Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[CH:37]=[N:38][CH:39]=[N:40][CH:41]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:37]=[N:38][CH:39]=[N:40][CH:41]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2cncnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 58 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.13 mmol), 5-tributylstannanyl-pyrimidine (71 mg, 0.19 mmol) and PdCl2(PPh3)2 (18 mg, 0.026 mmol) in 3 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (10-100% EtOAc/hexanes+1% AcOH) to give 35 mg of the title compound. MS: (+) m/z 465.29 (M+1).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].O>CS(C)=O>[NH2:4][C:5]1[C:10]([O:11][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: Nc1ncccc1O
Reactant: ClCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncccc1OCCCCl
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 48.7 ml (200 mmol) of a 4.1M sodium methoxide solution in 100 ml of dimethyl sulfoxide, 22.03 g (200 mmol) of 2-amino-3-hydroxypyridine was added at room temperature, followed by stirring at 80° C. for 10 minutes to dissolve the latter. After the reaction mixture was cooled, the methanol was distilled off. To this mixture, 19.8 ml (200 mmol) of 1-bromo-3-chloropropane was added at 0° C., followed by stirring for 30 minutes. The reaction mixture was poured into water (400 ml), extracted with chloroform, washed with2N aqueous sodium hydroxide and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate). The obtained crude crystal was washed with diethyl ether-n-hexane to yield 20.48 g (54.8%, white powder) of the desired product.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH3:26][O-:27].[Na+]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([O:27][CH3:26])[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: C[O-]
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Agent: [Na+]
Product: COc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
The product from example 44 step (viii) (0.1 g) was heated with a solution of sodium methoxide (made from sodium (0.2 g) in dry methanol (10 ml)) at reflux for 3 h. The mixture was partitioned between ethyl acetate and water. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure. Purification was by chromatography eluting with 70% ethyl acetate in isohexane to give the title product as a colourless solid.
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:2]([C:7](OC)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[Li+].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(O)C>[C:14]([O:13][C:11]([NH:1][C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:7][OH:8])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC[C@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Boc-DNle-OMe (4.23 g) in dry THF (30 ml) were added lithium chloride (0.85 g), sodium borohydride (0.76 g) and dry ethanol (60 ml), and the mixture was stirred at the same temperature for 2 h and at room temperature over night. The mixture was with ice-water, adjusted to pH 3 by the gradual addition of 10% aq. citric acid, and concentrated in vacuo. Water (200 ml) was added to the residue,and the mixture was extracted with dichloromethane (50 ml×3).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20]([CH2:22]Cl)=[O:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@H:8]([CH2:19][C:20](=[O:21])[CH2:22][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(CCl)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)CN1CCOCC1
Yield: 65.5 %

Procedure:
The resultant compound from Example 34 (610 mg, 1.84 mmol) in dimethylformamide (10 ml) was treated with NaI (33 mg, 0.22 mmol) and morpholine (0.60 ml, 6.88 mmol). After 2 h the mixture was diluted with ethyl acetate, washed with water and brine, and then dried over Na2SO4, and evaporated. Chromatography of the residue on silica gel with 60% ethyl acetate/40% hexane afforded 460 mg (65%) of an oil. 1H NMR (CDCl3) δ7.05-7.40 (m,10H), 5.11 (d,1H), 5.06 (d,1H), 3.68 (m,4H), 3.22-3.32 m,1H), 3.15 (d,1H), 3.08 (d,1H), 3.05 (m,1H), 2.87 (dd,1H), 2.77 (dd,1H), 2.35-2.50 (m,5H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])=[CH:36][CH:35]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 4-fluorobenzylamine (34 mg, 0.27 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration to afford 96 mg of the title compound as a colorless solid.
