Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]=C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:20]=O.CSC>ClCCl.CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=O
Reactant: C=CCN(CCc1ccccc1)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)OC(=O)N(CC=O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Dissolve N-t-butoxycarbonyl-N-allyl-2-phenyl-ethylamine (7.88 g, 21.44 mmol) in dichloromethane (200 mL) and methanol (5 mL). Cool to -78° C. Pass ozonized oxygen through the solution until a persistent light blue color is obtained. Pass nitrogen through the solution until the blue color dissipates. Add dimethyl sulfide (20 mL). Allow the reaction mixture to warm to ambient temperature and stir for 5 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)c(Cl)c2)CC1
Reaction time: 24 h
Yield: 77.7 %

Procedure:
To a stirred mixture of 4-amino-3-chlorobenzoic acid (58.3 mmol, 10 g), tert-butyl piperazine-1-carboxylate (58.3 mmol, 10.86 g) and triethylamine (146 mmol, 20.31 mL, 14.74 g) in dichloromethane (200 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (69.9 mmol, 13.41 g). The reaction was stirred for 24 hours then was diluted with ethyl acetate and water. The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure. Diethyl ether was added and the solid was filtered off to give the title compound (15.4 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:19][C:20](=O)[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=[O:23])C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[NH:15][C:20](=[O:19])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(I)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 88 %

Procedure:
Prepared from (2-amino-4-iodo-phenyl)-carbamic acid tert.-butyl ester (Example G1) (900 mg, 2.7 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester (880 mg, 4.1 mmol) according to the general procedure K. Obtained as a yellow solid (1.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl>[O:13]([CH2:12][CH2:11][NH:9][C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCOc1ccccc1
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NCCOc1ccccc1
Yield: 52.6 %

Procedure:
A suspension of 6.2 g (50 mmol) o-anisidine M10, 12.1 g (60 mmol) β-bromophenetole M20 and 8.3 g (60 mmol) K2CO3 in 25 ml acetonitrile was heated at reflux for 18 hours. The mixture was cooled, diluted with 100 ml CHCl3 and washed with 100 ml water and 100 ml saturated NaCl. The organic layer was dried over Na2SO4. The solvent was evaporated to give 14.5 g crude oil. This oil was purified by a plug packed with 60 g silica gel 100 with cyclohexane as eluant, wherein 6.4 g pure product were obtained (yield: 51%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:18]=3[O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[F:33][C:30]([F:31])([F:32])[CH2:29][O:28][C:18]1[C:19]([C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:34])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C=C(C)c1cc2c(-c3cc(C)cc(C(C)(C)C)c3OCC(F)(F)F)cccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=CC(=O)O)c1cc2c(-c3cc(C)cc(C(C)(C)C)c3OCC(F)(F)F)cccc2s1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
A mixture of 198 mg (0.41 mmol) of 3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thien-2-yl}but-2-enoic acid ethyl ester disolved in 4 mL of methanol, 5 mL of THF and 1 mL of a 2N aqueous solution of LiOH was heated to reflux for 2 hours. After cooling at room temperature and acidic work-up, the crude acid was purified using preparative HPLC (kromosil column, eluent: 8/92 water/methanol+0.1% TFA). Collection of the desired fractions, evaporation of the solvents and recrystallization from acetonitrile affords 110 mg (0.23 mmol, yield: 58%) of 3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thien-2-yl}but-2-enoic acid as a white solid. 1H NMR (400 MHz, CDCl3) d: 7.80 (d, J=8.2 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.40 (s, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.24 (d, J=1.9 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 6.32 (s, 1H), 3.61 (m, 1H), 3.58 (m, 1H), 2.58 (s, 3H), 2.37 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:25](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH3:24])=[N:22][N:23]=3)[C:15]=2[CH:14]=1.CN(C=O)C.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:25][C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH3:24])=[N:22][N:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4nnc(C)n43)n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Solvent: O
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4nnc(C)n43)[nH]1)cn2C
Temperature: 85 °C
Yield: 8.4 %

