnc2ccc(F)cc2c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCCl
Solvent: CO
Product: O=C(Nc1cnc2ccc(F)cc2c1)c1ccc(N2CC3CCC(CC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a sealed tube, a solution of trimethylaluminum in toluene (3N, 0.41 mL, 1.23 mmol) was added to a solution of 6-fluoro-quinolin-3-ylamine (90 mg, 0.56 mmol) and 4-(3-aza-bicyclo[3.2.2]non-3-yl)-benzoic acid ethyl ester (180 mg, 0.65 mmol) in 1,2-dichloroethane (2 mL). The solution was allowed to stir at room temperature for 15 minutes, and then heated at 83° C. for 16 hours. The tube was cooled and carefully opened. Methanol (0.5 mL) was added and the resultant mixture was allowed to stir at room temperature for several hours. The mixture was diluted with dichloromethane and preabsorbed onto silica gel. Flash chromatography, using a gradient of methanol (0% to 3%) in dichloromethane as the eluant, gave the product, 60 mg (28%), as a colorless solid. MS: m/z 390.0 (MH+). 1HNMR (DMSO-d6): δ 1.67 (m, 8 H), 2.14 (m, 2 H), 3.56 (d, 2 H), 6.97 (d, 2 H), 7.54 (d of t, 1 H), 7.77 (d of d, 1 H), 7.92 (d, 2 H), 8.04 (d of d, 1 H), 8.85 (d, 1 H), 9.13 (d, 1 H) and 10.3 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:15][CH2:14][C:12](=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].Cl.[CH3:17][O:18][C:19](=[O:28])[C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:15][CH2:14][CH:12]([NH:21][C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([O:18][CH3:17])=[O:28])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H](NC1CCC(NC(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a flask charged with 4-N-boc-aminocyclohexanone (commercially available from Combi-Blocks, San Diego, Calif.) (11.00 g, 51.6 mmol) was added DCE (206 mL) followed by (S)-(+)-2-phenylglycine methyl ester hydrochloride (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (10.40 g, 51.6 mmol). The resulting mixture was stirred at room temperature for 15 minutes prior to the addition of sodium triacetoxyborohydride (21.86 g, 103 mmol). The resulting suspension was stirred overnight at room temperature leading to conversion to desired product (˜1:1 cis:trans). To the mixture was added water, and the resulting mixture was transferred to a separatory funnel. The mixture was extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was purified with a 100 g SNAP column ramping DCM:MeOH (90:10) in DCM (0-25%), then isocratic at 25% (monitoring at 215 nm) to yield (S)-methyl 2-(((1 r,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2-phenylacetate (12.43 g, 34.3 mmol, 66.5% yield) as a mixture of isomers and as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH2:9][CH2:8][N:7]([CH2:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)=[O:12])[CH2:6][CH2:5]1>C(O)C>[OH:12][CH:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)[CH2:10][N:7]1[CH2:8][CH2:9][C:4]([OH:3])([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH2:5][CH2:6]1
Reactant: COc1cccc(C2(O)CCN(CC(=O)c3ccc4c(c3)CCC(=O)N4)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(C2(O)CCN(CC(O)c3ccc4c(c3)CCC(=O)N4)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a stirred solution of sodium borohydride (1.15 g, 30.3 mmol) in ethanol (100 ml) was added suspension of 6-{[4-Hydroxy-4-(3-methoxyphenyl)-1-piperidinyl]acetyl}-3,4-dihydroquinolin-2(1H)-one (5.98 g, 15.2 mmol) in ethanol (40 ml) at 0° C. and the reaction mixture was stirred at room temperature overnight. The precipitate was filtered and added to methanol (20 ml). The precipitate was collected by filtration to afford the title compound (4.13 g, 69%) as a white solid.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:54])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH:29]=[C:30]([F:53])[C:31]([F:52])([F:51])[C:32]([F:50])([F:49])[C:33]([F:48])([F:47])[C:34]([F:46])([F:45])[C:35]([F:44])([F:43])[C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])[CH3:27].[BH4-].[Na+]>CO>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][CH:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:54])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH:29]=[C:30]([F:53])[C:31]([F:51])([F:52])[C:32]([F:49])([F:50])[C:33]([F:47])([F:48])[C:34]([F:45])([F:46])[C:35]([F:43])([F:44])[C:36]([F:41])([F:42])[C:37]([F:38])([F:39])[F:40])[CH3:27]
Reactant: CN(CC=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CC=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.5 %