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=O)C=1.CC1(C)CO[CH:16]([CH:19]([C@@H:21]2[C@:38]3([CH3:39])[C@H:24]([C@H:25]4[C@H:35]([CH2:36][CH2:37]3)[C@:33]3([CH3:34])[C:28](=[CH:29][C:30](=[O:41])[C@@H:31]5[O:40][C@@H:32]53)C=C4)[CH2:23][CH2:22]2)C)OC1>C(Cl)(Cl)Cl>[O:40]1[C:31]2=[C:32]3[C@:33]([CH3:34])([CH2:28][CH2:29][C:30]2=[O:41])[C@@H:35]2[C@H:25]([C@H:24]4[C@:38]([CH3:39])([CH2:37][CH2:36]2)[C@@H:21]([CH2:19][CH3:16])[CH2:22][CH2:23]4)[C@@H:4]2[O:10][C@:8]123
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClC(Cl)Cl
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
A solution of 0.664 g (3.85 mmoles) of m-chloroperbenzoic acid in 50 ml of chloroform was mixed with a solution of 0.328 g (0.769 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one in 10 ml of chloroform and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and the precipitate was washed with chloroform. The filtrate and the washings were combined, diluted with chloroform and washed successively with aqueous potassium iodide solution and aqueous sodium chloride solution. Finally the organic layer was dried over magnesium sulfate and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane: 1:10, v/v) to recover 0.258 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3-one (yield: 76%).
Reaction SMILES: CO[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:16]([S:17][CH3:18])=[C:15]3[C:10]([N:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:12](=[O:21])[N:13]([CH3:20])[C:14]3=[O:19])=[N:9]2)=[CH:5][CH:4]=1.ClCC1C=CC([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][N:38]2[CH3:43])=CC=1>>[CH3:20][N:13]1[C:14](=[O:19])[C:15]2=[C:16]([S:17][CH3:18])[N:8]([CH2:7][C:6]3[CH:27]=[CH:28][C:3]([CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][N:38]4[CH3:43])=[CH:4][CH:5]=3)[N:9]=[C:10]2[N:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:12]1=[O:21]
Reactant: CN1CCCCC1c1ccc(CCl)cc1
Reactant: COc1ccc(Cn2nc3c(c2SC)c(=O)n(C)c(=O)n3CC(C)(C)C)cc1
Product: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(C2CCCCN2C)cc1

Procedure:
The synthetic procedure of this compound is analogous to EXAMPLE 5 wherein 2-(4-methoxybenzyl)-5-methyl-3-(methylthio)-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is used instead of 2-(4-methoxybenzyl)-5-methyl-7-neopentyl-3-(phenylthio)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, and 2-(4-(chloromethyl)phenyl)-1-methylpiperidine is used instead of 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole. MS (ESI) m/z 439.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH:18]=[O:19])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>CC(O)C>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH2:18][OH:19])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccc(OCCc2coc(-c3ccccc3)n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: OCc1cccc(OCCc2coc(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
14.0 g (47.9 mM) of 3-[2-(2-phenyl-4-oxazolyl)ethoxy]benzaldehyde, prepared as described in Preparation 2 herein, was diluted with 200 mL i-PrOH and treated with 2.89 g (76.6 mM) of sodium borohydride. The mixture was stirred at ambient temperature for 24 hr. 250 mL of H2O was added slowly over a period of 1 hr to quench the reaction and the resulting mixture was stirred for 1 hr. It was then concentrated under reduced pressure and the residue was diluted with 300 mL EtOAc and washed with H2O (300 mL) and brine (300 mL). All the organics were combined, dried over MgSO4, and concentrated to yield 13.6 g of a yellow waxy solid.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@H:11]([C:13](O)=[O:14])[CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[S:7]([NH:10][C@H:11]([C:13]([Cl:20])=[O:14])[CH3:12])([C:4]1[CH:5]=[CH:6][C:1]([CH3:16])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30.0 g of N-(p-toluenesulfonyl)-alanine and 6 to 7 drops of DMF (dimethylformamide) were dissolved in 100 ml of dichloromethane and 5 ml of oxalyl chloride was added dropwise. After stirring for 3 hours at room temperature the reaction mixture was evaporated down to a residue which was dissolved in 100 ml of dichloromethane. The dichloromethane was again evaporated and the resulting residue dissolved in 50 ml of dichloromethane followed by the addition of 100 ml hexane. After standing in the refrigerator overnight the crystals, so formed, were filtered and dried.
