Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:16]3[CH2:20][CH:19]([C:21]4[N:22]=[CH:23][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:25]=4)[O:18][N:17]=3)[N:13]=[C:12]([CH3:45])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:48][CH3:49].Cl>CO>[NH:24]1[CH:25]=[C:21]([CH:19]2[O:18][N:17]=[C:16]([C:14]3[N:13]=[C:12]([CH3:45])[N:11]=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:46]=[CH:47][C:2]([F:1])=[C:3]([O:48][CH3:49])[CH:4]=4)=[O:9])[CH:15]=3)[CH2:20]2)[N:22]=[CH:23]1
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)C3)nc(C)n2)ccc1F
Agent: Cl
Solvent: CO
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4c[nH]cn4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.6 %

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-6-((hydroxyimino)methyl)-2-methylpyrimidine-4-carboxamide (0.2 g, 0.628 mmol, Preparation #9,) and 1-trityl-4-vinyl-1H-imidazole (Organic Letters 2001, 3, 1319-1322) in DCM (20 mL) was added sodium hypochlorite solution (2.0 mL, Sd Fine Chem.) dropwise for about 10 min at RT and stirred for about another 1 h. The reaction mixture was diluted with DCM (30 mL) and washed with water (2×20 mL). The organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure. The resulting mixture was purified by silica gel chromatography eluting with 60 to 70% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-trityl-1H-imidazol-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide as a light yellow solid 0.154 g, (37.5%). To a stirred solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-trityl-1H-imidazol-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide(0.14 g, 0.24 mmol) in methanol (15 mL) was added concentrated HCl (1.2 mL). The reaction mixture was stirred at RT for about 4 h and excess solvent was evaporated under reduced pressure. The reaction mixture was quenched with 1N NaOH solution (5 mL), diluted with water (10 mL) and the product extracted with EtOAc (2×10 mL). The combined organic layers were washed successively with water (1×30 mL) and brine (1×20 mL). The organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure. The crude material was purified by preparative TLC (7% methanol in DCM) to afford 6-(5-(1H-imidazol-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 0.039 g (41.4%); 1H NMR (400 MHz, DMSO): δ 8.178 (s, 1), 12.121 (s, 1H), 9.494 (m, 1H), 7.65 (s, 1H), 7.305 (s, 1H), 7.186-7.146 (m, 2H), 6.910-6.905 (m, 1H), 5.845-5.795 (m, 1H), 4.490-4.475 (d, 2H, J=6 Hz), 3.81 (s, 3H), 3.715-3.692 (m, 2H), 2.77 (s, 3H); MS m/z: 410.40 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COC(OC)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[C:4]1([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]1[CH3:11]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(C)OC
Agent: [Ba+2]
Solvent: O
Product: Cc1cc(C)c(C2([N+](=O)[O-])C=CC=CC2C)c(C)c1
Yield: 92.9 %

Procedure:
A solution of 2-bromo-6-nitrotoluene (10.0 g, 46 mmol), mesitylboric acid (8.3 g, 51 mmol), Pd(PPh3)4 (2.7 g, 2.31 mmol) and barium hydroxide octahydrate (21.9 g, 69 mmol) in 2,2-dimethoxyethane (300 mL) and water (50 mL) was heated under reflux for six hours. The mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (0-1% ethyl acetate/hexane), to give the title compound (11.0 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:3]=1>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:11]=2)[N:3]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.00 g (11.2 mmol) of the above prepared [2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol was dissolved in 56 ml of CH2Cl2 and treated with 14.6 g (15 eq.) of MnO2. After vigorous stirring for 2 h at ambient temperature, the reaction mixture was filtered over Celite and carefully rinsed with CH2Cl2. Evaporation of the solvent left 2.659 g of the title compound as white crystals of mp. 61-63° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[C:5]1[CH:15]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:14][CH2:13][CH2:12][N:6]12.C1COCC1.CO.[Li+].[OH-]>CC(O)=O>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)=[C:5]1[CH:15]([CH2:16][C:17]([OH:19])=[O:18])[CH2:14][CH2:13][CH2:12][N:6]12
Reactant: COC(=O)CC1CCCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1CCCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a solution of the ester of Step 6 (45 mg) in a THF/MeOH (3:1) mixture at r.t. was added 1N LiOH (aqueous solution). The reaction mixture was stirred at r.t. for 2 h and AcOH was added. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The residue was swished in EtOAc to provide 20 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[S:6](=O)(=[O:9])([OH:8])[OH:7]>>[S:6]([OH:9])([O:5][CH:3]([CH3:4])[CH2:2][NH2:1])(=[O:8])=[O:7]
Reactant: CC(O)CN
Reactant: O=S(=O)(O)O
Product: CC(CN)OS(=O)(=O)O