Procedure:
To a round bottom flask was added 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.040 g, 0.086 mmol), DMF (0.865 mL), ethylenediamine (0.088 mL, 2.6 mmol) and TBAF (1.0 M in THF, 0.346 mL, 0.173 mmol). The reaction mixture was heated to about 85° C. for about 4 h. To the reaction mixture was added ethylenediamine (0.088 mL, 2.6 mmol) and TBAF (1.0 M in THF, 0.346 mL, 0.173 mmol). The reaction mixture was heated at about 85° C. for about 2 h. The reaction mixture cooled to room temperature and diluted with water (50 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by preparatory RP-HPLC (Table 2, Method u). The material was further purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.0024 g, 8.4%). LC/MS (Table 1, Method a) Rt=1.84 min; MS m/z: 333 (M+H)+.
Reaction SMILES: CS(O)(=O)=O.[CH:6]1([C:9](=O)[CH2:10][C:11]#[N:12])[CH2:8][CH2:7]1.[NH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O.[OH-].[Na+]>O.C1CCCCC1.C1(C)C=CC=CC=1>[CH:6]1([C:9]2[C:10]([C:11]#[N:12])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]3[C:15](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=2)[CH2:8][CH2:7]1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: N#CCC(=O)C1CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCCCC1
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
Into a glass flask having an internal volume of 200 mL, equipped with a stirring apparatus, a thermometer, a reflux condenser and a Dean-Stark apparatus, 80 mL of toluene and 20 mL of cyclohexane were put in an atmosphere of nitrogen, and 2.94 g (30.6 mmol) of methanesulfonic acid, 3.50 g (32.1 mmol) of 3-cyclopropyl-3-oxopropanenitrile and 6.59 g (30.6 mmol) of 2-amino-4′-fluorobenzophenone were added thereto with stirring. Then, the temperature was raised, and reaction was carried out at a temperature of from 90 to 95° C. for 4 hours while distilling off the formed water. After completion of the reaction, the reaction liquid was cooled to room temperature, and 100 mL of water and 5.5 mL (44.0 mmol) of 8 mol/L sodium hydroxide aqueous solution were added to make the reaction liquid basic. The obtained reaction liquid was extracted with 200 mL of ethyl acetate twice, then the organic layer was separated, and 2 g of anhydrous magnesium sulfate, 2 g of silica gel and 2 g of activated carbon were added, followed by stirring at room temperature for 1 hour. After filtration, the filtrate was concentrated under reduced pressure to obtain 8.45 g of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile as a pale yellow solid with a purity of 99% (area percentage by high performance liquid chromatography) (yield: 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:22])=[C:12]3[S:18][C:17]([CH2:19][OH:20])=[C:16]([CH3:21])[C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:32][C:33]([NH2:35])=[O:34].O>CN(C=O)C>[NH2:35][C:33](=[O:34])[CH2:32][N:14]1[CH:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=2)=[O:9])[C:11](=[O:22])[C:12]2[S:18][C:17]([CH2:19][OH:20])=[C:16]([CH3:21])[C:13]1=2
Reactant: NC(=O)CI
Reactant: Cc1c(CO)sc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(CC(N)=O)c12
Temperature: 50 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-7-hydroxy-2-(hydroxymethyl)-3-methylthieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.276 mmol), potassium carbonate (57 mg, 0.41 mmol) and iodoacetamide (255 mg, 1.38 mmol) in DMF (1.5 mL) was stirred at 50° C. for 18 hrs. Additional iodoacetamide (255 mg) and potassium carbonate (57 mg) were added, and the reaction was stirred at the same temperature for another 12 hrs. After cooling, cold water was added, and the resulting ppt was collected by filtration after chilling in an ice bath. The collected crude solid was recrystallized from aq. ethanol to give the title compound (65 mg) as a lt. brown solid.
Reaction SMILES: I[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:2]2[S:10][C:9]3[C:4](=[N:5][CH:6]=[CH:7][C:8]=3[O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)cc1
Reactant: OB(O)c1ccccc1
Product: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)sc23)cc1

Procedure:
This compound can be prepared from 4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 72, Step A) and phenylboronic acid using the procedure described for Example 94, Step A.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:30]([NH:29][C:23]2[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=2[F:21])=[O:31])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(OCCCN(C)C)c(-c3ccnn3C)c2)c1
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (43.9 mg, 0.160 mmol) in CH2Cl2 (2 mL) was added 2-fluoro-5-methylphenyl isocyanate (0.23 μL, 0.176 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 139 as a colorless solid (53.2 mg, 78%). LCMS m/z (%)=426 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.98 (bs, 1H), 8.42 (bs, 1H), 7.96 (dd, J=7.89, 1.96 Hz, 1H), 7.45 (d, J=1.82 Hz, 1H), 7.44-7.38 (m, 2H), 7.13-7.06 (m, 2H), 6.82-6.75 (m, 1H), 6.24 (d, J=1.85 Hz, 1H), 3.98 (t, J=6.35 Hz, 2H), 3.66 (s, 3H), 2.25 (s, 3H), 2.19 (t, J=7.03 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11](OC)[O:12]C)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3]>C(O)=O>[CH2:1]([N:4]([CH2:10][CH:11]=[O:12])[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(OC)OC)C(=O)OCC
Solvent: O=CO
Product: C=CCN(CC=O)C(=O)OCC

Procedure:
68 g (0.313 mol) of ethyl N-allyl-N-(2,2-dimethoxyethyl)carbamate are heated with 150 ml of formic acid at 100° C. for one hour. The mixture is poured onto ice and extracted several times with methylene chloride, the organic phases are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated and the residue is distilled.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=2)O1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 110 °C
Yield: 74.9 %