Reaction SMILES: [OH:1]CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO.N[C:57]([NH2:59])=[O:58].[CH3:60][CH:61]([OH:68])[CH2:62][O:63][CH:64]([CH2:66][OH:67])[CH3:65]>[Ni]>[C:57](=[O:1])([OH:58])[NH2:59].[CH3:60][CH:61]([OH:68])[CH2:62][O:63][CH:64]([CH2:66][OH:67])[CH3:65]
Reactant: NC(N)=O
Reactant: OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Agent: [Ni]
Agent: CC(O)COC(C)CO
Product: NC(=O)O
Temperature: 155 °C

Procedure:
810 parts of a polyethylene ether-diol of molecular weight 810 (H(OCH2CH2)18OH) and 60 parts of urea are heated in a stirred apparatus for 5 hours at 150° C., whilst passing a stream of nitrogen through the apparatus. After this time, the degree of conversion is 92%. Thereafter, 2,680 parts of dipropylene glycol, 1,200 parts of urea and 100 parts of the nickel-containing exchanger prepared as described in Example 1(a) are added. The reaction mixture is heated for 16 hours at 155° C., whilst passing a stream of nitrogen through the apparatus. After the mixture has cooled to about 100° C., the catalyst is filtered off. 4,350 parts of the co-carbamate mixture, consisting of 24% of a polyethylene ether-diol monocarbamate H(OCH2CH)18OCONH2 and 76% of dipropylene glycol monocarbamate, are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][CH:17]2[CH2:19][CH2:18]2)([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.Cl.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[N:29][C:30]2[CH2:31][CH2:32][NH:33][CH2:34][C:35]=2[CH:36]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH:17]1([CH2:16][C:10]2([C:13]([N:33]3[CH2:32][CH2:31][C:30]4[N:29]=[CH:28][C:27]([C:26]([F:25])([F:37])[F:38])=[CH:36][C:35]=4[CH2:34]3)=[O:15])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH2:19][CH2:18]1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CC2)(C(=O)O)C1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC2CC2)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
The title compound was prepared according to general procedure C described in connection with Scheme 5. To a solution of 1-(t-butoxycarbonyl)-3-(cyclopropylmethyl)pyrrolidine-3-carboxylic acid IIIb (300 mg, 1.11 mmol) in 16 mL of CH2Cl2 was added thionyl chloride (0.24 mL, 3.34 mmol) and two drops of DMF. The mixture was stirred for ˜1-2 h at room temperature. After removal of solvent, the residue was redissolved in CH2Cl2 (13 mL), followed by the addition of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (IVa) (320 mg, 1.16 mmol) and triethyl amine (0.78 mL, 5.5 mmol). LC-MS analysis indicated the completion of the reaction after one hour stirring at RT. The mixture was washed with water (×2) and brine (×3). After concentration of solvent, the crude residue was purified by flash chromatography on silica gel to give 300 mg (60% yield) of the desired product. MS (ESI) m/z: Calculated for C23H30F3N3O3: 453.2. found: 453.7 (M+Na)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:52])[C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:51])[CH2:18][N:19]([C:21](=[O:50])[C@H:22]([CH2:35][CH2:36][CH2:37][CH:38]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[NH2:39])[NH:23][C:24](=[O:34])[CH2:25][NH:26]C(OC(C)(C)C)=O)[CH3:20])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:53]>C(OCC)(=O)C>[ClH:53].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:52])[C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:51])[CH2:18][N:19]([C:21](=[O:50])[C@H:22]([CH2:35][CH2:36][CH2:37][CH:38]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[NH2:39])[NH:23][C:24](=[O:34])[CH2:25][NH2:26])[CH3:20])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CN(CC(=O)N1CCC[C@H]1C(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)[C@H](CCCC(N)C(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(CC(=O)N1CCC[C@H]1C(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)[C@H](CCCC(N)C(=O)OCc1ccccc1)NC(=O)CN
Temperature: 0 °C
Yield: 97 %

Procedure:
3.10 g (0.0043 mol) of tertiary butyloxycarbonylglycyl-ε-benzyloxycarbonyl-L-lysyl-sarcosyl-L-proline p-nitrophenyl ester was treated with 37 ml of a solution prepared by dissolving dry hydrogen chloride gas in ethyl acetate and adjusting the solution to a concentration of 3.5N while cooled with ice water for one hour. The product of this treatment was distilled to expel the solvent. The residue was solidified with ether. Consequently, there was obtained 2.74 g (yield 97%) of glycyl-ε-benzyloxycarbonyl-L-lysyl-sarcosyl-L-proline p-nitrophenyl ester hydrochloride.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:23]5[S:22][CH:26]=[CH:25][CH:24]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: OCc1cccs1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4cccs4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 2-thienylmethanol (121 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (45 mg) as an off-white solid.