Procedure:
FIG. 5 shows another synthetic reaction scheme for preparation of an mPEG-DTB-ligand compound in accord with the invention. The details of the reaction procedure are given in Examples 3A-3B. Briefly, cold 1-amino-2-propanol was reacted with sulfuric acid to form 2-amino-1-methylethyl hydrogen sulfate. This product was reacted with carbon disulfide and sodium hydroxide in aqueous ethanol to yield 5-methylthiazolidine-2-thione. An aqueous solution of hydrochloric acid was added to the 5-methylthiazolidine-2-thione and heated. After refluxing for one week, the product, 1-mercapto(methyl)ethyl ammonium chloride, was crystallized and recovered. This product was reacted with methoxy carbonylsulfenyl chloride to yield 2-(methoxycarbonyldithio)ethaneamine. Reaction of the 2-(methoxycarbonyldithio)ethaneamine with mPEG-chloroformate using the procedure described above with respect to FIG. 2 yields the desired mPEG-DTB-nitrophenyl compound suitable for reaction with a selected amine-containing ligand to form a compound in accord with the invention.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(S(=O)(=O)c3ccc(N)cc3)cc(N3CCCC3)n2)cc1
Yield: 70.8 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 77 mg (0.55 mmole) 4-methoxyphenylboronic acid, 18 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 2 hours in 7 ml toluene and 2 ml 2N aqueous potassium carbonate. The solvents are removed in vacuo. Flash chromatography (Silicagel, ethyl acetate/hexane 1/1) of the residue yields 145 mg (70%) pure 4-[2-(4-methoxy-phenyl)-6-pyrrolidine-1-yl-pyridine-4-sulfonyl]-phenylamine as a pale yellow solid mp.: 227-229° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:17])([O:11][O:12]C(C)(C)C)[CH3:10])[CH2:3][CH2:4][OH:5].CC(CCCC(C)(O)C)CCO.OO>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:17])([O:11][OH:12])[CH3:10])[CH2:3][CH2:4][OH:5]
Reactant: CC(CCO)CCCC(C)(C)OOC(C)(C)C
Agent: CC(CCO)CCCC(C)(C)O
Agent: OO
Product: CC(CCO)CCCC(C)(C)OO

Procedure:
The above-mentioned starting reactant, 3,7-dimethyl-7-(t-butylperoxy)octyl alcohol, was prepared by first reacting 3,7-dimethyl-7-hydroxy octyl alcohol with hydrogen peroxide to form 3,7-dimethyl-7-(hydroperoxy)octyl alcohol which was then alkylated with t-butyl alcohol to give said starting reactant.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[K+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH-:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN1CCCC1=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=2)(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: [NH-]S(=O)(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(Cl)cc2)n1
Yield: 84.6 %