Procedure:
To a degassed mixture of 4-bromo-2-nitroaniline (1 g, 4.6 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.42 g, 4.6 mmol), tripotassium phosphate trihydrate (3.9 g, 14.64 mmol) in dioxane and water (30 mL, 8:1) was added Pd(dppf)2Cl2 (337 g, 0.46 mmol). The mixture was refluxed at 110° C. for 3 hours. Filtration and concentration gave crude product, which was purified by silica gel column chromatography to afford the title compound (1.1 g, yield: 75%). MS (ESI): 320 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH2:12])=[CH:6][CH:7]=1
Reactant: NC(=O)CCc1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 103.9 %

Procedure:
To a solution of 3-(4-bromophenyl)propanamide (1.59 g) in tetrahydrofuran (24 ml) was added lithium aluminum hydride (370 mg) and the mixture was refluxed for 1.5 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into 1N aqueous sodium hydroxide solution (100 ml). The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave 3-(4-bromophenyl)-1-propanamine (1.55 g) as a yellow oil.
Reaction SMILES: [CH2:1]([P:7](=[O:10])([OH:9])[OH:8])[CH2:2][P:3](=[O:6])([OH:5])[OH:4].C(Cl)(=O)C(Cl)=O.[F:17]/[CH:18]=[C:19]1/[C@H:20]([N:27]2[CH:34]=[CH:33][C:31]([NH2:32])=[N:30][C:28]2=[O:29])[O:21][C@H:22]([CH2:25]O)[C@H:23]/1[OH:24]>CN(C=O)C>[CH2:1]([P:7]([O:9][CH2:25][C@H:22]1[O:21][C@@H:20]([N:27]2[CH:34]=[CH:33][C:31]([NH2:32])=[N:30][C:28]2=[O:29])/[C:19](=[CH:18]/[F:17])/[C@@H:23]1[OH:24])(=[O:8])[OH:10])[CH2:2][P:3](=[O:5])([OH:4])[OH:6]
Reactant: O=P(O)(O)CCP(=O)(O)O
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)/C2=C\F)c(=O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Nc1ccn([C@@H]2O[C@H](COP(=O)(O)CCP(=O)(O)O)[C@@H](O)/C2=C\F)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.7 %