Reaction SMILES: [H-].[Na+].CS([O:7][CH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@H:18]2[C@H:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:21]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:20]([CH2:39][O:40][CH3:41])[O:19]2)=[C:11]([NH:42][CH2:43][CH:44]([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)[N:10]=1)(=O)=O.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61](O)[CH2:60][CH2:59]1>O1CCCC1>[Si:24]([O:23][C@@H:22]1[C@H:21]([O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34])[C@@H:20]([CH2:39][O:40][CH3:41])[O:19][C@H:18]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:9]([CH2:8][O:7][CH:61]1[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]1)=[N:10][C:11]=2[NH:42][CH2:43][CH:44]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CN1CCC(O)CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COC4CCN(C)CC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 11.9 %

Procedure:
Sodium hydride (42 mg of an 80% dispersion in mineral oil, 1.4 mmol) was added to a stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (preparation 16) (540 mg, 0.7 mmol) and 1-methyl-4-piperidinol (160 mg, 1.4 mmol) in tetrahydrofuran (10 ml). The reaction mixture was heated at reflux for 24 hr and then the solvent removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with dichloromethane:methanol (95:5) to give the title compound (68 mg). MS: 818 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH2:17][CH3:18])=[N:12]1.[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([S:35]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][C:24]=1[F:43]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:36])(=[O:37])[NH:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[CH:25][C:24]=2[F:43])[C:13]([CH2:17][CH3:18])=[N:12]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 2.00 g (6.39 mmol) of 2-(2-bromo-5-nitrophenyl)-2,4-dihydro -5-ethyl-3H-1,2,4-triazol-3-one (from Step B) and 184 mg (7.67 mmol) of sodium hydride in 7 mL of DMF was stirred at 50° C. for 3 hours. A solution of 4'-(bromomethyl)-N-t-butyl-3'-fluoro -2-biphenylsulfonamide (from Step F dissolved in 6 ml of DMF was then added and the resulting mixture was stirred at 50° C. for another 3 hours. The reaction mixture was quenched by addition of water followed by extractions with EtOAc, CH2Cl2, and MeOH. Water was removed and the organic layers were washed with brine, and dried over anhydrous Na2SO4. The entire crude product mixture thus obtained was flash chromatographed over silica gel (gradient elution using 0.5-2.0% MeOH in CH2Cl2) to afford 3.54 g (88%) of the title compound as a yellow solid (contaminated with some upper and lower Rf impurities by TLC but suitable for use in the next step without further purification), mp 223°-225° C.; mass spectrum (FAB) m/e 631, 633 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23]C(=O)OC(C)(C)C)[N:15]([C:31]3[C:32]4[CH:39]([CH2:40][CH3:41])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)(OC(C)(C)C)=O.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51].C(Cl)Cl>>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH2:23])[N:15]([C:31]3[C:32]4[CH:39]([CH2:40][CH3:41])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Agent: CC(C)(C)OC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Reaction time: 2 h
Yield: 99.9 %

Procedure:
tert-Butyl (1′-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (422 mg, 0.762 mmol) was dissolved in a 1:1 TFA/DCM solution (10 mL). After 2 hours at room temperature, the LCMS suggested complete deprotection of the BOC amine. The reaction was concentrated to (1′-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine tris(2,2,2-trifluoroacetate) (606 mg, 0.762 mmol, 99.9% yield) as an oil. MS (APCI+) [M+H]: 454.2.