Procedure:
1.1 g of 11β-fluoro-7α-{5-[(3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hexadecafluoro-dec-2-enyl)-methyl-amino]-pentyl}-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 10 ml of methanol and carefully mixed with 148 mg of sodium borohydride. After 15 minutes of stirring at room temperature, the batch is added to saturated common salt solution, extracted with methylene chloride, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient and an ethyl acetate-acetone gradient, 127 mg of 11β-fluoro-7α-{5-[(3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hexadecafluoro-dec-2-enyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17-diol is obtained as a foam, [α]D=+35° (c=0.5 in CHCl3).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39]O)=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[NH2:45][CH2:46][CH2:47][CH2:48][OH:49].NC(C)(C)CO>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:45][CH2:46][CH2:47][CH2:48][OH:49])=[CH:33][C:32]=3[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NCCCO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)CO
Product: Cc1cc(OCCNCCCO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 57 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 3-amino-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol, respectively.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:13][C:14]2[N:19]=[N:18][C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[CH2:24][CH2:25]3)=[CH:16][CH:15]=2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCC1CCCCC1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(CCCC1CCCCC1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use 4-cyclohexylbutyric acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (18% yield). 1H NMR (300 MHz, CDCl3) δ 9.04, 8.32, 7.68, 7.56, 7.49, 7.30, 7.04-7.00, 3.99-3.23, 2.40, 1.89-1.83, 1.69-0.84.
Reaction SMILES: N[C@H](C(O)=O)CCCNC(=N)N.[NH:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@H:14]1[C:23]([OH:25])=[O:24].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[N:13]1([S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@H:14]1[C:23]([OH:25])=[O:24]
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2C(=O)O)cc1

Procedure:
To a solution of 100 mg of Tos-L-Tic (0.30 mmol), 122 mg of Arg(NO2)—OMe HCl (0.45 mmol), 61 mg of hydroxybenzotriazole (0.39 mmol), and 184 mg of 4-dimethylaminopyridine (1.51 mmol) in 50 mL of methylene chloride as added 174 mg (0.78 mmol) of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride. After stirring for 15 hours, 100 mL of additional methylene chloride was added to the reaction, and it was washed three times with 30 mL portions of 10% aqueous hydrochloric acid solution, then twice with 20 mL of 50% saturated sodium bicarbonate solution, and finally once with 20 mL of saturated brine. The product was then dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure. The product was next dissolved in 20 mL of methanol, and 230 mg of 10% palladium on carbon was added under nitrogen, followed by addition of 1 mL of formic acid, after which the reaction stirred for 15 hours. The catalyst was filtered off, and the solvent was then removed rapidly under reduced pressure to yield 22 mg of product. This material can also be synthesized by coupling a suitably protected arginine fragment with a suitably protected Tic fragment, deprotecting the Tic amino group, condensing this material with p-toluenesulfonyl chloride, and finally, deprotecting the arginine sidechain.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH2:39][N:34]([CH:32]5[CH2:33][O:30][CH2:31]5)[CH2:35][CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: C1CN(C2COC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4COC4)CC3)n(C)c2n1
Reaction time: 18 h
Yield: 37.1 %

Procedure:
TFA (2 mL) was added to a solution of 4-oxetan-3-ylpiperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.62 mmol) in DCM (10 mL) and the mixture was stirred at ambient temperature for 30 min, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to give 1-oxetan-3-ylpiperazine as a colourless oil. A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.51 mmol), 1-oxetan-3-ylpiperazine (88 mg, 0.62 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (10 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 99:1 to 98:2 to 95:5) to afford 513 as a white solid (98 mg, 37%). LCMS (Method I): RT=2.43 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.01 (dd, J=6.9, 2.4 Hz, 1 H); 7.78 (m, 1 H); 7.33-7.23 (m, 2 H); 4.70-4.60 (m, 4 H); 4.35 (m, 4 H); 3.97-3.75 (m, 7 H); 3.79 (s, 2 H); 3.57-3.49 (m, 1 H); 3.37 (q, J=7.5 Hz, 2 H); 2.66 (m, 4 H); 2.42 (m, 4 H); 1.46 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 3-(2-formyl-4-hydroxy-phenyl)-acrylic acid tert-butyl ester (4.97 g, 20.0 mmol) in DMF (40 mL) was added benzyl bromide (2.85 mL, 24.0 mmol) and Cs2CO3 (7.82 g, 24.0 mmol). The suspension was stirred at 80° C. for 30 min, and TLC indicated the reaction was complete. The mixture was quenched with H2O (500 mL) and extracted with EtOAc (2×100 mL). The combined organics were dried (Na2SO4) and concentrated to a residue, which was purified by silica gel chromatography (hexanes/EtOAc 9/1) to afford the title compound as yellow solid (6.70 g, 99%).