Procedure:
Ethylenediphosphonic acid (100 mg, 0.53 mmol) was treated with oxalyl chloride (2 mL, as solvent) and anhydrous DMF (0.1 mL, cat.). After heating at reflux for 10 minutes under an argon atmosphere a solution was obtained and after a further 3 h the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was coevaporated with anhydrous acetonitrile (3×10 mL). The residue was dissolved in anhydrous trimethyl phosphate (2 mL), cooled to −15° C. under an argon and (E)-2′-deoxy-2′-(fluoromethylene)cytidine (64 mg, 0.25 mmol) was added. After stirring for 2 h the reaction mixture was quenched with ice-cold TEAB solution (1.0 M, 5 mL) and stirred for 30 minutes. Purification by HPLC gave 2.9 mg of the titled compound 80.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:44]1[CH2:49][CH2:48][CH:47]([NH:50][C:51]2[CH:60]=[CH:59][N:58]=[C:57]3[C:52]=2[C:53]2[CH:65]=[CH:64][CH:63]=[CH:62][C:54]=2[C:55](=[O:61])[NH:56]3)[CH2:46][CH2:45]1>CN(C=O)C>[C:1]1([CH2:7][C:8]([N:44]2[CH2:45][CH2:46][CH:47]([NH:50][C:51]3[CH:60]=[CH:59][N:58]=[C:57]4[C:52]=3[C:53]3[CH:65]=[CH:64][CH:63]=[CH:62][C:54]=3[C:55](=[O:61])[NH:56]4)[CH2:48][CH2:49]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=c1[nH]c2nccc(NC3CCNCC3)c2c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N1CCC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
Phenylacetic acid (10 mg, 0.07 mmol), DIEA (28 mg, 0.22 mmol), and HATU (28 mg, 0.07 mmol) were dissolved in DMF (1 mL), and stirred for 30 min at room temperature. 358 (17 mg, 0.06 mmol) was added, and the reaction mixture was stirred for another 1 h at room temperature. The crude material was purified directly via HPLC to provide 360 (10 mg, 30% yield) as a solid. LC-MS (M+H=413, obsd.=413).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:47]=[C:46]([CH3:48])[C:41]4[NH:42][C:43](=[O:45])[O:44][C:40]=4[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[N:82]1([CH2:88][CH2:89]O)[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1>CN(C=O)C.C(O)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:47]=[C:46]([CH3:48])[C:41]4[NH:42][C:43](=[O:45])[O:44][C:40]=4[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:89][CH2:88][N:82]5[CH2:87][CH2:86][O:85][CH2:84][CH2:83]5)=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc2oc(=O)[nH]c12
Reactant: OCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)OCCN4CCOCC4)CC3)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 90 mg (0.13 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 48 mg (0.15 mmol) TBTU and 26 μL (0.19 mmol) triethylamine in 1.4 mL DMF was stirred for 1 h at RT. Then 18 μL (0.15 mmol) 2-morpholin-4-yl-ethanol was added. The reaction mixture was stirred for 16 h at RT. 4 drops of formic acid were added, the mixture was filtered through a syringe filter and purified by HPLC. The fractions containing the product were combined, made alkaline with 5% NaHCO3 solution, extracted with 50 mL EtOAc and the organic phase was dried on Na2SO4. After the desiccant and solvent had been eliminated the residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [CH2:1]([O:51][S:52]([OH:55])(=[O:54])=[O:53])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:30][O:31][S:32]([OH:35])(=[O:34])=[O:33])[O:13][C@H:12]([CH2:14][O:15][S:16]([OH:19])(=[O:18])=[O:17])[C@@H:11]([O:20][S:21]([OH:24])(=[O:23])=[O:22])[C@@H:10]2[O:25][S:26]([OH:29])(=[O:28])=[O:27])[C@H:5]([O:36][S:37]([OH:40])(=[O:39])=[O:38])[C@@H:4]([O:41][S:42]([OH:45])(=[O:44])=[O:43])[C@@H:3]1[O:46][S:47]([OH:50])(=[O:49])=[O:48].[OH-].[Na+:57]>>[CH2:1]([O:51][S:52]([O-:55])(=[O:53])=[O:54])[C@H:2]1[O:7][CH:6]([O:8][C@:9]2([CH2:30][O:31][S:32]([O-:35])(=[O:34])=[O:33])[O:13][C@H:12]([CH2:14][O:15][S:16]([O-:19])(=[O:17])=[O:18])[C@@H:11]([O:20][S:21]([O-:24])(=[O:23])=[O:22])[C@@H:10]2[O:25][S:26]([O-:29])(=[O:28])=[O:27])[C@H:5]([O:36][S:37]([O-:40])(=[O:38])=[O:39])[C@@H:4]([O:41][S:42]([O-:45])(=[O:44])=[O:43])[C@@H:3]1[O:46][S:47]([O-:50])(=[O:49])=[O:48].[Na+:57].[Na+:57].[Na+:57].[Na+:57].[Na+:57].[Na+:57].[Na+:57].[Na+:57]
Reactant: O=S(=O)(O)OC[C@H]1O[C@@](COS(=O)(=O)O)(O[C@H]2O[C@H](COS(=O)(=O)O)[C@@H](OS(=O)(=O)O)[C@H](OS(=O)(=O)O)[C@H]2OS(=O)(=O)O)[C@@H](OS(=O)(=O)O)[C@@H]1OS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)([O-])OC[C@H]1O[C@@](COS(=O)(=O)[O-])(OC2O[C@H](COS(=O)(=O)[O-])[C@@H](OS(=O)(=O)[O-])[C@H](OS(=O)(=O)[O-])[C@H]2OS(=O)(=O)[O-])[C@@H](OS(=O)(=O)[O-])[C@@H]1OS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
One portion of sucrose octasulfate solution prepared as described in I above was adjusted with 10% w/w aqueous sodium hydroxide to pH=9 with stirring at room temperature. The solution was evaporated at 50° C. in vacuo to remove pyridine and water. When 250 ml were distilled, 580 ml of ethylene glycol were added and the evaporation was continued until 10 mm vacuum. 100 ml of ethanol were added to the solution. The solution was filtered, and pH was adjusted to 9.5. 350 ml of ethanol were slowly added with vigorous stirring at 30°-35° C., and the substance will then precipitate. After the addition was ended, the mixture was cooled to 10° C., and the solid substance was filtered and washed with 50 ml of 1:1 ethanol/ethylene glycol and 200 ml of methanol. The wet filter cake was dried in vacuo at 50° C. The crude product was dissolved in 520 ml of ethylene glycol and heated to 40° C., and 100 ml of ethanol were added. The solution was filtered and pH was adjusted to 9.5. 350 ml of ethanol were slowly added with vigorous stirring at 30°-35° C. and the substance will then precipitate. After the addition was ended, the mixture was cooled to 10° C. and the solid substance was filtered. It was washed with 50 ml of 1:1 ethanol/ethylene glycol and 200 ml of ethanol. The wet filter cake was dried in vacuo at 50° C.. The substance was reprecipitated once as above and then dried for 2 hours at room temperature in 500 ml of ethanol. The substance was filtered, washed with 200 ml of ethanol and dried at 50° C. in vacuo.