Procedure:
0.39 g (0.0022 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and 1.0 g (0.0044 mol) of 4-chloro-benzenesulfonamide potassium salt were stirred in 10 ml of 1 -methyl-2-pyrrolidone at 150° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was saturated with sodium chloride, evaporated briefly in a vacuum, made acid with 4N HCl and extracted with dichloromethane. The two extracts were combined and chromatographed over silica gel with cyclohexane/ ethyl acetate 1:1 as the eluent. There was obtained 0.62 g (85%) of 4-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals. m.p. 196-198° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[C:17]([CH:19]1[CH2:21][CH2:20]1)#[CH:18]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH:19]1([C:17]#[C:18][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:21][CH2:20]1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#CC1CC1)c1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A 1 L three-necked round bottom flask was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl) -1H-indazole (31.2 g, 111 mmol; Intermediate 1) and triethylamine (500 mL). The flask was degassed with three vacuum/N2 cycles, followed by the addition of Pd(PPh3)2Cl2 (7.7 g, 11 mmol) and CuI (2.1 g, 11 mmol) under N2 atmosphere. The flask was again degassed with three vacuum/N2 cycles. Ethynylcyclopropane (70% in toluene, 20.9 g, 222 mmol) was then added via syringe and the reaction mixture was stirred at 80° C. for 16 hours. Upon completion, the solvent was evaporated. The residue was diluted with dichloromethane (600 mL), washed with water (2×200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was further purified on silica gel column (1:100-1:20 EtOAc/petroleum ether) affording the title compound (27.0 g). 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.82 (s, 1H), 7.70 (d, 1H), 7.39 (m, 1H), 5.84 (dd, 1H), 3.91-3.87 (m, 1H), 3.78-3.73 (m, 1H), 2.52-2.37 (m, 1H), 2.05-1.94 (m, 2H), 1.76-1.72 (m, 1H), 1.60-1.52 (m, 3H), 0.92-0.87 (m, 2H), 0.78-0.73 (m, 2H); LCMS: 267 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]#[N:9])[N:6]=1.[CH:10]1[C:23]2[CH:22]([C:24](Cl)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[C:8]([CH2:7][N:5]1[N:4]=[N:3][C:2]([NH:1][C:24]([CH:22]2[C:23]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:25])=[N:6]1)#[N:9]
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: N#CCn1nnc(N)n1
Product: N#CCn1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid, m.p. 204-205° and MS: m/e=333.2 (M++H) was prepared in accordance with the general method of example 1 from (5-amino-tetrazol-2-yl)-acetonitrile and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20](O)=[O:21])=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(N(CC)C(C)C)(C)C.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH2:45][CH:46]([F:48])[F:47])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:47][CH:46]([F:48])[CH2:45][NH:44][C:42]([CH2:41][NH:40][C:20]([C:18]1[S:19][C:15]([C:12]2[CH2:11][C:10]([C:4]3[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)([C:26]([F:29])([F:27])[F:28])[O:14][N:13]=2)=[C:16]2[CH2:25][CH2:24][CH2:23][C:17]=12)=[O:21])=[O:43]
Reactant: NCC(=O)NCC(F)F
Reactant: O=C(O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2)NCC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of compound 3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid (3 g, 6.4 mmol) in acetonitrile (30 mL) is added N,N-diisopropylethylamine (2.5 g, 19 mmol), 2-amino-N-(2,2-difluoro-ethyl)-acetamide hydrochloride (1.34 g, 7.7 mmol) and HATU (3.7 g, 9.6 mmol), after the addition the mixture is stirred at room temperature for 1 hour. After being detected by TLC and LCMS, the reaction mixture is concentrated and the residue is purified by column chromatography to afford desired product (3 g, 88%). MS (m/z): 588.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:12]([O:13][CH3:14])=[C:11]([CH3:15])[C:10]([O:16][CH3:17])=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.CC1[C:33](OC)=[CH:32][C:28](C(Cl)=O)=[C:27]([N+:36]([O-])=O)[C:26]=1[O:39]C.N1(CO)CCCC1>CN(C=O)C.C(Cl)Cl>[CH3:15][C:11]1[C:10]([O:16][CH3:17])=[CH:9][C:5]([C:6]([N:36]2[CH2:33][CH2:32][CH2:28][CH:27]2[CH2:26][OH:39])=[O:8])=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)Cl)c([N+](=O)[O-])c(OC)c1C
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: OCN1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1C
Reaction time: 8 h
Yield: 43 %

Procedure:
A catalytic amount of DMF (2 drops) was added to a stirred solution of 189 (3.96 g, 15.32 mmol) and oxalyl chloride (2.14 g, 16.85 mmol) in dry CH2Cl2 (50 mL) under a nitrogen atmosphere. The reaction mixture was allowed to stir overnight and the resulting acid chloride used directly in the next stage of the procedure. 4-methyl-3,5-dimethoxy-2-nitro-benzoyl chloride in anhydrous DCM (50 mL) was added dropwise over 0.5 hours to a stirring solution of pyrrolidine methanol (1.55 g, 15.32 mmol, 1.1 eq) and TEA (3.87 g, 38.3 mmol, 2.5 eq) in anhydrous DCM (50 mL) at 0° C. under a nitrogen atmosphere and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was washed with 1 N HCl (2×100 mL), and the organic layer was washed with distilled H2O (2×100 mL), brine (2×100 mL) and dried over anhydrous MgSO4. Evaporation of excess solvent yielded a yellow glass (190) (2.13 g, 6.56 mmol, 43% -2 steps); 1H NMR (270 MHz, CDCl3) δ6.61 (s, 1H), 4.30-4.28 (m, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.83-3.68 (m, 2H), 3.46-3.26 (m, 2H), 2.19 (s, 3H), 1.94-1.68 (m, 4H); 13C NMR (67.8 MHz, CDCl3) δ167.85, 161.15, 152.62, 135.70, 132.32, 123.17, 103.70, 65.87, 62.61, 61.37, 56.36, 50.20, 28.41, 24.50, 9.34.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[C:29]([O:33][C:34]([NH:36][C@@H:37]1[CH2:42][CH2:41][CH2:40][N:39]([C:43]2[N:51]([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[Cl:59])[C:50]3[C:49](=[O:60])[N:48]([CH3:61])[C:47](=[O:62])[N:46]([CH3:63])[C:45]=3[C:44]=2[C:64](O)=[O:65])[CH2:38]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[Cl:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[CH2:52][N:51]1[C:50]2[C:49](=[O:60])[N:48]([CH3:61])[C:47](=[O:62])[N:46]([CH3:63])[C:45]=2[C:44]([C:64]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:65])=[C:43]1[N:39]1[CH2:40][CH2:41][CH2:42][C@@H:37]([NH:36][C:34](=[O:35])[O:33][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:38]1
Reactant: C1COCCN1
Reactant: Cn1c(=O)c2c(c(C(=O)O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(c(C(=O)N3CCOCC3)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Hydroxybenzotriazole (117 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (147 mg), triethylamine (0.21 ml) and morpholine (63 μl) were added to a solution of 6-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (140 mg) in N,N-dimethylformamide (3 ml), and the resulting mixture was stirred at 25° C. for 20 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a preparative thin-layer chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (106 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].C([Li])CCC.[CH:15](N1CCCCC1)=[O:16]>O1CCCC1.CCCCCC>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH:15]=[O:16])=[CH2:5]
Reactant: O=CN1CCCCC1
Reactant: C=Cc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccccc1C=O
Temperature: -65 °C

Procedure:
To a solution of 2-bromostyrene (115 mmol) in dry tetrahydrofuran (200 ml) at -65° C. under nitrogen was added dropwise n-butyllithium (115 mmol) in hexane. The reaction mixture was stirred at -65° C. for an additional hour and a solution of N-formylpiperidine (125 mmol) in tetrahydrofuran (50 ml) was added dropwise. The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was cooled to 0° C. and then quenched with saturated ammonium chloride (50 ml). The reaction mixture was extracted with diethyl ether (2×50 ml) and the combined organic phases were washed with 3N hydrochloric acid (2×50 ml), saturated aqueous sodium bicarbonate (50 ml), and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield the Compound 2a which was directly used in the next reaction.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: Cn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(N2CCNCC2)nc2cccnc21

Procedure:
A solution of 2.74 g (8.63 mmol) of tert.butyl 4-(3-methyl-3H-imidazo[4,5]pyridin-2-yl)-piperazin-1-carboxylate and 3.5 ml of trifluoroacetic acid in 50 ml of dichloromethane is stirred for 14 hours while refluxing. Dilute sodium carbonate is added cautiously, the organic phase is separated off and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([S:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.C(Cl)[Cl:12]>>[Cl:12][CH2:2][C:3]1[CH:4]=[C:5]([S:9][CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCl
Reactant: CSc1cccc(CO)c1
Product: CSc1cccc(CCl)c1

Procedure:
3-Hydroxymethyl-1-methylthiobenzene (3.3 g, 21 mmol) is dissolved in absolute CH2Cl2 (20 ml) under an argon atmosphere. A solution of SOC12 (2.6 g, 21 mmol) in absolute CH2Cl2 (10 ml) is added dropwise with stirring to this initial mixture in the course of 15 min, initially under reflux, then at an internal temperature of 30° C. The reaction mixture is stirred under reflux for 2.25 h. The reaction mixture is concentrated and the oily crude product is purified by bulb tube distillation (7.9×10−2 mbar, 125-140° C.): colorless oil; yield: 3.3 g (88%)
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:14]1[CH2:15][CH2:16][CH:12]([OH:11])[CH2:13]1
Reactant: Clc1nc2ccccc2o1
Reactant: O[C@@H]1CCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OC1CCN(c2nc3ccccc3o2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
To a stirring solution of 5.1 mL (44.6 mmol) of 2-chlorobenzoxazole in 35 mL of THF at 0° C. was added 4.28 g (49.0 mmol, 1.1 equiv.) of (R)-3-hydroxypyrrolidine and 4.42 mL (32 mmol, 0.72 equiv.) of triethylamine. The resulting solution was stirred 12 h at RT, the precipitate was filtered, washed with THF (3×5 mL), and the filtrate concentrated in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 to EtOAc as eluent afforded 3.74 g of the title compound: low resolution MS (ESP) m/e 205 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][C@H:17]([C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:22]1([C:20]([C@H:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([C@H]1CCNC1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Pyrrolidine (51 μL, 1.03 mmol) was added to a solution of (S)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.93 mmol), HATU (391 mg, 1.03 mmol) and DIPEA (410 μL, 2.35 mmol) in DMF and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 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 to afford the title compound as a pale brown oil (110 mg, 70%). 1H NMR (CDCl3, 400 MHz) δ 4.01 (m, 3 H); 3.52-3.41 (m, 3 H); 3.25-3.11 (m, 2 H); 3.10-2.97 (m, 2 H); 2.89 (dt, J=11.4, 7.5 Hz, 1 H); 2.11-1.99 (m, 1 H); 2.01-1.91 (m, 2 H) and 1.93-1.82 (m, 2 H).